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There are over 50 diseases in the Lysosomal Disease family. There are no cures and very few therapies to lessen the severity of the symptoms any of these disorders.

You may have heard about some Lysosomal Disorders, like Tay-Sachs, Gaucher, or Niemann-Pick. But because the individual disorders are often rare, names like Batten, Fabry, Krabbe and Pompe probably seem foreign to you. Other names, like Mucopolysaccharidoses, Cystinosis, Mucolipidosis and Aspartylglycosaminuria are not only unfamiliar, but virtually unpronounceable as well.

Following is a list of lysosomal diseases, with information on patient resources and ways to become involved in the search for cures for every syndrome in the Lysosomal Disease family:

List of Lysosomal Disorders

Activator Deficiency/GM2 Gangliosidosis
Definition:

In a normal lysosome, a protein called GM2 ganglioside activator and an enzyme known as beta-hexosaminidase A work together to break down a fatty substance called GM2 ganglioside. If there is a mutation in the GM2 ganglioside activator, the enzyme beta-hexosaminidase A cannot break down the fatty substance. Hence, the GM2 ganglioside accumulates in the central nervous system. The accumulation of GM2 ganglioside causes progressive destruction of the nerve cells in the brain and spinal cord and gives rise to the symptoms associated with this disorder.

Activator Deficiency/GM2 Gangliosidosis is a very rare disorder affecting one child per 320,000 live births.

Symptoms:

The symptoms of Activator Deficiency/GM2 Gangliosidosis appear in infancy at around six months of age. At this age, motor skills begin to decline and muscles begin to weaken. The affected child’s ability to turn over, to crawl or sit also begins to decline. A startled response to noise and cherry-red spot in the eye are additional features of this disorder. As the condition progresses, seizures, mental retardation, vision and hearing loss, as well as paralysis, may also occur.

Inheritance Pattern:

Activator Deficiency/GM2 Gangliosidosis is an autosomal recessive disorder.

Diagnosis and Testing:

Activator Deficiency/GM2 Gangliosidosis is detected by assaying beta-hexosaminidase A in the blood. Prenatal genetic screening is also available if one family member is affected with the disease.

Life Expectancy:

Life expectancy is approximately three years of age.

Treatment:

Currently, there is no cure for Activator Deficiency/GM2 Gangliosidosis. Anti-seizure medication can be administered to control seizure episodes. One drug under investigation inhibits the synthesis of the gangliosides or the fatty substance that accumulates in the brain and spinal cord. It is the hope that as research continues to explore treatment possibilities, a cure will be found for Activator Deficiency/GM2 Gangliosidosis.

Alpha-Mannosidosis
Definition:

Alpha-mannosidosis is caused by deficient activity of the enzyme alpha-D-mannosidase. As a result, sugar chains accumulate in lysosomes resulting in general cellular dysfunction. Alpha-Mannosidosis is classified into types I through III based on severity and age of onset. In contrast to the usual classifications scheme of these disorders, type III is the most severe.

Symptoms:

Symptoms range widely in their onset and severity. The onset of the most severe form, Type III, begins within the first months of life and includes a quick progression of mental retardation, liver and spleen enlargement, hearing loss, respiratory infections and skeletal abnormalities. Often the appearance of an affected individual includes the following coarse facial features: protruding forehead, leveled nasal bridge, small nose and wide mouth. Muscular weakness or spinal abnormalities can occur due to the build up of storage materials in the muscle. A milder form of Alpha-mannosidosis involves mild to moderate mental retardation which develops during childhood or adolescence.

In sum, all symptoms of Alpha-mannosidosis are progressive. However, some research has demonstrated that symptoms stabilize during the second decade of life.

Diagnosis and Testing:

A diagnosis is made by measuring the enzymatic activity of alpha-D-mannosidase in white blood cells. If there is a decreased level of the enzyme in comparison to standard levels, a diagnosis can be made. It is thought that this disorder might be under diagnosed for a few different reasons — the diagnosis is often made late in the disease's progression, symptoms are often mild, or the biochemical diagnosis does not yield conclusive results.

Life Expectancy:

The life expectancy in Alpha-mannosidosis is highly variable. Individuals with early onset severe disease often do not survive beyond childhood, whereas those with milder disorders may survive well into adult life.

Treatment:

There is no cure for Alpha-Mannosidosis. Treatment is limited to reducing or controlling the symptoms of this disorder by, for example, taking medication to control seizures, using a hearing aid to assist with hearing loss, and by having routine physical therapy to assist with muscular pain and weakness. In some cases, a wheelchair is recommended if muscle or spinal impairments immobilize the individual affected. Bone marrow transplants performed at an early age have shown promise to halting the progression of this disorder.

Patient Groups:

International Society for Mannosidosis & Related Diseases
P.O. Box 328
Dexter, MI 48130
www.mannosidosis.org
tel: (734) 449-8222
fax: (734) 449-2282
Terri Klein, Executive Director
info@ismrd.org

Aspartylglucosaminuria
Definition:

Aspartylglucosaminuria (AGU) is caused by deficiency of the enzyme N-aspartyl-beta-glucosaminidase. This enzyme normally cleaves long sugar chains known as oligosaccharides in the lysosome. When N-aspartyl-beta-glucosaminidase is deficient, as it is in the case of AGU, these long sugar chains build up and eventually lead to the clinical features of AGU. Symptoms may progress in degrees of severity over time.

AGU is prevalent in the Finnish population, where it is estimated to affect 130 individuals of the country's total population of 4.5 million. Incidence worldwide is estimated at one in 2,111,000 births. AGU is one of nine identified Glycoprotein Storage Diseases.

Symptoms:

Symptoms of AGU become present between the two and four years of age. Respiratory infections, clumsiness and/or delay in speech are initial symptoms while normal development occurs in affected children until they enter their teenage years. At around 13-16 years of age, individuals display mental and motor skill development equal to that of a five or six year old. From puberty through 25-28 years of age, the disorder progresses rapidly, resulting in severe mental retardation.

Coarse facial features, osteoporosis, skeletal abnormalities, connective-tissue impairments and seizures may also occur.

Inheritance Pattern:

AGU is an autosomal recessive disorder.

Testing and Diagnosis

The diagnosis of AGU is made initially by demonstrating increased concentrations of oliogosaccharides, short chains of sugars, that accumulate in the urine. The diagnosis is then confirmed by measuring the activity of the enzyme aspartylglucosaminidase in the blood or in a skin biopsy. Mutations can be demonstrated in this gene and used to screen prenatally.

Life Expectancy:

Individuals with AGU develop severe mental retardation in their late 20s. They can expect to live into adulthood.

Treatment:

There is no cure for AGU. Treatment is limited to reducing or controlling symptoms of this disorder. For example, medication may control seizures. It is encouraged that individuals with AGU routinely see their genetic counselors, neurological, ophthalmological, and other specialists as symptoms arise, to maintain the control of their effects.

Patient Groups:

International Society for Mannosidosis & Related Diseases
P.O. Box 328
Dexter, MI 48130
www.mannosidosis.org
tel: (734) 449-8222
fax: (734) 449-2282
Terri Klein, Executive Director
info@ismrd.org

Cholesteryl ester storage disease
Definition:

Cholesteryl ester storage disease results from storage of cholesteryl esters and triglycerides in the blood and lymph cells, as well as in the lymphoid tissue. This build up occurs because lysosomal acid lipase, the essential enzyme to break down triglycerides and cholesteryl esters in lysosomes, is deficient. Although there is a build up of both triglycerides and cholesteryl esters in Cholesteryl ester storage disease, there is a greater accumulation of cholesteryl esters than triglycerides.

Cholesteryl esters are a transport form of cholesterol, and triglycerides are the chemical forms in which fats exist in the body. When these two substances accumulate, this build up damages blood and lymph cells as well as the lymphoid tissue, and leads to the symptoms that mark Cholesteryl ester storage disease.

Symptoms:

Children affected develop an enlarged liver. This symptom can lead to cirrhosis and chronic liver failure before adulthood. Calcium deposits may appear in the adrenal glands causing these glands to harden. Severe premature atherosclerosis, or the hardening of the arteries, may also develop. Jaundice may also develop late in disorder’s progression. Elevated levels of serum Low Density Lipoprotein (LDL), also known as the “bad cholesterol”, are also seen.

Inheritance Patterns:

Cholesteryl ester storage disease is an autosomal recessive disorder.

Life Expectancy:

Individuals afflicted with this disease live into adulthood. No further data regarding life expectancy is available.

Diagnosis and Testing:

Diagnosis is based on the clinical features of this disorder as well as performing an enzyme assay which looks for a deficiency of the enzyme acid lipase in liver cells, cultured white blood cells, or tissues specimens. A Prenatal diagnosis can also be performed to determine if there is an absence of acid lipase activity in the fetus.

Treatment:

There is no disease modifying treatment for Cholesteryl ester storage disease. Combining drugs that reduce blood cholesterol with a low cholesterol diet has been effective at reducing some of the signs associated with this disorder.

Chronic Hexosaminidase A Deficiency
Definition:

Chronic Hexosaminidase A Deficiency is caused by the absence of a vital enzyme called hexosaminidase A (Hex-A). Without Hex-A, a fatty substance or lipid called GM2 ganglioside accumulates abnormally in cells, especially in the nerve cells of the brain. Gangliosides need to be biodegraded rapidly in early life, as the brain develops. This ongoing accumulation causes progressive damage to the cells. It is similar to Tay-Sachs disease, but develops much later and at a slower pace. People with the late-onset condition have a small residual amount of Hex-A rather than a complete absence of the enzyme.

Symptoms:

The age of onset of symptoms associated with Chronic Hexosaminidase A Deficiency ranges from early childhood to 10 years of age. Symptoms of Chronic Hexosaminidase A Deficiency include progressive dystonia, spinocerebellar degeneration, motor neuron disease, and in some individuals, a bipolar form of psychosis.

Individuals with adult-onset disease display progressive muscle wasting, weakness, muscle twitching, and poor articulation of words. There can be tremendous variability in the degree and onset of symptoms within the same family. For instance, psychosis may be severe by age 20 in one individual, whereas another family member may only exhibit neuromuscular findings into their 50s or 60s.

Inheritance Pattern:

Chronic Hexosaminidase A Deficiency is an autosomal recessive disorder.

Diagnosis and Testing:

Patients and carriers of Chronic Hexosaminidase A Deficiency can be identified by a simple blood test that measures the enzymatic activity of beta-hexosaminidase A in blood or tissue samples.

Carrier detection can also be performed for males, females and for pregnant females to determine carrier status of Chronic Hexosaminidase A Deficiency. A measure of the enzyme hexosaminidase A (Hex-A) is taken using white blood cells or blood. It is a highly accurate and inexpensive procedure for determining one’s carrier status.

Life Expectancy:

Because the chronic form Hexosaminidase A Deficiency was discovered recently, prognosis for this type of the disease is not completely known.

Treatment:

For individuals with Chronic Hexosaminidase A deficiency who have psychiatric manifestations, conventional antipsychotic or antidepressant therapy may be used. For older individuals who have psychiatric manifestations, the response to these therapeutic methods often has variable outcomes.

Treatment with lithium salts and electroconvulsive therapy has been reported to be beneficial in lessening episodes of psychotic depression.

Cystinosis
Definition:

Cystinosis is a very rare metabolic, genetic disorder that causes a particular amino acid known as cystine to accumulate in the body’s organs. The accumulation occurs because a lysosomal membrane protein, called cystinosin, whose function is to transport the amino acid, cystine, out of the lysosome, is defective. The inability of cystinosin to function properly renders cystine unable to be transported out of the lysosome, where it instead accumulates.

Cystine is marked by low solubility which means that it does not dissolve well into another substance. Given its low solubility, cystine forms crystals within the lysosome. It is believed that these crystals destroy cells and give rise to the symptoms of this disorder.

The mutated gene in Cystinosis has been identified. Molecular diagnosis and carrier testing is now possible.

There are three forms of Cystinosis: Infantile, juvenile, and adult. Infantile is the most severe of the three forms. The adult form of the disorder is considered benign.

Cystinosis affects approximately one in every 100,000 to 200,000 live births. In the province of Brittany, France, the incidence is much higher affecting one in every 26,000 individuals. In the United States, approximately 300-400 children are afflicted with Cystinosis.

Symptoms:

In the infantile form of Cystinosis, symptoms begin to appear around 10 months of age, when the affected child’s growth measures far behind the standards for this age bracket. Frequent urination, constant thirst, and irritability are common features of the disorder during this time. By one year of age, an affected child cannot walk and can only bear a small amount of his or her body weight with caution. Corneal crystals appear during this time. The affected child may develop rickets and suffer episodes of dehydration. During the affected individual’s 20s to 30s, swallowing difficulties and muscle complications arise.

In the juvenile form, symptoms appear between eight and 12 years of age and are marked by kidney and visual complications.

The primary complication associated with Cystinosis is the failure of the kidneys to absorb nutrients and minerals. These substances, lost in the urine, must be replaced. This condition, also called renal tubular Fanconi Syndrome, is marked by a craving for salty food, picky eating habits, and by slow physical growth. If this condition is left untreated, an affected child can develop kidney failure by 10 years of age.

In the adult form, cystine develops in the corneas but kidney function is not affected.

Inheritance Pattern:

Cystinosis is an autosomal recessive disorder.

Life Expectancy:

Life expectancy for the infantile and juvenile forms of Cystinosis is during the affected individual’s 20s to 30s.

Diagnosis and Testing:

Cystinosis is diagnosed by measuring the levels of cystine in blood or tissue samples. If these levels are elevated in comparison to standard cystine values, a diagnosis can be made. Additionally, slit-lamp examination of the eyes to look for cystine crystals can be performed as early as one year of age. Prenatal testing is also available for known carriers.

Treatment:

In the past, treatment for Cystinosis was limited to replacing the loss of substances in the urine, but with the advent of the drug Cysteamine and kidney transplants, the management and prognosis of this disorder has greatly improved.

The FDA-approved drug Cysteamine (Cystagon) is the standard treatment for this disorder. This drug lowers the levels of cystine in the cells and effectively prevents or delays renal failure. The drug also improves the growth of children afflicted with Cystinosis.

Other therapies are focused on treating such symptoms of this disorder as an inability of the kidneys to absorb nutrients and minerals. Ensuring that the child consumes fluids that contain electrolytes is imperative to prevent kidney failure. Phosphates, a type of electrolyte, and vitamin D are routinely given to patients, to increase the uptake of phosphate by the kidneys and to prevent rickets.

Kidney transplants have been effective for individuals affected by Cystinosis, but patients are encouraged to take Cystagon to prevent further complications. Cysteamine eyedrops remove the cystine crystals that accumulate in the corneas.

Patient Groups:

Cystinosis Foundation
604 Vernon Street
Oakland, CA 94610
www.cystinosisfoundation.org
tel: (800) 392-8458
fax: (559) 222-7997
Jean Hotz, President
Email@cystinosis.com

Cystinosis Research Foundation
18802 Bardeen Avenue
Irvine, CA 92612
www.natalieswish.org
tel: (949) 223-7610
fax: (949) 756-5955
Nancy Stack
HEYSTACK4@aol.com

Cystinosis Research Network
302 Whytegate Court
Lake Forest, IL 60045
www.cystinosis.org
tel: (866) 276-3669
fax: (847) 235-2773
Christy Greeley
Greeleycd@aol.com

Danon disease
Definition:

A mutated gene that codes a protein called LAMP2 causes Danon Disease. LAMP2 protein is a glycoprotein molecule comprised of a carbohydrate and a protein. It is typically found on the membrane of the lysosome. LAMP2 is deficient in individuals affected by Danon Disease. It is unknown how this deficiency disrupts the function of the lysosome.

Danon Disease is an X-linked dominant disorder that predominantly affects cardiac muscle. It affects both males and females, although males tend to see the majority of mental retardation and muscle weakness. Given the lack of awareness and understanding about this disorder, it may be commonly misdiagnosed. The exact frequency of occurrence of Danon Disease is not known. To date, only 15 cases of Danon Disease have been reported worldwide.

Symptoms:

Muscle weakness, heart disease, and mental retardation are three main symptoms associated with this disorder. Signs of muscle weakness and heart disease begin to manifest in early childhood or adolescence. Some affected individuals are unable to walk as muscular complications progress. Heart disease associated with Danon Disease involves heart arrhythmias and cardiomyopathy, or severe heart muscle disease. Visual problems may also occur.

In females, the symptoms of Danon Disease are less severe and manifest later than they do in affected males. Muscle weakness is present, but commonly less debilitating than it is in males. Heart disease, which may occur, will manifest in adulthood. Symptoms may include visual problems.

Inheritance Pattern:

Danon Disease is an X-linked dominant disorder. It selectively and more often affects boys, since males have only one X chromosome. Females have two X chromosomes and therefore have an extra X to protect them from disorders of this inheritance nature, but cases of Danon Disease afflicting females have been reported. Danon Disease also commonly affects males more severely than it does females. Boys often develop symptoms in childhood or in adolescence. Symptoms may not appear in females until adolescence or adulthood.

Life Expectancy:

Life expectancy for Danon Disease is 30 years of age or younger and result from cardiac failure.

Diagnosis and Testing:

Several mutations have been found on the LAMP2 gene, and genetic analysis is a necessary diagnostic tool for confirming or disconfirming a diagnosis of Danon Disease. Prenatal genetic screening is available. A muscle tissue biopsy, which reveals large vacuoles containing elevated levels of glycogen, a kind of a sugar, used in conjunction with genetic screening may confirm a diagnosis.

Treatment:

Medications to treat the heart disease are often prescribed and in severe cases, a heart transplant is often needed. Supportive treatment, such as physical therapy, may improve muscle strength and balance.

Fabry disease
Definition:

Fabry disease, which is also known as alpha-galactosidase-A deficiency, causes a buildup of fatty material in the autonomic nervous system, eyes, kidneys, and cardiovascular system. Fabry disease is an X-linked lipid storage disease, meaning that males are affected primarily. Cases affecting females also occur with symptoms ranging from mild to severe.

The inherited deficient enzyme, alpha-galactosidase A (alpha-gal A), causes a build up of glycosphingolipids, which are a type of carbohydrate-attached fat, within the vessels of the lysosome. The accumulation of fatty material damages the autonomic nervous system, eyes, kidneys, and cardiovascular system.

Symptoms:

Symptoms of Fabry disease usually appear in childhood or early adolescence and increase with age. Symptoms include an inability to perspire, little body hair, fevers, gastrointestinal problems, renal complications leading to renal failure, and heart enlargement. Many who have the disease experience a feeling of burning pain at the extremities, especially after exercise or in hot weather. Other symptoms include angiokeratomas, which are purplish-reddish small, raised, and benign spots that occur all over the body, but predominantly on the lower torso. There is also a build up of cloudy material in the clear portions of the cornea. This buildup does not affect vision.

The accumulation of fatty storage in the blood vessel walls puts the individual at an increased risk for cardiac complications, such as a stroke or heart attack.

Inheritance Patterns:

This disorder is an X-linked, inherited lysosomal storage disorder.

Diagnosis and Testing:

Diagnosing Fabry disease is a challenge because the range of clinical symptoms are often attributed incorrectly to other diseases, and due to a lack of awareness surrounding this rare disorder. Although symptoms of Fabry disease may first become apparent in childhood, diagnosis is not typically confirmed until 30 years of age. Once an initial clinical diagnosis has been made from the symptoms presented, a biochemical diagnosis measuring a deficiency of enzyme alpha-gal A is performed using white blood cells, tears, or tissue specimens.

Life Expectancy:

Average life expectancy of Fabry disease is 50 years of age. Death results from complications due to heart disease, renal failure, or stroke.

Treatment:

Recent research has shown that enzyme replacement can reduce the storage of glycosphingolipids, ease pain, and improve organ function.

There are many things the affected individual can do to reduce the symptoms associated with Fabry disease. Eliminating strenuous activities helps to lessen discomfort associated with the disease and pain-reducing drugs are often prescribed to alleviate the discomfort.

For cardiovascular complications, different medications can be prescribed to control chest pain and prevent blood clotting. Bypass surgery can be performed or pacemakers can be inserted if heart problems are severe or medications cannot control the symptoms.

If renal symptoms are mild, a low-protein diet is often recommended. Should symptoms become more severe, some patients may undergo kidney replacement or dialysis. Taking enzymes, motility agents, as well as following a low-fat diet are often recommended to control gastrointestinal symptoms. Laser technology can also remove skin rashes associated with Fabry disease.

Patient Groups:

Fabry Support and Information Group
PO Box 510
Concordia, MO 64020
www.fabry.org
tel: (660) 463-1355
fax: (660) 463-1356
Jack Johnson, Founder
info@fabry.org

National Tay-Sachs & Allied Diseases Association
2001 Beacon Street, Suite 204
Boston, MA 02135
www.ntsad.org
tel: (800) 906-8723
fax: (617) 277-0134
Sue R. Kahn, Executive Director
info@ntsad.org

Farber Disease
Definition:

Also known as Farber’s lipogranulomatosis or ceramidase deficiency, Farber Disease is a rare autosomal recessive disorder caused by an accumulation of fatty material leading to abnormalities in the joints, liver, brain, skin, and throat.

Normally, the enzyme ceramidase breaks down fatty material in the body’s cells. But for those who have Farber Disease, the gene responsible for making this enzyme is mutated. Hence, the fatty material is never broken down and, instead, accumulates in various parts of the body, leading to the signs and symptoms of this disorder. Farber disease is extremely rare: Fifty cases were documented in 2002. This disorder affects males, females, and ethnic groups equally.

Symptoms:

Typically, the symptoms of Farber Disease appear within the first few weeks of life. Neurological conditions, such as impaired mental ability and difficulty swallowing, are some of the first symptoms to appear in an affected newborn. Other symptoms include painful joint swelling, hoarse cries, swollen lymph nodes, nodule formations under the tissue, around vocal chords or joints, and breathing difficulties. In severely progressive cases, an enlarged liver and spleen can also be present. Children born with this type of Farber Disease usually die within six months.

Inheritance Patterns:

Farber disease is an autosomal recessive disorder.

Diagnosis and Testing:

Examinations of tissue specimens or white blood cells which detect reduced levels of acid ceramidase activity will confirm a diagnosis.

Life Expectancy:

Life expectancy is six months to two years of age. Commonly, the cause of death is lung disease.

Treatment:

There are few treatments for Farber Disease. Corticosteroids are often prescribed to reduce the pain. As long as there are no lung or nervous system complications, bone marrow transplants may improve the small masses of swollen tissue. These nodules can also be surgically removed or reduced in older patients.

Fucosidosis
Definition:

Fucosidosis is a rare lysosomal disorder affecting fewer than one in two million individuals. It is one of nine identified Glycoprotein Storage Diseases. Fucosidosis is caused by lack of the enzyme, alpha-fucosidase. This enzyme normally cleaves long sugar chains known as oligosaccharides in the lysosome. When the enzyme is absent, sugar chains accumulate and eventually lead to the clinical features of Fucosidosis. The symptoms of this disorder may progress in degrees of severity over time.

There are two different types of Fucosidosis, Type I and Type II, characterized by the age of onset and by the types of physical and mental manifestations of the disorder.

Symptoms:

Fucosidosis Type I typically appears in the first three to 18 months of life. Symptoms include coarsening of facial features, a large liver, spleen and/or heart, and abnormal bone deformities. Cherry-red spots may be present on the surface of the eye. Mental retardation and seizures are also present. Additionally, sweat chloride may be elevated. Fucosidosis Type I results in a rapid deterioration of the neurologic system.

Type II Fucosidosis appears between 12 and 24 months of life. Children affected usually have mild coarsening of facial features, abnormal bone deformities, mental retardation, and an enlarged liver, spleen and/or heart. In addition, angiokeratomas may also appear. Twisted blood vessels within the membrane covering of the eye and inner eyelid are characteristic features of Type II Fucosidosis.

Inheritance Pattern:

Fucosidosis is an autosomal recessive disorder.

Diagnosis and Testing:

The diagnosis of Fucosidosis is made first by screening the urine for increased concentration of oligosaccharides, short chains of sugars that accumulate in the urine and other tissues. The diagnosis is then confirmed by measuring the activity of the enzyme alpha-fucosidase in blood or tissue biopsies. Prenatal diagnosis may be performed by measuring enzyme activity or, ideally, by demonstrating the presence of mutations in the alpha-fucosidose gene.

Life Expectancy:

Individuals with Fucosidosis Type I often die in childhood. Patients with Fucosidosis Type II may survive into adulthood.

Treatment:

There is no cure for Fucosidosis. Treatment is limited to reducing or controlling the symptoms of this disorder, for example, medication to control seizures. It is encouraged that individuals with Fucosidosis routinely see their genetic counselors, neurological, ophthalmological, and other specialists as symptoms arise and to keep symptoms controlled.

Patient Groups:

International Society for Mannosidosis & Related Diseases
P.O. Box 328
Dexter, MI 48130
www.mannosidosis.org
tel: (734) 449-8222
fax: (734) 449-2282
Terri Klein, Executive Director
info@ismrd.org

Galactosialidosis
Definition:

Galactosialidosis is one of nine identified Glycoprotein Storage Diseases. The disorder is caused by the lack of an enzyme called Protective Protein/Cathepsin A (PPCA). This enzyme works with two other enzymes, beta-Galactosidase and Neuraminidase to break down long sugar chains, oligosaccharides, in the lysosome. However, PPCA also protects beta-Galactosidase and Neuraminidase from being broken down in the lysosomes. Therefore, those stricken with Galactosialidosis are deficient in these enzymes as well.

There are three different types of Galactosialidosis: infantile, late infantile and juvenile/adult. Each is characterized by the age of onset and type of physical and mental manifestations. The juvenile/adult Galactosialidosis form is the most common of the three forms.

Symptoms:

The onset of infantile Galactosialidosis occurs between birth and three months of age. In the fetus, infants with this type of Galactosialidosis are presented with hydrops, edema, or the accumulation of fluid, . When the affected child is born, edema in various parts of the body and an enlarged liver, spleen, and/or heart is also present. Skeletal changes, especially along the spine and as well as cognitive and motor delay are also present. Kidney function may be impaired as well.

The onset of late infantile Galactosialidosis is within the first few months of life. Coarse facial features, enlargement of the spleen and liver, and abnormal bone formations, usually in the spine, are also present. A cherry-red spot or clouding of the cornea may occur. If mental retardation is present, it is generally mild. Deafness may also occur.

The onset of juvenile/adult Galactosialidosis is typically around 16 years of age. Some cases have reported symptoms appearing as late in life of affected individuals, as in their 20s and 30s. Individuals with juvenile/adult Galactosialidosis are predominantly of Japanese origin. Coarse facial features, spinal cord changes, ataxia, seizures, and declining mental capacities are some of the classic symptoms of this form of the disorder. Cherry-red spots, clouding of the cornea, purplish-red spots on the skin, and vision loss may also be present.

Inheritance Pattern:

Galactosialidosis is an autosomal recessive disorder.

Diagnosis and Testing:

To determine if the patient has Galactosialidosis, a urine test is performed to measure increased levels oligosaccharides, the type of sugar chains in the lysosome that accumulate as a result of the malfunctioning enzyme. A urine test is routinely followed by a blood test or skin biopsy which will show reduced activity of the enzymes B-Galactosidase and Neuraminidase. Prenatal screening is also available to examine B-Galactosidase and Neuraminidase activity in the fetus. Genetic testing is also available in combination with these diagnostic tests to look for the mutation that causes Galactosialidosis.

Life Expectancy:

Life Expectancy for infantile Galactosialidosis is one year of age or younger. Children with late infantile Galactosialidosis survive through the first and into their second decade, and individuals with juvenile/adult Galactosialidosis survive into adult life.

Treatment:

There is no cure for Galactosialidosis. Treatment is limited to reducing or controlling the symptoms of this disorder, by for example, taking medication to control seizures. It is encouraged that individuals with Galactosialidosis routinely see their genetic counselors, neurological, ophthalmological, and other specialists as symptoms arise and to keep symptoms controlled. Bone marrow transplant is under investigation as an experimental therapy.

Patient Groups:

International Society for Mannosidosis & Related Diseases
P.O. Box 328
Dexter, MI 48130
www.mannosidosis.org
tel: (734) 449-8222
fax: (734) 449-2282
Terri Klein, Executive Director
info@ismrd.org

Gaucher Disease Type I
Definition:

Gaucher Disease is the most common of the lipid storage diseases. It is caused by a deficiency of the enzyme glucocerebrosidase, which leads to a collection of fatty material in the spleen, liver, kidneys, lungs, brain, and bone marrow. It has three subtypes, with Gaucher Disease Type I being the most prevalent. It is also the most common genetic disease among Ashkenazi Jews in North America.

A genetic defect in the enzyme, that normally breaks down the chemical glucocerebroside in the cell, allows this substance to accumulate excessively in the liver, spleen, and lymph nodes, giving rise to the symptoms associated with Gaucher Disease Type I.

Symptoms:

Typically, the first sign of this disorder is an enlarged spleen. Anemia, low blood platelets, consequent fatigue, bruising, and a yellow fatty deposit on the white part of the eye are also symptoms. Skeletal weakness and bone disease may occur, leading to collapsed hips, shoulders, and spine.

Inheritance Patterns:

Gaucher Disease Type I is an autosomal recessive disorder.

Diagnosis and Testing:

A blood or skin test is performed to confirm a diagnosis of Gaucher Disease Type I. This blood test measures the amount of the enzyme glucocerebrosidase and compares it to normal enzyme activity levels. If the disorder is present, low levels of this enzyme will be present as well.

Carrier testing can also be performed. This involves looking at the genetic changes or mutations causing the genes to malfunction. In the Ashkenazi Jewish population, four common mutations (N370S, L444P, 84GG, and IVS2) account for roughly 95% of all nonfunctional Gaucher genes. If a mutation is found, the individual is a carrier. If none of the four mutations are found, there is still a chance that the individual is a carrier because other mutations could be present. A small percentage of non-Jewish individuals carry one of these common mutations.

Life Expectancy:

The majority of Type I patients may live into adulthood.

Treatment:

Enzyme replacement treatment given intravenously every two weeks can dramatically decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations of the disease. For patients who cannot be treated with enzyme replacement therapy, an enzyme inhibiting medication, miglustat, can be taken orally and has demonstrated some benefit. Successful bone marrow transplantation cures the non-neurological manifestations of the disease. However, this procedure carries significant risk and is rarely performed in Gaucher patients. Surgery to remove the spleen may be required on rare occasions (if the patient is anemic or when the enlarged organ affects the patient’s comfort). Blood transfusion may benefit some anemic patients. Other patients may require joint replacement surgery to improve mobility and quality of life.

Patient Groups:

Children's Gaucher Disease Research Fund
P.O. Box 2123
Granite Bay, CA 95746
www.childrensgaucher.org
tel: (916) 797-3700
fax: (916) 797-3707
Gregory Macres, Founder, Chairman
research@childrensgaucher.org

National Gaucher Foundation
2227 Idlewood Road, Suite 12
Tucker, GA 30084
www.gaucherdisease.org
tel: (800) 504-3189
fax: (770) 934-2911
Rhonda P. Buyers, Executive Director
rhonda@gaucherdisease.org

National Tay-Sachs & Allied Diseases Association
2001 Beacon Street, Suite 204
Boston, MA 02135
www.ntsad.org
tel: (800) 906-8723
fax: (617) 277-0134
Sue R. Kahn, Executive Director
info@ntsad.org

Gaucher Disease Type II
Definition:

Gaucher Disease Type II is more severe but less common than Gaucher Disease Type I. Fewer than one in 100,000 babies have Gaucher Disease Type II. Similar to Type I, it results from the deficiency of glucocerebrosidase, the enzyme necessary for the breakdown of a particular fatty substance, glucocerebroside. Unlike Gaucher Disease Type I, Type II affects individuals of all races and ethnicities equally.

Symptoms:

Symptoms usually appear in an affected infant a few months following birth. There is a classic triad of neurologic symptoms that include crossed eyes (strabismus), a clenched jaw (trismus), and arching back of the neck (retrocollis). Most children also have enlargement of the liver and spleen.

Inheritance Pattern:

Gaucher Disease Type II is an autosomal recessive inheritance pattern.

Life expectancy:

Life expectancy for Gaucher Disease Type II is two years of age or younger.

Diagnosis and Testing:

A blood test is performed to confirm a diagnosis of Gaucher Disease Type II. This blood test measures the amount of the enzyme glucocerebrosidase and compares it to normal enzyme activity levels. If the disorder is present, low levels of enzyme will be present as well.

Additional tests can also be performed to determine the severity of the disorder. X-rays, MRIs, and CT scans can be performed to detect skeletal abnormalities. Further blood tests can be performed to measure low platelet counts and liver function. MRIs and CT scans can also measure the spleen and liver, and nerve tests can be performed to survey how the nerves and brain have been affected by the disease.

Anyone with a family member who has Gaucher Disease, as well as anyone who displays symptoms of Gaucher Disease, would be a candidate for such tests.

Treatment:

Treatment for Gaucher Disease Type II includes pain management. Various therapies can reduce the pain associated with this disorder. Blood transfusions can help treat the anemia that may occur in some affected individuals. Psychological counseling is encouraged to help families manage some of the emotional toll this disorder imparts. Enzyme replacement therapy does not prevent the nervous system damage that occurs in Gaucher Disease Type II.

Patient Groups:

Children's Gaucher Disease Research Fund
P.O. Box 2123
Granite Bay, CA 95746
www.childrensgaucher.org
tel: (916) 797-3700
fax: (916) 797-3707
Gregory Macres, Founder, Chairman
research@childrensgaucher.org

National Gaucher Foundation
2227 Idlewood Road, Suite 12
Tucker, GA 30084
www.gaucherdisease.org
tel: (800) 504-3189
fax: (770) 934-2911
Rhonda P. Buyers, Executive Director
rhonda@gaucherdisease.org

National Tay-Sachs & Allied Diseases Association
2001 Beacon Street, Suite 204
Boston, MA 02135
www.ntsad.org
tel: (800) 906-8723
fax: (617) 277-0134
Sue R. Kahn, Executive Director
info@ntsad.org

Gaucher Disease Type III
Definition:

Similar to Gaucher Disease Type II, Gaucher Disease Type III is very rare, affecting one in every 100,000 babies. Although this disorder occurs within the general population, it is highly prevalent in the Swedish provinces of Norrbotten and Vasterbotten. Increased prevalence rates have also been reported in Japan and Spain. This disease affects males and females equally.

Similar to Type I and Type II, Gaucher Disease Type III results from the deficiency of glucocerebrosidase, the enzyme necessary for the breakdown of a particular fatty substance, glucocerebroside. Glucocerebroside accumulates inside the lysosome and causes the cell to become engorged. These engorged cells are called Gaucher cells and have a bloated appearence under the microscope.

Symptoms:

Symptoms can appear between early infancy and the affected child’s early teenage years. Given that this disorder affects the child’s central nervous system, symptoms such as irregular eye movements, seizures, and mental retardation occur. It also affects the body’s organs as well and mirrors many of the symptoms of Gaucher Disease Type I, such as abnormal skeletal formation, enlarged spleen, anemia, bruising, and blood clotting.

Inheritance Pattern:

Gaucher Disease Type III is an autosomal recessive disorder.

Life Expectancy:

Those individuals with Gaucher Disease Type III who live until their adolescence also have a significant chance of living into their thirties.

Diagnosis and Testing:

A blood or skin test is performed to confirm a diagnosis of Gaucher Disease Type III. This blood test measures the amount of the enzyme glucocerebrosidase and compares it to normal enzyme activity levels. If this disorder is present, low levels of this enzyme will be present. Additional tests can be performed to determine the severity of the disorder. X-rays, MRI’s, and CT scans can be performed to detect skeletal abnormalities. Further blood tests can also measure low platelet counts and liver function. MRI’s and CT scans can also measure the spleen and liver. Nerve tests can be performed to survey how the nerves and brain have been affected.

Anyone with a family member who has Gaucher Disease, as well as anyone who displays the symptoms of Gaucher Disease, would be a candidate for such tests.

Treatment:

Treatment for Gaucher Disease Type III includes pain management. Various therapies can reduce the pain associated with this disorder. Blood transfusions can help treat the anemia that may occur in some individuals. Psychological counseling is encouraged to help families manage some of the emotional toll this disorder imparts. Enzyme replacement therapy does not prevent the nervous system damage that occurs in Gaucher Disease Type III, but can effectively treat the systemic manifestations. Recent studies suggest that enzyme replacement therapy, when combined with miglustat, may be beneficial for Gaucher Type III.

Patient Groups:

Children's Gaucher Disease Research Fund
P.O. Box 2123
Granite Bay, CA 95746
www.childrensgaucher.org
tel: (916) 797-3700
fax: (916) 797-3707
Gregory Macres, Founder, Chairman
research@childrensgaucher.org

National Gaucher Foundation
2227 Idlewood Road, Suite 12
Tucker, GA 30084
www.gaucherdisease.org
tel: (800) 504-3189
fax: (770) 934-2911
Rhonda P. Buyers, Executive Director
rhonda@gaucherdisease.org

National Tay-Sachs & Allied Diseases Association
2001 Beacon Street, Suite 204
Boston, MA 02135
www.ntsad.org
tel: (800) 906-8723
fax: (617) 277-0134
Sue R. Kahn, Executive Director
info@ntsad.org

GM1 Gangliosidosis - Infantile
Definition:

Infantile/GM1 Gangliosidosis is caused by a deficiency in the enzyme acid, beta-galactosidase-1, and results in the accumulation of ganglioside in the tissues. This disorder affects the cells of the central and peripheral nervous systems, but particularly the nerve cells. There are three types of GM1 Gangliosidosis, each characterized by the age of onset. The three types are: early infantile, late infantile and adult. Early infantile GM1 Gangliosidosis is the most severe of the three forms.

The Gypsy population, specifically of Roman descent has a 2% carrier rate of the mutated gene that causes GM1 Gangliosidosis.

Symptoms:

Symptoms of early infantile GM1 Gangliosidosis begin to appear just following birth. There are many varied symptoms of this form. They are: seizures, liver and spleen enlargement, nerve degeneration, skeletal abnormalities, coarse facial features, distended abdomen, sensitivity to sound and problems walking. Half of those affected may also develop a red spot in their eyes.

Life Expectancy:

Life expectancy for early infantile GM1 Gangliosidosis is between one and two years of age.

Inheritance Pattern:

GM1 Gangliosidosis is an autosomal recessive disorder.

Diagnosis and Testing:

An enzyme assay using blood or skin specimens is performed to confirm a diagnosis of GM1 Gangliosidosis. This test measures the amount of the enzyme acid beta-galactosidase-1 and compares it to normal enzyme activity levels. If this disorder is present, low levels of this enzyme will be present.

Treatment:

Currently, there is no treatment for GM1 Gangliosidosis. Bone marrow transplants have been met with limited success in reducing the progression of the disorder, but no long-term benefits were seen. Palliative treatment has been used to reduce some of the neurologic symptoms associated with this disorder. Gene therapy and enzyme replacement therapy are two treatments that are currently under investigation as a hope to cure GM1 Gangliosidosis.

Patient Groups:

National Tay-Sachs & Allied Diseases Association
2001 Beacon Street, Suite 204
Boston, MA 02135
www.ntsad.org
tel: (800) 906-8723
fax: (617) 277-0134
Sue R. Kahn, Executive Director
info@ntsad.org

GM1 Gangliosidosis - Late infantile/Juvenile
Definition:

Late infantile/Juvenile/GM1 Gangliosidosis is caused by a deficiency in the enzyme acid beta-galactosidase-1 and results in the accumulation of ganglioside in the tissues. This disorder affects the cells of the central and peripheral nervous systems, particularly the nerve cells.

Symptoms:

Symptoms of late infantile GM1 Gangliosidosis commonly occur between the ages of one and three years. Affected children develop neorological symptoms such as ataxia, seizures, dementia, and speech difficulties.

Inheritance Patterns:

GM1 Gangliosidosis is an autosomal recessive disorder.

Diagnosis and Testing:

An enzyme assay using blood or skin specimens is performed to confirm a diagnosis of GM1 Gangliosidosis. This test measures the amount of the enzyme acid beta-galactosidase-1 and compares it to normal enzyme activity levels. If this disorder is present, low levels of this enzyme will be present.

Life Expectancy

Many children with late infantile GM1 Gangliosidosis survive until teenage years.

Treatment:

Bone marrow transplants have been met with limited success in reducing the progression of the disorder, but no long-term benefits were seen. Palliative treatment has been used to reduce some of the neurologic symptoms associated with this disorder. Gene therapy and enzyme replacement therapy are two treatments that are currently under investigation as a hope to cure GM1 Gangliosidosis.

Patient Groups:

National Tay-Sachs & Allied Diseases Association
2001 Beacon Street, Suite 204
Boston, MA 02135
www.ntsad.org
tel: (800) 906-8723
fax: (617) 277-0134
Sue R. Kahn, Executive Director
info@ntsad.org

GM1 Gangliosidosis - Adult/Chronic
Definition:

Adult/Chronic/GM1 Gangliosidosis is caused by a deficiency in the enzyme acid beta-galactosidase-1 and results in the accumulation of ganglioside in the tissues. This disorder affects the cells of the central and peripheral nervous systems, particularly the nerve cells.

Symptoms:

Symptoms of Adult GM1 Gangliosidosis typically occur between the ages of three and 30 years. Symptoms include similar neurological complications as the early and late infantile forms, but for adult GM1 Gangliosidosis, they are less severe and progress at a slower rate. Clouding of the cornea, muscle atrophy, small red to purplish lesions on the skin of the lower torso, and dystonia can occur.

Inheritance Patterns:

GM1 Gangliosidosis is an autosomal recessive disorder.

Diagnosis and Testing:

An enzyme assay using blood or skin specimens is performed to confirm a diagnosis of GM1 Gangliosidosis. This test measures the amount of the enzyme acid beta-galactosidase-1 and compares it to normal enzyme activity levels. If this disorder is present, low levels of this enzyme will be present.

Life Expectancy:

Life expectancy for adult GM1 Gangliosidosis varies widely.

Treatment:

Bone marrow transplants have been met with limited success in reducing the progression of the disorder, but no long-term benefits were seen. Palliative treatment has been used to reduce some of the neurologic symptoms associated with this disorder. Gene therapy and enzyme replacement therapy are two treatments that are currently under investigation as a hope to cure GM1 Gangliosidosis.

Patient Groups:

National Tay-Sachs & Allied Diseases Association
2001 Beacon Street, Suite 204
Boston, MA 02135
www.ntsad.org
tel: (800) 906-8723
fax: (617) 277-0134
Sue R. Kahn, Executive Director
info@ntsad.org

I-Cell disease/Mucolipidosis II
Definition:

I-Cell disease results from deficiency of several lysosomal enzymes. The genes’ coding for these enzymes are normal. The enzymes are normally translated, but are not normally transported to the lysosomes from the endoplasmic reticulum because they lack a specific targeting signal. Without the proper functioning of N-acetylglucosamine-1-phototransferase, a build up of these substances occur when enzymes are unable to travel inside of the lysosome. These substances accumulate into masses, referred to as inclusion bodies, inside the lysosome, and can be seen under a microscope when a diagnosis for the disorder is trying to be made.

There are two forms of I-Cell disease/Mucolipidosis: Type II and Type III. Together they affect one in 325,000 live births worldwide.

Symptoms:

Typically, by the age of 6 months, failure to thrive and developmental delay are obvious symptoms of this disorder. Other symptoms include coarse facial features, skeletal problems, and stiff claw-shaped hands. Carpal tunnel syndrome pain and loss of sensation in the fingertips are common. Hernias, enlarged liver and spleen, a thickening and weakening of the heart muscle, chronic ear infections, and corneal clouding are also present. Additional symptoms are poorly and late formed teeth, as well as a dental condition called gingival hyperplasia, in which the gums are very prominent.

Inheritance Pattern:

I-Cell disease/Mucolipidosis II is an autosomal recessive disorder.

Life Expectancy:

Life expectancy for I-Cell disease/Mucolipidosis II disease is younger than five years of age.

Diagnosis and Testing:

An enzyme assay which measures the amount of N-acetylglucosamine-1-phototransferase typically confirms a diagnosis. White blood cells are examined to measure the amount of this enzyme. If they are low in comparison to normal standards for N-acetylglucosamine-1-phototransferase, a diagnosis of this disorder can be made. A skin biopsy can also be performed which measures the same enzyme in a cultured tissue sample. Low levels of N-acetylglucosamine-1-phototransferase found in comparison to normal standards confirm a diagnosis.

The gene responsible for this disorder has been identified, rendering accurate diagnosis, prenatal diagnosis, and carrier testing to be possible.

Treatment:

There is no cure for I-Cell disease/Mucolipidosis II disease. Treatment is limited to controlling or reducing the symptoms that are associated with this disorder. Nutrition supplements, particularly iron and vitamin B12, are often recommended for individuals with I-Cell disease. Physical therapy to improve motor delays and speech therapy to improve language acquisition are treatment options. Surgery can remove the thin layer of corneal clouding to temporarily improve the complication.

Patient Groups:

International Society for Mannosidosis & Related Diseases
P.O. Box 328
Dexter, MI 48130
www.mannosidosis.org
tel: (734) 449-8222
fax: (734) 449-2282
Terri Klein, Executive Director
info@ismrd.org

Infantile Free Sialic Acid Storage Disease/ISSD
Definition:

ISSD is caused when sialic acid, a kind of charged sugar, is unable to be transported out of the lysosomal membrane and instead, sialic acid accumulates in the tissue and free sialic acid is excreted in the urine. ISSD is the most severe form of the sialic acid storage diseases.

ISSD affects 1 in 528,000 live births worldwide.

Symptoms:

Symptoms present by eight months of age and are marked by developmental delay followed by neurological complications such as seizures, involuntary eye movements, and ataxia or involuntary muscle movements. An enlarged liver, spleen, and heart, and coarse facial features are also symptoms.

Inheritance Pattern:

ISSD is an autosomal recessive disorder.

Life Expectancy:

Life expectancy for ISSD is early childhood.

Diagnosis and Testing:

A diagnosis can be made by measuring cultured tissue samples for increased levels of free sialic acid. Prenatal testing is also available for known carriers of this disorder.

Treatment:

There is no treatment for ISSD. Treatment is limited to controlling the symptoms of this disorder such as administering anti-convulsant medication to control seizure episodes.

Juvenile Hexosaminidase A Deficiency
Definition:

Juvenile Hexosaminidase A Deficiency is caused by the absence of a vital enzyme called hexosaminidase A (Hex-A). Without Hex-A, a fatty substance or lipid called GM2 ganglioside accumulates abnormally in cells, especially in the nerve cells of the brain. Gangliosides need to be biodegraded rapidly in early life as the brain develops. This ongoing accumulation causes progressive damage to the cells, similar to that which occurs in Tay-Sachs Disease.

Symptoms:

Juvenile Hexosaminidase A Deficiency progresses more slowly and later than Tay-Sachs disease, with symptoms appearing between the ages of two and five. Juvenile hexosaminidase A deficiency typically begins with ataxia between two and 10 years of age. Speech and mental cognition begins to deteriorate at this time. By the age of 10, seizures and muscle spasticity are typically present. Loss of vision occurs much later than in the acute infantile form of the disease, and optic atrophy and retinitis pigmentosa may also be seen. A vegetative state develops by 10 to 15 years of age. In some cases, the disease pursues a particularly aggressive course, culminating in death in two to four years from the onset of symptoms.

Inheritance Pattern:

Juvenile Hexosaminidase A Deficiency is an autosomal recessive disorder.

Diagnosis and Testing:

Patients and carriers of Juvenile Hexosaminidase A Deficiency can be identified by a simple blood test that measures the enzymatic activity of beta-hexosaminidase A in blood or tissue samples.

Carrier detection can be performed for males, females, and for pregnant females to determine carrier status of Juvenile Hexosaminidase A Deficiency. A measure of the enzyme hexosaminidase A (Hex-A) is taken using white blood cells or blood samples. It is a highly accurate procedure for determining one’s carrier status.

Life Expectancy:

Life expectancy of Juvenile Hexosaminidase A Deficiency is between 10 and 15 years of age.

Treatment:

There is no cure or effective treatment for Juvenile Hexosaminidase A Deficiency. Anticonvulsant medicine can help to control seizures. Other treatment options include adequate nutrition and hydration, and techniques to keep the airway open.

Enzyme replacement and gene therapies are being investigated as possible treatments to slow or prevent the progression of Juvenile Hexosaminidase A Deficiency.

Krabbe Disease/Infantile Onset
Definition:

Krabbé Disease is one of a group of genetic disorders called leukodystrophies. Krabbé Disease is a rare disorder that affects the central and peripheral nervous systems and leads to the breakdown of the nerve’s protective myelin coating along with brain cells.

Krabbé Disease is caused by a deficiency of galactocerebrosidase, an enzyme essential for myelin metabolism. The myelin sheath is a fatty covering that protects nerve fibers. Without it, the nerves in the brain cannot function properly. Krabbé Disease is also characterized by the presence of cells that have more than one nucleus, also known as globoid cells.

There are four forms of Krabbé Disease: infantile, late infantile, juvenile, and adult-onset. The disease most often affects infants, with onset before 6 months of age, but can occur in adolescence and in adulthood. It affects one in 100,000 individuals in the United States. Some communities in Israel have found higher incidences of approximately six cases of the disease per 100,000 live births.

Symptoms:

Symptoms of Krabbé Disease include irritability, fever without an associated infection, seizures, difficulties in feeding, vomiting, and a severe decline of mental and motor development. Signs include weakness, spasticity, and a loss of vision and hearing.

Inheritance Pattern:

Krabbé Disease is an autosomal recessive disorder.

Life Expectancy:

Life expectancy is two years of age or younger.

Diagnosis and Testing:

Krabbé Disease can be detected through a blood test that indicates low levels of the enzyme galactosylceramidase (galactocerebrosidase) in white blood cells. An MRI of the affected individual’s head as well as tests that measure the speed of nerve signals can be performed to confirm a diagnosis. Gene testing which looks for the mutated gene, GALC, that causes the disorder can be performed along with tests that search for the presence of the globoid cells that are characteristic to this disorder.

Treatment:

There is no cure for Krabbé Disease but success has been forged in preventing much of the neurological impairment associated with this disease, by using umbilical cord blood stem cells prior to disease onset or with early bone marrow transplantation. Treatment includes supportive therapies to lessen some of the symptoms. Physical therapy may increase circulation and improve elasticity in the limbs affected.

Patient Groups:

Hunter’s Hope Foundation
P.O. Box 643
Orchard Park, NY 14127
www.huntershope.org
tel: (877) 984-4673
fax: (716) 667-1212
Jim Kelly
info@huntershope.org

Krabbe Disease/Late Onset
Definition:

Krabbé Disease is one of a group of genetic disorders called leukodystrophies. Krabbé Disease is a rare disorder that affects both the central and peripheral nervous systems and leads to the breakdown of the nerve’s protective myelin coating along with brain cells.

Krabbé Disease is caused by a deficiency of galactocerebrosidase, an enzyme essential for myelin metabolism. The myelin sheath is a fatty covering that protects nerve fibers. Without it, the nerves in the brain cannot function properly. Krabbé Disease is also characterized by the presence of cells that have more than one nucleus, also known as globoid cells.

Krabbé Disease affects one in 100,000 individuals in the United States. Some communities in Israel have found higher incidences of approximately six cases per 100,000 live births.

Symptoms:

Symptoms of Krabbé Disease/Late Onset begin in late childhood or in early adolescence. Until symptoms appear, the individual affected appears normal. When symptoms appear, they typically include visual problems followed by walking difficulties and stiff muscles. Mental regression also occurs. The symptoms associated with Krabbé Disease/Late Onset vary widely from case to case. Even in cases where members within the same family have the disorder, a spectrum of symptoms can occur.

Inheritance Pattern:

Krabbé Disease is an autosomal recessive disorder.

Life Expectancy:

Individuals affected with Krabbe Disease/Late Onset can expect to live into their adulthood years.

Diagnosis and Testing:

Krabbé Disease can be detected via a blood test indicating low levels of the enzyme galactosylceramidase (galactocerebrosidase) in white blood cells. Mutation analysis of the GALC gene should show two mutations in affected individuals.

Treatment:

There is no cure for Krabbé Disease, but success has been forged to prevent much of the neurological impairment associated with this disease, by using umbilical cord blood stem cells prior to disease onset or early bone marrow transplantation. Treatment includes supportive therapies to lessen some of the symptoms. Physical therapy may increase circulation and improve elasticity in the limbs affected.

Patient Groups:

Hunter’s Hope Foundation
P.O. Box 643
Orchard Park, NY 14127
www.huntershope.org
tel: (877) 984-4673
fax: (716) 667-1212
Jim Kelly
info@huntershope.org

Metachromatic Leukodystrophy
Definition:

Metachromatic leukodystrophy (MLD) is the most common form of a family of genetic diseases known as the leukodystrophies. This disorder, also known as Arylsulfatase A deficiency, affects the central and peripheral nervous systems and leads to the breakdown of the nerve’s protective myelin sheath and brain cells. The myelin sheath is a fatty covering that protects nerve fibers. Without it, the nerves in the brain cannot function properly.

MLD is caused by a lack of the arylsulfatase A enzyme. Without this enzyme, lipids accumulate in the cells of the nervous system, liver, and kidneys. This accumulation of lipids eventually destroys the myelin sheath.

There are three forms of MLD: late infantile, juvenile, and adult. The late infantile form is the most common of the three.

Commonly, children affected with MLD are misdiagnosed initially. Misdiagnoses among affected adults include a variety of psychological conditions since the disease first manifests with psychological symptoms.

Symptoms:

Children with late-infantile MLD begin showing symptoms just after age one. It is then that they begin to experience difficulty walking. Symptoms include developmental delays, muscle wasting, weakness, and stiffness, a progressive loss of vision which eventually leads to blindness, and swallowing difficulties. Seizures, paralysis, and dementia can also occur.

Symptoms for the juvenile form of MLD occur between three and 10 years of age. Symptoms first manifest in impaired school performance, mental deterioration and dementia before symptoms associated with the late-infantile form begin to develop. The late infantile form progresses at a slower rate.

The adult form commonly begins after age 16 as a psychiatric disorder or as progressive dementia. The progression of the disorder is slower in the adult form than it is in the other two forms, but its pattern is similar.

Inheritance Pattern:

MLD is an autosomal recessive disorder.

Diagnosis and Testing:

A diagnosis can be confirmed by measuring the levels of the enzyme, arylsulfatase A, activity in the blood. If low levels of the enzyme are found, a urine test is performed to confirm the presence of sulfatides, a class of lipids.

A CT scan or an MRI of the brain may reveal demyelination, or the loss of the myelin sheath. Electrophysiological tests can be performed on various limbs to detect decreased nerve conduction. Genetic screening can determine a diagnosis and/or whether a family member is a carrier.

Life Expectancy:

Life expectancy for late infantile MLD is five years of age or younger. Life expectancy for juvenile form of MLD is between 10 and 15 years, following a diagnosis.

Treatment:

There is no cure for MLD. Bone marrow or stem cell transplantation may be performed to delay the disorder's progression in some cases, but will not reverse the damage that the brain has endured. These procedures are therefore more successful when MLD is caught before there has been damage to the brain.

Other treatments are supportive and palliative, helping to lessen some of the symptoms associated with this disorder. For example, physical therapy can improve the muscular weakness and stiffening that occurs with this disorder, and medication can control seizure episodes, reduce muscle pain and/or lessen psychological conditions. Assistive devices such as feeding tubes may ensure that nutrition is being maintained. Should muscle deformities lead to a loss of function of a particular joint, surgery may alleviate the contracture.

Patient Groups:

Adrenoleukodystrophy Foundation
9906 South Maplewood Avenue
Tulsa, OK 74137
www.aldfoundation.org
Ph: (918)298-8542
David A. Cry, President
davidcry@aldfoundation.org

Hunter’s Hope Foundation
P.O. Box 643
Orchard Park, NY 14127
www.huntershope.org
tel: (877) 984-4673
fax: (716) 667-1212
Jim Kelly
info@huntershope.org

MLD Foundation (Metachromatic Leukodystrophy)
21345 Miles Drive
West Linn, OR 97068
www.mldfoundation.org
tel: (800) 617-8387
fax: (503) 212-0159
Dean Suhr, President
deansuhr@mldfoundation.org

United Leukodystrophy Foundation
2304 Highland Drive
Sycamore, IL 60178
www.ulf.org
tel: (800) 728-5483
fax: (815) 895-2432
Timothy R. Brazeal, Executive Director
office@ulf.org

Mucopolysaccharidoses disorders
Pseudo-Hurler polydystrophy/Mucolipidosis IIIA
Definition:

Pseudo-Hurler Polydystrophy/Mucolipidosis IIIA is caused by the lack of a number of enzymes which, although present in the cell, lack a signal needed to transport them inside the lysosome. The enzyme responsible for giving the targeting signal to the enzymes to enter into the lysosome, is called N-Acetylglucosamine-1-phosphotransferase. It is this enzyme that malfunctions in individuals afflicted with Pseudo-Hurler Polydystrophy/Mucolipidosis IIIA. Lipids, proteins and carbohydrates inside the lysosome need to be metabolized via enzymes. Without the proper functioning of N-acetylglucosamine-1-phototransferase, a build up of these substances occurs because enzymes are unable to travel inside of the lysosome. These substances accumulate into masses referred to as inclusion bodies inside the lysosome.

This disorder is called Pseudo-Hurler because it resembles a mild form of Hurler disease, one of the mucopolysaccharide (MPS) diseases.

Symptoms:

The symptoms of Pseudo-Hurler Polydystrophy/Mucolipidosis IIIA include mild enlargement of organs, skeletal deformities, carpal tunnel syndrome, aortic valve disease and corneal clouding.

Inheritance Pattern:

Pseudo-Hurler Polydystrophy/Mucolipidosis IIIA is an autosomal recessive disorder.

Life Expectancy:

Some children with severe forms of this disease do not live beyond childhood. However, there is a great variability among patients, hence many can live into adulthood.

Diagnosis and Testing:

An enzyme assay, measuring the amount of N-acetylglucosamine-1-phototransferase, can confirm a diagnosis. White blood cells are examined to measure the amount of this enzyme. Amounts of the enzyme found to be low in comparison to normal standards for N-acetylglucosamine-1-phototransferase may result in a diagnosis of this disorder. A skin biopsy measures the same enzyme in a cultured tissue sample. Low levels of N-acetylglucosamine-1-phototransferase in comparison to the normal standards may confirm a diagnosis.

The gene responsible for this disorder has been identified, allowing for accurate diagnosis, prenatal diagnosis and carrier testing.

Treatment:

There is no cure for Pseudo-Hurler Polydystrophy/Mucolipidosis IIIA. Treatment is limited to controlling or reducing symptoms associated with this disorder. Physio-therapy, particularly hydrotherapy has proven effective at relieving muscle stiffness and increasing mobility. The use of crutches, a wheelchair or scooters are treatment options as the metabolic bone disease progresses. The insertion of rods in the spine to stabilize the vulnerable areas can treat scoliosis. Heart valve replacement surgery may be necessary as this disorder progresses.

MPSI Hurler Syndrome
Definition:

Individuals who do not fit neatly into the Hurler or Scheie categories are classified as having Hurler-Scheie disease or Hurler-Scheie syndrome. Hurler-Scheie disease is described as a condition with quick disease progression, little or no developmental delay, and symptom severity and mortality in between what is associated with Hurler and Scheie disorders. Medical literature also describes this disorder as being the intermediate form of MPS I.

Hurler-Scheie/MPS I is caused by a mutated gene that manufactures the enzyme, alpha-L-iduronidase. The enzyme, which is needed to break down sugars known as glycosaminoglycans or GAGs, is either produced in very low amounts or is completely absent in individuals affected with this disorder. The sugars are used to build tissues, cartilage, skin, tendons, and joint fluid in the body. Individuals affected with Hurler-Scheie/MPS I have too much GAG in their system. An excessive amount of GAGs result in the clinical symptoms of Hurler-Scheie/MPS I.

This disorder affects one in 100,000 individuals worldwide and approximately one in 25,000 children born in the United States will be afflicted with one of the forms of MPS.

Symptoms:

Symptoms of Hurler-Scheie/MPS I appear between the ages of three and eight. Some of the hallmark symptoms include stiff joints, skeletal abnormalities, clouding of the cornea, an enlarged liver and/or spleen, and coarse facial features. Other symptoms include carpal tunnel syndrome, heart disease, upper respiratory infections, hernias, and lung disease.

Inheritance Pattern:

Hurler-Scheie/MPS I is an autosomal recessive disorder.

Diagnosis and Testing:

A urine test measuring increased levels of glycosaminoglycans (GAGs), the type of sugar chain in the lysosome that accumulate as a result of the malfunctioning enzyme, can detect Hurler-Scheie/MPSI. A urine test is routinely followed by a blood test or skin biopsy, which will show reduced activity of the enzyme alpha-L-iduronidase. Prenatal screening is available to examine alpha-L-iduronidase activity in the fetus. Genetic testing is also available in combination with these diagnostic tests to look for the mutation that causes Hurler-Scheie/MPS I.

Life Expectancy:

Life expectancy for severe Hurler-Scheie/MPS I is late adolescence or pre-teenage years. Individuals affected with a mild Hurler-Scheie/MPS I can live to adulthood.

Treatment:

Treatments for Hurler-Scheie/MPS I include procedures to treat some of the symptoms associated with this disorder as well as its cause. There are many, various treatments aimed at reducing or controlling the symptoms of this disorder. For instance, supplemental oxygen or a tracheostomy may be given to reduce breathing complications. Physical therapy can alleviate the muscle and joint stiffness associated with this disorder. Surgery may also be necessary for a hernia, spinal cord compression, carpel tunnel syndrome, and/or heart valve replacement.

Enzyme replacement therapy has been utilized to help reduce symptoms of this disorder by supplementing or replacing the absent or deficient enzyme. Since the synthesized enzyme does not cross the blood-brain barrier, this therapy will not affect the neurological symptoms associated with Hurler-Scheie/MPS I.

Bone marrow or stem cell transplantation may also be an option for individuals with severe Hurler-Scheie/MPS I.

Patient Groups:

National MPS Society
4220 NC Highway 55, Suite 140
Durham NC, 27713
www.mpssociety.org
tel: (919) 806-0101
fax: (919) 806-2005
Barbara Wedehase, Executive Director
info@mpssociety.org

MPSI Scheie Syndrome
Definition:

Scheie Syndrome/MPS I is caused by a mutated gene that manufactures the enzyme alpha-L-iduronidase. This enzyme, which is needed to break down sugars known as glycosaminoglycans or GAGs, is either produced in very low amounts or is completely absent in individuals affected with this disorder. These sugars are used to build tissues, cartilage, skin, tendons, and a joint fluid in the body. Individuals affected with Scheie Syndrome/MPS I have too much GAG in their system. An excessive amount of GAGs result in the clinical symptoms of Scheie Syndrome/MPS I.

Scheie syndrome is the mildest form of the MPS I disorders. Individuals affected with this disorder typically have normal intelligence and milder forms of the physical symptoms associated with MPS I disease. Scheie syndrome is estimated to affect one in 500,000 individuals worldwide.

Symptoms:

The symptoms of Scheie Syndrome/MPS I appear between the ages of three and eight. Some of the hallmark symptoms may include stiff joints, skeletal abnormalities, clouding of the cornea, hearing loss, an enlarged liver and/or spleen, and coarse facial features. Other symptoms can include carpal tunnel syndrome, heart disease, upper respiratory infections, hernias, and lung disease.

In contrast to Hurler syndrome, where individuals don’t grow beyond four feet in height, those with Scheie Syndrome/MPS I grow to a normal height.

Inheritance Pattern:

Scheie/MPS I is an autosomal recessive disorder.

Diagnosis and Testing:

A urine test is used to diagnose Scheie/MPSI, by measuring increased levels of glycosaminoglycans (GAGs), the type of sugar chain in the lysosome that accumulates as a result of the malfunctioning enzyme. A urine test is routinely followed by a blood test or skin biopsy, which will reveal reduced activity of the enzyme alpha-L-iduronidase. Prenatal screening is available to examine alpha-L-iduronidase activity in the fetus. Genetic testing is also available in combination with these diagnostic tests to look for the mutation that causes Hurler-Scheie/MPS I.

Life Expectancy:

A normal life expectancy is associated with Scheie/MPS I.

Treatment:

Treatment for Scheie/MPS I includes reducing some of the symptoms associated with this disorder as well as treating its cause. There are many, various treatments aimed at reducing or controlling the symptoms of this disorder. For instance, supplemental oxygen or a tracheostomy may assist with breathing complications. Physical therapy can alleviate muscle and joint stiffness associated with this disorder. Surgery may also be necessary for a hernia, spinal cord compression, carpel tunnel syndrome, and/or heart valve replacement.

Enzyme replacement therapy has been utilized to help reduce symptoms of this disorder by supplementing or replacing the absent or deficient enzyme. Bone marrow or stem cell transplantation may also be an option for individuals with Scheie/MPS I.

Patient Groups:

National MPS Society
4220 NC Highway 55, Suite 140
Durham NC, 27713
www.mpssociety.org
tel: (919) 806-0101
fax: (919) 806-2005
Barbara Wedehase, Executive Director
info@mpssociety.org

MPS I Hurler-Scheie Syndrome
Definition:

Individuals who do not fit neatly into the Hurler or Scheie categories are classified as having Hurler-Scheie disease or Hurler-Scheie syndrome. Hurler-Scheie disease is described as a condition with quick disease progression, little or no developmental delay, and symptom severity and mortality in between what is associated with Hurler and Scheie disorders. Medical literature also describes this disorder as being the intermediate form of MPS I.

Hurler-Scheie/MPS I is caused by a mutated gene that manufactures the enzyme, alpha-L-iduronidase. The enzyme, which is needed to break down sugars known as glycosaminoglycans or GAGs, is either produced in very low amounts or is completely absent in individuals affected with this disorder. The sugars are used to build tissues, cartilage, skin, tendons, and joint fluid in the body. Individuals affected with Hurler-Scheie/MPS I have too much GAG in their system. An excessive amount of GAGs result in the clinical symptoms of Hurler-Scheie/MPS I.

This disorder affects one in 100,000 individuals worldwide and approximately one in 25,000 children born in the United States will be afflicted with one of the forms of MPS.

Symptoms:

Symptoms of Hurler-Scheie/MPS I appear between the ages of three and eight. Some of the hallmark symptoms include stiff joints, skeletal abnormalities, clouding of the cornea, an enlarged liver and/or spleen, and coarse facial features. Other symptoms include carpal tunnel syndrome, heart disease, upper respiratory infections, hernias, and lung disease.

Inheritance Pattern:

Hurler-Scheie/MPS I is an autosomal recessive disorder.

Diagnosis and Testing:

A urine test measuring increased levels of glycosaminoglycans (GAGs), the type of sugar chain in the lysosome that accumulate as a result of the malfunctioning enzyme, can detect Hurler-Scheie/MPSI. A urine test is routinely followed by a blood test or skin biopsy, which will show reduced activity of the enzyme alpha-L-iduronidase. Prenatal screening is available to examine alpha-L-iduronidase activity in the fetus. Genetic testing is also available in combination with these diagnostic tests to look for the mutation that causes Hurler-Scheie/MPS I.

Life Expectancy:

Life expectancy for severe Hurler-Scheie/MPS I is late adolescence or pre-teenage years. Individuals affected with a mild Hurler-Scheie/MPS I can live to adulthood.

Treatment:

Treatments for Hurler-Scheie/MPS I include procedures to treat some of the symptoms associated with this disorder as well as its cause. There are many, various treatments aimed at reducing or controlling the symptoms of this disorder. For instance, supplemental oxygen or a tracheostomy may be given to reduce breathing complications. Physical therapy can alleviate the muscle and joint stiffness associated with this disorder. Surgery may also be necessary for a hernia, spinal cord compression, carpel tunnel syndrome, and/or heart valve replacement.

Enzyme replacement therapy has been utilized to help reduce symptoms of this disorder by supplementing or replacing the absent or deficient enzyme. Since the synthesized enzyme does not cross the blood-brain barrier, this therapy will not affect the neurological symptoms associated with Hurler-Scheie/MPS I.

Bone marrow or stem cell transplantation may also be an option for individuals with severe Hurler-Scheie/MPS I.

Patient Groups:

National MPS Society
4220 NC Highway 55, Suite 140
Durham NC, 27713
www.mpssociety.org
tel: (919) 806-0101
fax: (919) 806-2005
Barbara Wedehase, Executive Director
info@mpssociety.org

MPS II Hunter syndrome
Definition:

Hunter/MPS II is caused by the mutated gene that manufactures the enzyme iduronate sulfatase. This enzyme, needed to break down sugars known as mucopolysaccharides, is either produced in very low amounts or is completely absent in individuals afflicted with this disorder. The sugars are used to build tissues, cartilage, skin, tendons, and joint fluid in the body. Individuals affected with Hunter/MPS II have too many mucopolysaccharides in their system. An excessive amount of mucopolysaccharides results in the clinical symptoms of Hunter/MPS II.

There are two different types of Hunter/MPS II, classified by their age of onset and the severity of the symptoms: The early onset type is characterized by more severe symptoms and the late-onset form is characterized by more mild symptoms.

Hunter/MPS II is estimated to affect one in 100,000 to 150,000 births worldwide.

Symptoms:

Symptoms of both forms of this disorder include coarse facial features, a large head, stiff joints, hearing loss, increased hair production, enlarged liver and spleen, and carpel tunnel syndrome. The early onset form of Hunter/MPS II manifests shortly after two years of age. Symptoms include those that are general to each of the forms, as well as mental deterioration, mental retardation, aggression, and hyperactivity.

The late-onset form of Hunter/MPS II includes those symptoms that are general to each of the forms, as well as mental deterioration.

Inheritance Pattern:

Hunter/MPS II is an X-linked recessive disorder.

Life Expectancy:

Life expectancy for early-onset Hunter/MPS II is younger than 20 years of age.

Life expectancy for the late-onset form is between 20 and 60 years of age.

Diagnosis and Testing:

A urine test is able to measure increased levels of mucopolysaccharides, the type of sugar chain in the lysosome that accumulates as a result of the malfunctioning enzyme. A urine test is routinely followed by a blood test or skin biopsy, which will reveal reduced activity of the enzyme iduronate sulfatase. Prenatal screening is available to examine iduronate sulfatase activity in the fetus. Genetic testing is also available in combination with these diagnostic tests to look for the mutation that causes Hunter/MPS II.

Treatment:

In 2006, the FDA approved the first drug to treat this disorder. Elaprase is an enzyme replacement therapy designed to arrest or halt the disorder’s progress.

Other forms of treatment involve reducing some of the symptoms that are associated with this disorder. Such treatments include enlisting the support of a breathing device to improve upper airway obstructions. Physical therapy can alleviate the muscle and joint stiffness associated with this disorder. Surgery may also be necessary for a hernia, spinal cord compression, carpel tunnel syndrome, and/or heart valve replacement. Anticonvulsant medication may also be prescribed as well as medication to improve sleep.

Bone marrow transplantation has show variable results in individuals with the early-onset form of Hunter/MPS II.

Patient Groups:

National MPS Society
4220 NC Highway 55, Suite 140
Durham NC, 27713
www.mpssociety.org
tel: (919) 806-0101
fax: (919) 806-2005
Barbara Wedehase, Executive Director
info@mpssociety.org

Sanfilippo Type A/MPS III A
Definition:

Sanfilippo type A/MPS III A is caused by a mutated gene that manufactures the enzyme heparan sulfatase. This enzyme is needed to break down a specific type of sugar or mucopolysaccharides called heparan sulfate. The enzyme, heparan sulfatase, is either produced in very low amounts or is completely absent in individuals afflicted with Sanfilippo type A/MPS III A. The sugars are used to build connective tissues in the body. Individuals affected with Sanfilippo type A/MPS III A have too much heparan sulfate in their system. Excessive amounts of the sugars lead to the clinical symptoms of Sanfilippo type A/MPS III A.

There are four types of Sanfilippo/MPS III: A, B, C, and D. The four forms of this disorder have very little clinical differences. The differing characteristic is the specific gene that codes for the specific enzyme. The incidence of all four together is estimated at one in 70,000 births worldwide. Type A is the most common form of this disorder in Northwestern Europe.

Symptoms:

Children born with Sanfilippo type A/MPS III A appear normal, but as more cells become damaged, the signs and symptoms associated with the disorder begin to appear. Symptoms are progressive and classified in stages based upon those presented. Behavioral problems associated with this disorder appear around two years of age.

In the initial stage, the affected child will display delayed speech skills as well as some mild facial abnormalities. In the following stage, the affected child will become extremely active, restless, suffer sleeplessness and exhibit difficult behavior. Many chew on their hands, clothes, or on other items. Over time, speech and comprehension will diminish. By age six, most children will develop severe mental retardation. By age 10, the affected child’s movement will become very limited. In the final stage, this child will become immobile and generally unresponsive.

Although most of the symptoms are neurological in nature, some children affected may also develop diaherra, cavities and an enlarged liver and spleen. Another physical chacteristic of this disorder is an abundance of coarse hair.

Inheritance Pattern:

Sanfilippo type A/MPS III A is an autosomal recessive disorder.

Life Expectancy:

Current life expectancy is 14 to 20 years of age.

Diagnois and Testing:

A urine test is utilized to diagnose Sanfilippo type A/MPS III A, by measuring increased levels mucopolysaccharides, the type of sugar chain in the lysosome that accumulates as a result of the malfunctioning enzyme. A urine test is routinely followed by a blood test or skin biopsy, which will show reduced activity of the enzyme heparan sulfatase. Prenatal screening is available to examine heparan sulfatase activity in the fetus. Genetic testing is also available in combination with these diagnostic tests to look for the mutation that causes Sanfilippo type A/MPS III A.

Treatment:

There is no cure for Sanfilippo type A/MPS III A. If the disease is caught early, bone marrow transplantation may be beneficial in slowing down its progression. In most cases, treatment is limited to reducing or controlling symptoms of this disorder. Medications to control behavioral problems have not been proven to be effective. Anti-convulsant medication is often prescribed to control seizures, devices are inserted into the affected child’s mouth to help with swallowing difficulties, and wheelchairs are often required as the disorder progresses to its final and immobile stage. Genetic counseling is also encouraged.

Since gene therapy is currently being investigated in animal studies, there is great hope that this procedure will produce a cure for this disorder in the coming years. Other potential treatments are enzyme replacement therapies that cross the blood-brain barrier, therefore allowing the neurological symptoms to be treated. Stem cell transplants are also another mode of treatment currently under investigation. It is accepted within the medical community that a diagnosis made very early in the course of the disorder may render treatment more effective than it might be following a later diagnosis.

Patient Groups:

National MPS Society
4220 NC Highway 55, Suite 140
Durham NC, 27713
www.mpssociety.org
tel: (919) 806-0101
fax: (919) 806-2005
Barbara Wedehase, Executive Director
info@mpssociety.org

Sanfilippo Type B/MPS III B
Definition:

Sanfilippo type B/MPS III B is caused by a mutated gene that manufactures alpha-n-acetylglucosaminidase, an enzyme needed in the process of breaking down a specific type of sugar or mucopolysaccharides. The enzyme, alpha-n-acetylglucosaminidase, is either produced in very low amounts or is completely absent in individuals afflicted with Sanfilippo type B/MPS III B. These sugars are used to build connective tissues in the body. Individuals affected with Sanfilippo type B/MPS III B have too many mucopolysaccharides in their system. An excessive amount of the sugars result in the clinical symptoms of Sanfilippo type B/MPS III B.

There are four types of Sanfilippo/MPS III: A, B, C, and D. There is very little clinical difference in the four different forms of this disorder. The differing characteristic is the mutation of the specific gene codes for the specific enzyme. The incidence of all four combined is estimated to be one in 70,000 births worldwide.

Symptoms:

Children born with Sanfilippo type B/MPS III B appear normal, but as cells become damaged, signs and symptoms associated with this disorder begin to appear. Symptoms are progressive and classified in stages based upon those presented. Behavioral problems associated with this disorder appear around two years of age.

In the initial stage, the affected child will display delayed speech skills as well as some mild facial abnormalities. In the following stage, the affected child will become extremely active, restless, suffer sleeplessness and exhibit difficult behavior. Many chew on their hands, clothes, or on other items. Over time, speech and comprehension will diminish. By age 10, the affected child’s movement will become very limited. In the final stage, the child affected with this disorder will become immobile and generally unresponsive.

Although most of the symptoms are neurological in nature, some children may also develop diaherra, cavities and an enlarged liver and spleen. Another phsyical chacteristic of this disorder is an abundance of coarse hair.

Inheritance Pattern:

Sanfilippo type B/MPS III B is an autosomal recessive disorder.

Life Expectancy:

Current life expectancy is 14 to 20 years of age.

Diagnois and Testing:

A urine test may be utilized to diagnose Sanfilippo type B/MPS III B. It measures increased levels of mucopolysaccharides, the type of sugar chain in the lysosome that accumulates as a result of the malfunctioning enzyme. A urine test is routinely followed by a blood test or skin biopsy, which will reveal reduced activity of the enzyme alpha-n-acetylglucosaminidase. Prenatal screening is available to examine alpha-n-acetylglucosaminidase activity in the fetus. Genetic testing is also available in combination with these diagnostic tests to look for the mutation that causes Sanfilippo type B/MPS III B.

Treatment:

There is no cure for Sanfilippo type B/MPS III B. If the disease is caught early, bone marrow transplant may slow down the progression of this disorder. In most cases, treatment is limited to reducing or controlling its symptoms. Medications to control the behavioral problems associated with this disorder have not been found to be effective. Anti-convulsant medication is often prescribed to control seizures, devices can be inserted in the mouth to aid swallowing, and wheelchairs are often required as the disorder progresses to its final and immobile stage. Genetic counseling is also encouraged.

Other potential treatments include enzyme replacement therapies that cross the blood-brain barrier, thereby treating neurological symptoms of the disease. It is recognized within the medical community that future treatment may be more effective following a diagnosis made early in the course of this disorder.

Patient Groups:

National MPS Society
4220 NC Highway 55, Suite 140
Durham NC, 27713
www.mpssociety.org
tel: (919) 806-0101
fax: (919) 806-2005
Barbara Wedehase, Executive Director
info@mpssociety.org

Sanfilippo Type C/MPS III C
Definition:

Sanfilippo type C/MPS III C is caused by a mutated gene that manufactures the enzyme acetyl-CoA:alpha-glucosaminide acetyltransferase. This enzyme is needed to break down a specific type of sugar or mucopolysaccharides. The enzyme acetyl-CoA:alpha-glucosaminide acetyltransferase, is either produced in very low amounts or is completely absent. The sugars are used to build connective tissues in the body. Individuals affected with Sanfilippo type C/MPS III C have too many mucopolysaccharides in their system. An excessive amount of these sugars leads to the clinical symptoms of Sanfilippo type C/MPS III C.

There are four types of Sanfilippo/MPS III: A, B, C, and D. There is very little clinical difference in the four different forms of this disorder. The differing characteristic is the mutation of the specific gene that codes for the specific enzyme. The incidence of all four types together is estimated to be one in 70,000 births worldwide.

Symptoms:

Babies born with Sanfilippo type C/MPS III C appear normal, but as more cells become damaged, the signs and symptoms associated with the disorder begin to appear. Symptoms are progressive and classified in stages based upon those presented. Behavioral problems associated with this disorder appear at around two years of age.

In the disorder’s initial stage, the affected child will display delayed speech skills as well as some mild facial abnormalities. In the following stage, the affected child will become extremely active, restless, suffer sleeplessness and exhibit difficult behavior. Many chew on their hands, clothes or on other items. Over time, speech and comprehension will diminish. By age 10, the affected child’s movement will become very limited. In the final stage, the child becomes immobile and generally unresponsive.

Although most of the symptoms associated with this disorder are neurological in nature, some children affected may also develop diaherra, cavities and an enlarged liver and spleen. Another phsyical chacteristic of this disorder is an abundance of coarse hair.

Inheritance Pattern:

Sanfilippo type C/MPS III C is an autosomal recessive disorder.

Life Expectancy:

The life expectancy of individuals afflicted with this disorder is 14 to 20 years of age.

Diagnois and Testing:

A urine test is utilized to diagnose Sanfilippo type C/MPS III C. It measures increased levels mucopolysaccharides, the type of sugar chain in the lysosome that accumulates as a result of the malfunctioning enzyme. A urine test is routinely followed by a blood test or skin biopsy, which will reveal reduced activity of the enzyme acetyl-CoA:alpha-glucosaminide acetyltransferase. Prenatal screening is available to examine acetyl-CoA:alpha-glucosaminide acetyltransferase activity in the fetus. Genetic testing is also available in combination with these diagnostic tests to look for the mutation that causes Sanfilippo type C/MPS III C.

Treatment:

There is no cure for Sanfilippo type C/MPS III C. If the disease is caught early, bone marrow transplantation may be beneficial in slowing down the progression of this disorder. In most cases, treatment is limited to reducing or controlling the symptoms of this disorder by making sure that neurologists, ophthalmologists, and genetic counselors are consulted routinely. Medications to control the behavioral problems associated with this disorder have not proven effective. Anti-convulsant medication may control seizures, devices can be inserted in the mouth to assist swallowing, and wheelchairs are often required as the disorder progresses to its final and immobile stage. Genetic counseling is also encouraged.

Other potential treatments include enzyme replacement therapies that cross the blood-brain barrier, therefore allowing the neurological symptoms to be treated. Stem cell transplants are presently under investigation. It is recognized within the medical community that a diagnosis made early in the course of this disorder will render treatment more effective than following a later diagnosis.

Patient Groups:

National MPS Society
4220 NC Highway 55, Suite 140
Durham NC, 27713
www.mpssociety.org
tel: (919) 806-0101
fax: (919) 806-2005
Barbara Wedehase, Executive Director
info@mpssociety.org

Sanfilippo Type D/MPS III D
Definition:

Sanfilippo type D/MPS III D is caused by a mutated gene that manufactures the enzyme, N-acetylglucosamine-6-sulfate sulfatase. This enzyme is needed to break down a specific type of sugar or mucopolysaccharides. The enzyme, N-acetylglucosamine-6-sulfate sulfatase, is either produced in very low amounts or is completely absent in individuals afflicted with this disorder. The sugars are used to build connective tissues in the body. Individuals affected with Sanfilippo type D/MPS III D have too many mucopolysaccharides in their system. An excessive amount of the sugars leads to the clinical symptoms of Sanfilippo type D/MPS III D.

There are four types of Sanfilippo/MPS III: A, B, C, and D. There is little clinical difference in the four different forms of the disorder. The differing characteristic is the mutation of the specific gene that codes for the specific enzyme. The incidence of all four types together is estimated to be one in 70,000 births worldwide.

Symptoms:

Babies born with Sanfilippo type D/MPS III D appear normal, but as more cells become damaged, the signs and symptoms associated with this disorder begin to appear. Symptoms are progressive and classified in stages based upon those presented. Behavioral problems associated with this disorder appear at around two years of age.

In the initial stage of this disorder, the affected child will display delayed speech skills as well as some mild facial abnormalities. In the following stage, the affected child will become extremely active, restless, suffer sleeplessness, and exhibit difficult behavior. Many chew on their hands, clothes, or on other items. Over time, speech and comprehension will diminish. By age 10, the affected child’s movement will become very limited. In the final stage, the child becomes immobile and generally unresponsive.

Although most of the symptoms are neurological in nature, some children may also develop diaherra, cavities, and an enlarged liver and spleen. Another phsyical chacteristic of this disorder is an abundance of coarse hair.

Inheritance Pattern:

Sanfilippo type D/MPS III D is an autosomal recessive disorder.

Life Expectancy:

The life expectancy of children afflicted with this disorder is 14 to 20 years of age.

Diagnois and Testing:

A urine test may be utilized to diagnose Sanfilippo type D/MPS III D. This test measures increased levels of mucopolysaccharides, the type of sugar chain in the lysosome that accumulates as a result of the malfunctioning enzyme. A urine test is routinely followed by a blood test or skin biopsy, which will reveal reduced activity of the enzyme N-acetylglucosamine-6-sulfate sulfatase. Prenatal screening is available to examine N-acetylglucosamine-6-sulfate sulfatase activity in the fetus. Genetic testing is also available in combination with these diagnostic tests to look for the mutation that causes Sanfilippo type D/MPS III D.

Treatment:

There is no cure for Sanfilippo type D/MPS III D. If the disease is caught early, bone marrow transplantation may slow the progression of this disorder. In most cases, treatment is limited to reducing or controlling the symptoms of the disorder. Medications to control the behavioral problems have proven ineffective. Anti-convulsant medication may control seizures, devices can be inserted in the mouth to assist swallowing, and wheelchairs are often required as the disorder progresses to its final and immobile stage. Genetic counseling is also encouraged.

Other potential treatments include enzyme replacement therapies that cross the blood-brain barrier, allowing the neurological symptoms associated with the disorder to be treated. Stem cell transplants are under investigation. It is accepted within the medical community that a diagnosis made early in the course of this disorder will render treatment more effective than it might be following a later diagnosis.

Patient Groups:

National MPS Society
4220 NC Highway 55, Suite 140
Durham NC, 27713
www.mpssociety.org
tel: (919) 806-0101
fax: (919) 806-2005
Barbara Wedehase, Executive Director
info@mpssociety.org

Morquio Type A/MPS IVA
Definition:

Morquio type A/MPS IV A is caused by a mutated gene that manufactures the enzyme, N-acetylgalactosamine 6-sulfatase. This enzyme is needed to break down a specific type of sugar or mucopolysaccharides called keratan sulfate. This sugar is used to build connective tissues and bones in the body. Individuals affected with Morquio type A/MPS IV A have too many keratan sulfates in their system because the enzyme, N-acetylgalactosamine 6-sulfatase, which is needed to break down keratan sulfate, is absent or present in only very small quantities. An excessive amount of keratan sulfate results in the clinical symptoms of Morquio type A/MPS IV A.

There are two forms of Morquio MPS IV: Type A and Type B. Type A is the most common of the two forms. There is little difference in the clinical symptoms between both forms of the disorder and a wide range of symptoms associated with each form.

The incidence of both forms of Morquio MPS IV together is estimated to be one in 200,000 live births worldwide.

Symptoms:

Typically, symptoms begin to appear at around 18 months of age. The wide range of symptoms for Morquio MPS IV Type A is classified into the following sections:

Skeletal Symptoms:

Skeletal symptoms appear at around 18 months of age, when growth also begins to decline. Children with a severe form of this disorder typically stop growing at around eight years of age, with their final height measuring between three and four feet.

Curvature of the spinal column creates deformity of the rib cage and chest. This chest deformation results in restricted breathing as well as serious chest and lung infections. Other bone abnormalities are common, such as dislocated hips or shoulders, knock-knees, weak wrists, loose joints, scoliosis as well as an unstable neck, which can lead to nerve damage or paralysis.

Facial Symptoms:

A short neck, wide mouth, enlarged tongue, poorly formed teeth, and flattened nose bridges are some of the facial characteristics of children affected with Morquio type A/MPS IV A.

Neurological Symptoms:

Corneal clouding and hearing loss are two neurological symptoms associated with this disorder.

Organ damage:

Leaky or blocked heart valves, heart murmurs, hernias as well as an enlarged liver and spleen are symptoms associated with this disorder.

Inheritance Pattern:

Morquio type A/MPS IV A is an autosomal recessive disorder.

Life Expectancy:

Life expectancy for individuals with mild Morquio type A/MPS IV A is 60 years of age. Life expectancy for individuals with severe Morquio type A/MPS IV A is 30 years of age or younger.

Diagnosis and Testing:

A urine test can provide a diagnosis of Morquio type A/MPS IV A. It measures increased levels mucopolysaccharides, the type of sugar chain in the lysosome that accumulates as a result of the malfunctioning enzyme. A urine test is routinely followed by a blood test or skin biopsy, which will reveal reduced activity of the enzyme N-acetylgalactosamine 6-sulfatase. Prenatal screening is available to examine N-acetylgalactosamine 6-sulfatase activity in the fetus. Genetic testing is also available in combination with these diagnostic tests to look for the mutation that causes Morquio type A/MPS IV A.

Treatment:

There is no cure for Morquio type A/MPS IV A. In most cases, treatment is limited to reducing or controlling the symptoms of this disorder by making sure that neurologists, ophthalmologists, orthopedists, cardiologists and genetic counselors are consulted routinely. Although a diet low in sugar does not reduce the levels of mucopolysaccharides in the body, some parents avoid certain foods like sugar and artificial additives that may increase hyperactivity. Dairy may also be avoided to reduce the amount of mucus production or if diarrhea is present. Exercise is highly encouraged to maintain muscle strength, as is maintaining proper dental hygiene practices to reduce further tooth decay.

Medications to reduce joint pain, and antibiotics to treat pulmonary infections are prescribed as needed.

A cervical spine fusion may be recommended to control the unstable neck characteristic of this disorder. Hip and/or knee replacement surgery may also be necessary. A back brace is often used to slow the progression of scoliosis and delay the necessity of back surgery.

Bone marrow transplants have been utilized as a possible treatment option but have not proven effective at reducing the progression of the disorder or at halting its course. There is hope that enzyme replacement therapy will produce a cure in the coming years.

Patient Groups:

International Morquio Organization
8164 W. Circulo De Los Morteros
Tucson, AZ 85743
www.morquio.com
tel: (520) 744-2531
fax: (520) 744-2535
Mary Smith, President
mbs85705@yahoo.com

National MPS Society
4220 NC Highway 55, Suite 140
Durham NC, 27713
www.mpssociety.org
tel: (919) 806-0101
fax: (919) 806-2005
Barbara Wedehase, Executive Director
info@mpssociety.org

Morquio Type B/MPS IVB
Definition:

Morquio type B/MPS IV B is caused by a mutated gene that manufactures the enzyme, beta-galactosidase. This enzyme is needed to break down a specific type of sugar or mucopolysaccharides called keratan sulfate. This sugar is used to build connective tissues and bones in the body. Individuals affected with Morquio type B/MPS IV B have too many keratan sulfates in their system because the enzyme, beta-galactosidase, needed to break down keratan sulfate, is absent or present in only very small quantities. The excessive amounts of keratan sulfate lead to the clinical symptoms of Morquio type B/MPS IV B.

There are two forms of Morquio MPS IV, Type A and Type B. Type A is more common of the two forms. There is little difference in the clinical symptoms between both forms of the disorder and a wide range of symptoms associated with each form.

The incidence of both forms of Morquio MPS IV is estimated to be 1 in 200,000 live births worldwide.

Symptoms:

The wide range of symptoms for Morquio type B/MPS IV B have been classified into sections. Typically, symptoms begin to appear at around 18 months of age.

Skeletal Symptoms:

Skeletal symptoms appear at around 18 months of age, when growth also begins to decline. Children with a severe form of this disorder typically stop growing around eight years of age, their final height measuring between three and four feet.

Curvature of the spinal column leads to deformity of the chest Restricted breathing as well as serious chest and lung infections are consequences of this chest deformation. Other bone abnormalities such as dislocated hips or shoulders, knock-knees, weak wrists, loose joints, scoliosis and an unstable neck, leading to nerve damage or paralysis, are common symptoms of this disorder.

Facial Symptoms:

A short neck, wide mouth, enlarged tongue, poorly formed teeth and flattened nose bridges are some of the facial characteristics of children affected with Morquio type B/MPS IV B.

Neurological Symptoms:

Corneal clouding and hearing loss are two neurological symptoms associated with this disorder.

Organ damage:

Leaky or blocked heart valves and heart murmurs are symptoms of thisdisorder, as are hernias and/or an enlarged liver and spleen.

Inheritance Pattern:

Morquio type B/MPS IV B is an autosomal recessive disorder.

Life Expectancy:

Life expectancy for individuals afflicted with mild Morquio type B/MPS IV B is 60 years of age. The life expectancy for individuals affected with severe Morquio type B/MPS IV B is 30 years of age or younger.

Diagnosis and Testing:

A urine test may determine whether an individual has Morquio type B/MPS IV B. The test measures increased levels mucopolysaccharides, the type of sugar chain in the lysosome that accumulate as a result of the malfunctioning enzyme. A urine test is routinely followed by a blood test or skin biopsy, which will reveal reduced activity of the enzyme beta-galactosidase. Prenatal screening is available to examine beta-galactosidase activity in the fetus. Genetic testing is also available in combination with these diagnostic tests to look for the mutation that causes Morquio type B/MPS IV B.

Treatment:

There is no cure for Morquio type B/MPS IV B. In most cases, treatment is limited to reducing or controlling the symptoms of this disorder by consulting on a regular basis with neurologists, ophthalmologists, orthopedists, cardiologists and genetic counselors. Although a diet low in sugar does not reduce the levels of mucopolysaccharides in the body, some parents avoid certain foods like sugar and artificial additives that may increase hyperactivity. Dairy products may also be avoided to reduce the amount of mucus production or if diarrhea is present. Exercise is highly encouraged to maintain muscle strength, along with maintaining proper dental hygiene practices to reduce further tooth decay.

Medications to reduce joint pain and antibiotics to treat pulmonary infections are prescribed as needed.

A cervical spine fusion is may result in control of the unstable neck that is characteristic of this disorder. Hip and/or knee replacement surgery may also be necessary. A back brace may slow the progression of scoliosis and delay the necessity of back surgery.

Bone marrow transplants have been used as possible treatment option but have not proven effective at reducing the progression of this disorder or halting its course. Enzyme replacement therapy is being researched as a possible cure in the future.

Patient Groups:

National MPS Society
4220 NC Highway 55, Suite 140
Durham NC, 27713
www.mpssociety.org
tel: (919) 806-0101
fax: (919) 806-2005
Barbara Wedehase, Executive Director
info@mpssociety.org

MPS IX Hyaluronidase Deficiency
Definition:

MPS IX (Hyaluronidase deficiency) is a condition that was first noted in 1996. It is caused by a deficiency of the enzyme, hyaluronidase. This enzyme is used in the lysosome to break down a complex string of sugars known as Glycosaminoglycans (GAGs), often referred to as mucopolysaccharides. In individuals inflicted with MPS IX , the GAG accumulates resulting in symptoms of this disorder. In this disorder, the accumulation of these sugars primarily affects the joints.

To date, there has been one reported case of MPS IX.

Symptoms:

Symptoms include nodular soft-tissue masses located around joints, with periodic episodes of painful swelling of the masses . This pain spontaneously ends within three days.

Other symptoms of this disease include a flattened nose bridge and a cleft palate. Short stature is also a noted symptom. Intelligence has not been noted in MPS IX.

Inheritance Patterns:

MPS IX is an autosomal recessive disorder.

Life Expectancy:

Given the rare occurrence of this disorder, life expectancy is not known at this time.

Diagnosis and Testing:

An enzyme assay, which measures the amount of the enzyme, hyaluronidase in cultured tissue cells, confirms a diagnosis of MPS IX. Individuals affected by MPS IX would have very low amounts of this enzyme in their cells.

Pelvic radiography can identify soft-tissue masses and bone erosion. Recently, the mutated gene and its corresponding chromosome have been identified.

Treatment:

Since there has been only one reported case of MPS IX, and the individual had a very mild type of this disorder, very few treatments have been developed. Regular radiography scans are recommended to measure the presence of soft-tissue masses and of bone erosion.

Patient Groups:

National MPS Society
4220 NC Highway 55, Suite 140
Durham NC, 27713
www.mpssociety.org
tel: (919) 806-0101
fax: (919) 806-2005
Barbara Wedehase, Executive Director
info@mpssociety.org

MPS VI Maroteaux-Lamy
Definition:

MPS VI or Maroteaux-Lamy is a rare disorder that results when an individual has very little or is missing the enzyme Arylsulfatase B (ASB). ASB is used in the lysosome to break down a complex string of sugars known as Glycosaminoglycans (GAGs), often referred to as mucopolysaccharides. In individuals with MPS VI, the GAG accumulates resulting in symptoms of the disorder. GAGS are vital building blocks in the structure of the skin, bones and organs.

MPS VI is very rare, affecting approximately 1,100 people in the “developed” world. There are between 50 and 300 patients afflicted with MPS VI in the United States.

Symptoms:

As more GAG accumulates in the body, symptoms of this disease become more progressive. Similar to other MPS disorders, there is no one hallmark sign or symptom that characterizes MPS VI. The symptoms, widespread in onset, severity and in type, can manifest in early infancy, adolescence or in adulthood, depending upon how much unrecycled GAG accumulates in the cells.

In regard to skeletal symptoms, they can include, short stature, bone abnormalities, stiff joints and coarse facial features. Growth typically stops by the time the affected individual reaches 10 years of age.

Symptoms specific to the organs include an enlarged liver and/or spleen, distended abdomen, hernias and heart murmurs. Other symptoms may include difficulty breathing, noisy breathing, and an increase in ear and sinus infections. Corneal clouding is also a common symptom of MPS VI. Blindness and paralysis can also occur.

Unlike many closely related MPS disorders, MPS VI does not affect intelligence.

Inheritance Patterns:

MPS VI is an autosomal recessive disorder.

Life Expectancy:

Life expectancy is in the teen years for individuals affected with a severe form of MPS VI. Individuals inflicted with a more mild form of the disorder can expect to live longer.

Diagnosis and Testing:

Diagnosis of MPS VI is often delayed or the disease, misdiagnosed. Two tests are used to diagnose MPS VI. A urine analysis measures the amount of GAG in the urine. Individuals with MPS VI have abnormally large amounts of GAG in their urine. An enzyme assay measuring the amount of the enzyme, arylsulfatase B in blood or tissue samples, confirms a diagnosis. Individuals with MPS VI have very low amounts of this enzyme in their cells.

Prenatal diagnosis is also available.

Treatment:

There is no cure for MPS VI but there are many treatments that can be administered to prevent permanent tissue damage, to delay symptom progression and to improve the quality of life for affected individuals.

Physical therapy is often used to improve joint flexibility. Surgery may correct skeletal abnormalities, remove tonsils or improve respiratory problems, chronic ear infections and vision issues.

Stem cell transplants have been used in few cases with limited success. Enzyme replacement therapy is a treatment option that has been used with limited success. Clinical trials show significant improvement with respect to distance walked and stairs climbed in a set amount of time.

Patient Groups:

National MPS Society
4220 NC Highway 55, Suite 140
Durham NC, 27713
www.mpssociety.org
tel: (919) 806-0101
fax: (919) 806-2005
Barbara Wedehase, Executive Director
info@mpssociety.org

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MPS VII Sly Syndrome
Definition:

MPS VII or Sly syndrome is a rare disorder that results when an individual has very little or is missing the enzyme beta-glucuronidase. This enzyme is used in the lysosome to break down a complex string of sugars known as Glycosaminoglycans (GAGs), often referred to as mucopolysaccharides. In individuals inflicted with MPS VII, the GAG accumulates and results in symptoms of this disorder. GAGS are vital building blocks in the structure of the skin, bones and organs.

MPS VII is very rare, affecting approximately one in every 1,300,000 live births.

Symptoms:

The neonatal form of MPS VII is one of the few lysosomal storage disorders with clinical manifestations in utero or at birth. In this extreme case, the affected infant develops a condition known as hydrops fetalis in which the child retains unusually large amounts of fluid in his or her body.

As GAG accumulates the symptoms become more progressive.

There is no one hallmark sign or symptoms that characterizes MPS VII. The symptoms, which are widespread in onset, severity and in type, can manifest in early infancy, adolescence or during adulthood, depending upon how much GAG accumulates in the cells.

Coarse facial features including a bulging forehead, an enlarged tongue and lips and a flattened nose bridge are often seen in individuals inflicted with this disorder. Physical growth in height is significantly lower than average in affected individuals.

As the GAG and related materials accumulate in the brain, between one and three years of age, a slow deterioration of intelligence and mental capacities may appear. Some individuals with a mild form of MPS VII may be able to read and walk.

Chronic ear infections, hearing difficulties and sleep apnea are other common symptoms of this disease. Symptoms specific to the organs include an enlarged liver and/or spleen, distended abdomen, hernias and heart murmurs. Other symptoms may include difficulty breathing, noisy breathing, and an increase in sinus infections. Corneal clouding is a common symptom of MPS VII. Bowel problems including diarrhea and constipation are also common.

A poorly formed spinal cord, an unstable neck, scoliosis, stiff joints, stubby hands, thick skin and an excess of hair on the face and back may also occur.

Inheritance Patterns:

MPS VII is an autosomal recessive disorder.

Life Expectancy:

Life expectancy is younger than two to three months of age for children inflicted with an extreme case of MPS VII. Life expectancy for those with milder forms of MPS VII is varied: Some can live until their teenaged years while others can live to adulthood.

Diagnosis and Testing:

Two tests are used to determine whether a person has MPS VII. A urine measures the amount of GAG in the urine. Individuals with MPS VII have abnormally large amounts of GAG in their urine. An enzyme assay measures the amount of the enzyme, beta-glucuronidase in blood or tissue samples, confirming a diagnosis. Individuals with MPS VII have very low amounts of this enzyme in their cells.

Prenatal diagnosis is also available.

Treatment:

There is no cure for MPS VII, but there are many treatments that can be administered to delay symptom progression and to improve the quality of life in affected individuals.

Some parents find that putting their child on a diet reducing dairy, sugar and additives can improve gastrointestinal and hyperactivity symptoms experienced by affected children.

Physical therapy may improve joint flexibility and range of motion.

Surgical procedures may improve respiratory problems as well as chronic ear infections. Cornea transplant is also an effective treatment.

Patient Groups:

National MPS Society
4220 NC Highway 55, Suite 140
Durham NC, 27713
www.mpssociety.org
tel: (919) 806-0101
fax: (919) 806-2005
Barbara Wedehase, Executive Director
info@mpssociety.org

Mucolipidosis I/ Sialidosis
Definition:

Sialidosis is characterized by a deficiency of the digestive enzyme, alpha-neuraminidase. The lack of this enzyme results in an abnormal accumulation of complex carbohydrates known as mucopolysaccharides, and of fatty substances known as mucolipids. Both of these substances accumulate in bodily tissues. There are four types of Sialidosis: Type I, Type II congenital, Type II infantile, and Type II juvenile. Each type of Sialidosis is characterized by the age of onset and by the type of physical and mental manifestations of this disorder. Type I affects both sexes with equal frequency.

Symptoms:

Symptoms for Sialidosis Type I have a variable range of onset, presenting anywhere from eight to 25 years of age. Symptoms may include sudden involuntary muscle contractions, red spots in the eyes, as well as epilepsy, visual problems, and ataxia. Smoking and menstruation may aggravate the involuntary muscle contractions that are associated with this disorder. Over time, vision decreases and the involuntary muscle contractions can interfere with walking.

Symptoms of Sialidosis Type II congenital are either present at birth or appear within the first year of life. Symptoms include red spots in the eyes as well as detiorating vision over time. An enlargemetn of the spleen and liver, sudden involuntary muscle contractions, coarse facial features, skeletal malformations such as hip dislocation, lack of muscle tone and/or mild mental retardation may also occur.

Symptoms of the Type II infantile form of Sialidosis begin within the first year of life. Mental retardation, coarse facial features, skeletal abnormalities, cherry red spots in the eye, renal complications, and/or spleen or liver enlargement may appear.

Symptoms of the Type II juvenile form of Sialidosis begin anywhere from two to 20 years of age. Coarse facial features, sudden involuntary muscle contractions and cherry red spots are among symptoms of this disorder. Unique to this form of the disorder is the appearance of red to purplish growths on the skin.

Inheritance Pattern:

Sialidosis is an autosomal recessive disorder.

Diagnosis and Testing:

Diagnosis of Sialidosis involves a urine test measuring increased levels oligosaccharides, the type of sugar chains in the lysosome that accumulate as a result of the malfunctioning enzyme. A urine test is routinely followed by a blood test or skin biopsy, which will reveal reduced activity of the enzyme alpha- neuraminidase. Prenatal screening is available to examine alpha- neuraminidase activity in the fetus. Genetic testing is also available in combination with these diagnostic tests to look for the mutation that causes Sialidosis.

Life Expectancy:

Early onset forms of Life Sialidosis are associated with death in early childhood. Later onset forms may be compatible with adult survival.

Treatment:

There is no cure for Sialidosis. Treatment is limited to reducing or controlling the symptoms of this disorder by a patient’s neurologists, ophthalmologists and genetic counselors. Neurologists may assist in controling seizures or nervous system complications. An ophthalmologist may monitor vision loss, and physical and occupational therapists offer help in maintaining muscle movement and reducing muscle discomfort.

Patient Groups:

International Society for Mannosidosis & Related Diseases
P.O. Box 328
Dexter, MI 48130
www.mannosidosis.org
tel: (734) 449-8222
fax: (734) 449-2282
Terri Klein, Executive Director
info@ismrd.org

Mucolipidosis IIIC
Definition:

Mucolipidosis IIIC is also known as variant pseudo-Hurler polydystrophy and results from mutations in the N-Acelylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) y-subunit gene. This enzyme attaches the appropriate targeting signal to lysosomal enzymes. Because of its deficiency multiple lysosomal enzymes are deficient in the lysosome, leading to the accumulation of many classes of large molecules.

Symptoms:

Symptoms for Mucolipidosis IIIC begin in childhood and can vary considerably. This disorder is characterized by metabolic bone disease in which more bone is broken down than being built. This results in brittle bones and mobility difficulties for individuals afflicted with this disorder. Some individuals with Mucolipidosis IIIC may show mobility problems as early as four or five years of age, others at 10 years of age.

Symptoms for Mucolipidosis IIIC include carpal tunnel syndrome, dental complications, enlarged gums, stunted growth, corneal clouding and ear infections. Learning disabilities may be present but many individuals with Mucolipidosis IIIC have a normal intelligence. Orthopedic complications like scoliosis, claw-hands, short stature, stiff and painful joints, and other skeletal abnormalities are also present.

Inheritance Pattern:

Mucolipidosis IIIC is an autosomal recessive disorder.

Life Expectancy:

Many individuals with Mucolipidosis IIIC disease live into adulthood.

Diagnosis and Testing:

An enzyme assay, which measures the amount of N-Acetylglucosamine-1-phosphotransferase, typically confirms a diagnosis. White blood cells are examined to measure the amount of this enzyme. If they measure low in comparison to normal levels, a diagnosis can be made. A skin biopsy for this disorder measures the same enzyme in a cultured tissue sample. Low levels of N-Acetylglucosamine-1-phosphotransferase, in comparison to the normal standards may confirm a diagnosis.

The gene responsible for this disorder has been identified, rendering accurate diagnosis, prenatal diagnosis and carrier testing possible.

Treatment:

There is no cure for Mucolipidosis IIIC. Treatment is limited to controlling or reducing symptoms associated with this disorder. Physio-therapy, particularly hydrotherapy, has proven effective at relieving muscle stiffness and to increase affected individual’s mobility. Crutches, a wheelchair or scooters are treatment options as this metabolic bone disease progresses. Inserting rods in the spine to stabilize the vulnerable areas can treat scoliosis.

Patient Groups:

International Society for Mannosidosis & Related Diseases
P.O. Box 328
Dexter, MI 48130
www.mannosidosis.org
tel: (734) 449-8222
fax: (734) 449-2282
Terri Klein, Executive Director
info@ismrd.org

National MPS Society
4220 NC Highway 55, Suite 140
Durham NC, 27713
www.mpssociety.org
tel: (919) 806-0101
fax: (919) 806-2005
Barbara Wedehase, Executive Director
info@mpssociety.org

Mucolipidosis IV
Definition:

Mucolipidosis IV is a rare, inherited, neurodegenerative disorder caused by a deficiency of a transport channel receptor protein. This deficiency results in the accumulation of certain fatty substances known as mucolipids and mucopolysaccharides, which are long sugar chains within the cells of many tissues in the body.

In 2000, the gene responsible for this disorder was identified. Three mutations were found to result in the clinical symptoms of Mucolipidosis IV. Two of these mutations account for more than 90% of the Mucolipidosis IV cases found in the Ashkenazi Jewish population. As a result of this discovery, accurate carrier testing and prenatal diagnosis is available for families with a history of the disorder and for couples of Ashkenazi Jewish descent.

More than 80% of those diagnosed with Mucolipidosis IV are from the Ashkenazi Jewish population. In addition, it is estimated that one in 90 Ashkenazi Jews carry the gene for Mucolipidosis IV.

Since its first medical classification in 1974, seventy cases of Mucolipidosis IV have been reported worldwide.

Symptoms:

The two most characteristic symptoms of Mucolipidosis IV are psychomotor retardation or delayed development in muscle movement and coordination, and eye abnormalities including corneal clouding and a degeneration of the retina. By the end of the affected child’s first year of life, signs of the degeneration of the central nervous system appear. The affected child displays difficulties sitting, and many do not learn to walk. By age two or three, many children affected with this disorder become progressively mentally retarded.

Symptoms include agenesis of the corpus callosum, the failure of the band of tissue connecting the two hemispheres of the brain, to develop.

Inheritance Pattern:

Mucolipidosis IV is an autosomal recessive disorder.

Life Expectancy:

Life expectancy is unknown. Individuals afflicted with Mucolipidosis IV who are 45 years of age have been identified.

Diagnosis and Testing:

Genetic testing can confirm a diagnosis in individuals suspected of having Mucolipidosis IV. Prenatal genetic testing is also available. Additionally, tissue samples can be examined under an electron microscope to search for storage bodies, known as cytoplasmic inclusions, in the cells. If these storage bodies are found, a diagnosis of this disorder may result.

Treatment:

There is no cure for Mucolipidosis IV. Treatment is limited to controlling or reducing symptoms associated with this disorder. Physical, occupational, and speech therapies may improve the affected individual’s motor and language skills. Genetic counseling is available as well.

Patient Groups:

Mucolipidosis IV Foundation
719 East 17th Street
Brooklyn, NY 11230
www.ml4.org
tel: (718) 434-5067
Randy Yudenfriend, President
ML4www@aol.com

Multiple sulfatase deficiency
Definition:

Multiple Sulfatase Deficiency is a rare, inherited metabolic disorder in which all sulfatase enzymes are deficient or do not work properly. These enzymes are responsbile for breaking down and recycling complex sulfate-containing sugars from lipids and mucopolysaccharides within the lysosome. The accumlation of lipids and mucopolysaccharides inside the lysosome results in symptoms associated with this disorder. Worldwide, forty cases of Multiple Sulfatase Deficiency have been reported to date.

Symptoms:

Symptoms of this disorder commonly appear between one and two years of age. Symptoms include mildly coarsened facial features, deafness, and an enlarged liver and spleen. Abnormalities of the skeleton, such as a curving of the spine and breast bone may occur. The skin of individuals afflicted with this disorder, is typically dry. Children affected by this disorder develop more slowly than normal and may display delayed speech and walking skills.

Inheritance Pattern:

Multiple Sulfatase Deficiency is an autosomal recessive disorder.

Life expectancy:

Life expectancy for Multiple Sulfatase Deficiency is commonly before 10 years of age.

Diagnosis and Testing:

A test is performed to measure elevated levels of mucopolysaccharides and others sugars in the urine. White blood cells or a cultured tissue sample are also meaured to detect low levels of the sulfatase enzymes. Prenatal testing is available if it is known that a family member is affected with Multiple Sulfatase Deficiency.

Treatment:

There is no cure for Multiple Sulfatase Deficiency. Treatment is limited to controlling or reducing the symptoms associated with this disorder. A hearing aid may improve hearing; physical and speech therapy may also help to improve the affected individual’s motor and speech skills. Rods can be surgically inserted in the spine to treat scoliosis.

Niemann-Pick disease Type A
Definition:

Niemann-Pick Type A, sometimes referred to as infantile Niemann-Pick disease, results from deficient activity of acid sphingomyelinase (ASM), which metabolizes sphingomyelin. In Niemann-Pick type A, sphingomyelin accumulates within cells, eventually leading to their death. Children with Niemann-Pick A have very little residual activity of ASM.

Niemann-Pick Disease Types A and B both result from deficient activity of ASM. The degree of deficiency is most marked in Niemann-Pick A and less severe in Niemann-Pick B. Niemann-Pick C does not result from an enzyme defect but is caused by mutations in two separate genes, both of which affect the trafficking of lipids within cells.

Niemann-Pick Disease Type A affects all races and ethnicities but is more common among the Ashkenazi Jewish population. The carrier frequency for either Niemann-Pick Disease Type A or B is estimated at one in one thousand Ashkenazi Jews. Niemann-Pick Type A is more frequent than Niemann-Pick Type B and accounts for 60% of the cases of ASM deficiency.

Symptoms:

The symptoms of Niemann-Pick Type A manifest in the first few months of life. At six months of age, feeding difficulties occur, along with progressive loss of early motor skills and enlargement of the abdominal organs. The skin may also discolor, taking on a brownish to yellowish hue. Approximately half of affected children will develop a cherry-red spot in their eye. As the disease progresses, motor and mental functions decline.

Inheritance Pattern:

Niemann-Pick Type A is an autosomal recessive disorder.

Life Expectancy:

Life expectancy for Niemann-Pick Type A is commonly between two and three years of age.

Diagnosis and Testing:

Niemann-Pick Disease Type A is diagnosed by measuring the activity of acid sphingomyelinase (ASM) in blood cells or tissue biopsies. Typically, patients with Niemann-Pick A have less than one percent of normal activity. Prenatal screening can be performed using enzyme assay on fetal fluid or cells but is most accurate when molecular analysis for mutation in the ASM gene is performed.

Treatment:

There is no effective treatment for children affected by Niemann-Pick Type A. Symptom management includes controlling the associated respiratory, cardiovascular, and gastroenterology symptoms. Nutritional and physical therapy are additional supportive treatment options to assist with feeding difficulties and the decline of motor skills in children affected by Niemann-Pick disease Type A.

Patient Groups:

National Niemann-Pick Disease Foundation
P.O. Box 49
401 Madison Ave. Ste B
Fort Atkinson, WI 53538
www.nnpdf.org
tel: (920) 563-0930
fax: (920) 563-0931
Nadine Hill, Director of Family Services
nnpdf@nnpdf.org

National Tay-Sachs & Allied Diseases Association
2001 Beacon Street, Suite 204
Boston, MA 02135
www.ntsad.org
tel: (800) 906-8723
fax: (617) 277-0134
Sue R. Kahn, Executive Director
info@ntsad.org

Niemann-Pick disease Type B
Definition:

Niemann-Pick Type B is caused by the deficiency of the enzyme, acid sphingomyelinase (ASM) required to metabolize a lipid called sphingomyelin. If ASM is absent or functioning improperly, sphingomyelin cannot be broken down effectively and instead builds up within the cell. This accumulation eventually causes cell death and the major organ systems to fail. Those individuals affected with Niemann-Pick Type B have approximately 10% of the normal level of ASM in their bodies.

There are three separate forms of Niemann-Pick disease. Types A and Type B are genetically related and are disorders of lipid metabolism. The third type, Type C, is a disorder of lipid transport. Athough all races and ethnicities are affected by Niemann-Pick Type B, there is a higher incidence of the acute infantile form of this disorder within the Ashkenazi Jewish population. It is estimated that one in 1000 Ashkenazi Jews is a carrier for either Niemann-Pick Disease Type A or Type B. Worldwide, cases of Niemann-Pick Type A and B together total approximately 1,200, but the incidence of Type B as an individual disorder is unknown.

Symptoms:

The symptoms of Niemann-Pick Type B manifest during pre-teen years. Symptoms include an enlarged liver and spleen. The affected child experiences progressive organ enlargement, poor growth and susceptibility to respiratory infections ,but rarely displays neurological problems.

Inheritance Pattern:

Niemann-Pick Type B is an autosomal recessive disorder.

Life Expectancy:

Individuals with Niemann-Pick Type B typically live into adulthood.

Diagnosis and Testing:

Patients with Niemann-Pick Type B typically have less than 10 percent of normal activity of ASM but more than 3 to 5 percent activity. Prenatal diagnosis is possible by measuring enzyme activity or by identifying mutations in the ASM gene.

Treatment:

Bone marrow transplantation has been met with some success in patients with Niemann-Pick Type B. Some affected individuals may require supplemental oxygen because of decreased lung function. Enzyme replacement therapy is currently under investigation.

Patient Groups:

National Niemann-Pick Disease Foundation
P.O. Box 49
401 Madison Ave. Ste B
Fort Atkinson, WI 53538
www.nnpdf.org
tel: (920) 563-0930
fax: (920) 563-0931
Nadine Hill, Director of Family Services
nnpdf@nnpdf.org

National Tay-Sachs & Allied Diseases Association
2001 Beacon Street, Suite 204
Boston, MA 02135
www.ntsad.org
tel: (800) 906-8723
fax: (617) 277-0134
Sue R. Kahn, Executive Director
info@ntsad.org

Niemann-Pick disease Type C
Definition:

Niemann-Pick Disease Type C is very different than Type A or B. It is caused by an inability to transport cholesterol and other lipids properly within the cell, whereas Type A and Type B are caused by an enzyme deficiency that leads to an accumulation of a specific lipid inside the cell. Consequently in Type C, excessive amounts of cholesterol accumulate within the liver and spleen, and excessive amounts of other lipids accumulate in the brain.

The incidence of Niemann-Pick Disease Type C is estimated to be 1 in 150,000 people worldwide. There is a higher incidence of Niemann-Pick Type C among the Spanish-American population of southern New Mexico and Colorado.

The classic form of Niemann-Pick Disease Type C is more than half of all Niemann-Pick Disease Type C cases. There are infantile and adult forms of this disorder.

The gene designated NPC 1 was identified in 1997. Mutations in this gene cause approximately 95 percent of Niemann-Pick Disease Type C cases. A second gene, NPC 2, was identified in 2000. This accounts for the remaining cases of Niemann-Pick Disease Type C.

Symptoms:

The age of symptom onset and the rate at which the disorder progresses vary widely for Niemann-Pick Type C. Symptoms may appear as early as a few months of age or as late as adulthood. Symptoms include the inability to move one’s eyes up and down, an enlarged liver or spleen, or jaundice. In early stages of this disease, commonly one or two symptoms may appear. Typically, neurological symptoms begin appearing between the ages of 4 and 10. Generally, the later the onset of neurological symptoms, the slower the disorder will progress.

Symptoms for individuals who have a form of Niemann-Pick Disease Type C that occur later in childhood or in early adulthood are marked by psychiatric symptoms, slowing of speech, and ataxia or uncoordinated mobility.

Inheritance Pattern:

Niemann-Pick Type C is an autosomal recessive disorder.

Life Expectancy:

Life expectancy for individuals with the infantile form of Niemann-Pick Type C is younger than 20 years of age. Individuals with the adult form can live into adulthood.

Diagnosis and Testing:

A diagnosis of Niemann-Pick Type C is made using cells cultured from a skin biopsy. The tests performed include measurement of cholesterol esterification and staining to show the accumulation of free cholesterol within cells.

More than 250 mutations have been identified in the NPC 1 and 2 genes. As a result, the diagnosis cannot be made by direct molecular testing although this is used to confirm the biochemical disgnosis described above.

Treatment:

There is no curative treatment recognized for Niemann-Pick Type C. A trial of low cholesterol diet and cholesterol-lowering medications does not appear to influence the course of disease, and studies have shown no affect on the neurological progression. More recently, a trial of substrate reduction therapy has shown promising result.

Patient Groups:

Ara Parseghian Medical Research Foundation
3530 E. Campo Abierto, Suite 105
Tucson, AZ 85718
www.parseghian.org
tel: (520) 577-5106
fax: (520) 577-5212
Glen Shepherd, Executive Director
gshepherd@parseghian.org

National Niemann-Pick Disease Foundation
P.O. Box 49
401 Madison Ave. Ste B
Fort Atkinson, WI 53538
www.nnpdf.org
tel: (920) 563-0930
fax: (920) 563-0931
Nadine Hill, Director of Family Services
nnpdf@nnpdf.org

National Tay-Sachs & Allied Diseases Association
2001 Beacon Street, Suite 204
Boston, MA 02135
www.ntsad.org
tel: (800) 906-8723
fax: (617) 277-0134
Sue R. Kahn, Executive Director
info@ntsad.org

Neuronal Ceroid Lipofuscinoses
CLN6 Disease - Atypical Late Infantile
Definition:

Atypical late infantile CLN6 disease is part of a group of progressive degenerative neurometabolic disorders known as neuronal ceroid lipofuscinoses (NCLs). NCLs are characterized by an abnormal accumulation of lipopigaments, subtances combined of fats and proteins within the brain’s nerve cells, eyes, skin, muscle, and within other tissues throughout the body.

Although this disorder has clinical symptoms similar to other NCLs, it is distinct because its cause is known. The cause of a number of NCLs remains nebulous. Atypical late infantile CLN6 disorder is caused by a mutation on the CLN6 gene, which leads to an accumulation of transmembrane proteins in the cells. The gene CLN6 provides the code for a protein known as linclin, which plays an important role in the function of cellular membranes and in providing energy to nerve cells. This mutation essentially eliminates the function of the CLN6 gene and gives rise to the symptoms of this disorder. More than 18 mutations on the CLN6 gene have been identified. This condition causes nerve cells, found in the brain, retina, and in the central nervous system to die.

Atypical late infantile CLN6 predominately affects individuals of Portuguese, Indian, Pakistani, or Czech origin, although the exact prevalence figures are not known. It is estimated that the NCLs affect two to four of every 100,000 live births in the United States.

Symptoms:

Symptoms of Atypical late infantile CLN6 begin between 18 months to four years of age. Blindness, seizures, and loss of cognition are symptoms of this disorder. Loss of motor skills typically occurs between four and 10 years of age. As the disorder progresses, the individual affected becomes incapacitated.

Inheritance Pattern:

Atypical late infantile CLN6 is an autosomal recessive disorder.

Life Expectancy:

Life Expectancy for Atypical late infantile CLN6 is between 10 and 30 years of age.

Diagnosis and Testing:

A DNA analysis confirms a mutation on the CLN6 gene, hence a diagnosis of Atypical late infantile CLN6. For this analysis, blood or tissue sample is tested from individuals who are suspected of having the disorder and/or from members of families wherein a carrier of the CLN6 gene has been identified. Prenatal screening is also available.

Treatment:

There is no cure for Atypical late infantile CLN6. Treatment is limited to reducing or controlling the symptoms of this disorder. Neurologists are able to help control seizures or nervous system complications. An ophthalmologist can monitor vision loss, and physical and occupational therapists can assist the affected individual to maintain muscle movement and reduce muscle discomfort.

As the CLN6 gene has been mapped, genetic research is focused on yielding a greater understanding of the disorder’s mechanism and a discovery of therapies to prevent the loss of brain cells, a characteristic of this disorder.

CLN6 Disease - Late Onset variant
Definition:

Late onset variant CLN6 disorder is part of a group of progressive degenerative neurometabolic disorders known as neuronal ceroid lipofuscinoses (NCLs). NCLs are characterized by an abnormal accumulation of lipopigaments, which are substances combined of fats and proteins within the brain’s nerve cells, eyes, skin, muscle, and within other tissues throughout the body.

The mutated gene in variant late infantile NCL was recently cloned. This breakthrough allows for carrier testing, for accurate diagnosis, and fuels promise for a future cure. Late onset variant CLN6 disorder is caused by a mutation on the CLN6 gene, which leads to an accumulation of transmembrane proteins in the cells. The gene CLN6 provides the code for a protein known as linclin. Linclin plays an important role in the function of cellular membranes and in providing energy to nerve cells. This mutation essentially eliminates the function of the CLN6 gene and gives rise symptoms of this disorder. More than 18 mutations on the CLN6 gene have been identified. This disorder causes nerve cells, found in the brain, retina, and in the central nervous system, to die.

Late onset variant CLN6 predominately affects those of Indian ancestry as well as descendants of Spanish settlers in Costa Rica, although the exact prevalence among those groups are not known. It is estimated that the NCLs affect two to four of every 100,000 live births in the United States.

Symptoms:

Symptoms of Late onset variant CLN6 begin between five to seven years of age. Seizures and a loss of motor skills appear first. Blindness occurs after initial symptoms appear. As the disorder progresses, cognition declines and the affected individual becomes increasingly incapacitated.

Inheritance Pattern:

Early juvenile CLN6 is an autosomal recessive disorder.

Life Expectancy:

Life Expectancy for Late onset variant CLN6 is during the mid 20s.

Diagnosis and Testing:

A DNA analysis may be utilized to confirm a mutation on the CLN6 gene and a diagnosis of Late onset variant CLN6. For this test, blood or a tissue sample is analyzed from individuals suspected of having the disorder or from members of families wherein a carrier of the CLN6 gene has been identified. Prenatal screening is also available.

Treatment:

There is no cure for Late onset variant CLN6. Treatment is limited to reducing or controlling the symptoms of this disorder. Neurologists can assist in controlling seizures or nervous system complications. An ophthalmologist can monitor vision loss, and physical and occupational therapists can help the affected individual maintain muscle movement and reduce muscle discomfort.

CLN6 Disease - Early Juvenile
Definition:

Early juvenile CLN6 disease is part of a group of progressive degenerative neurometabolic disorders known as neuronal ceroid lipofuscinoses (NCLs). NCLs are characterized by an abnormal accumulation of lipopigaments, subtances combined of fats and proteins within the brain’s nerve cells, eyes, skin, muscle, and within other tissues throughout the body.

Although this disorder has clinical symptoms similar to other NCLs, it is distinct because its cause is known. The cause of a number of NCLs still remains nebulous. Early juvenile CLN6 disorder is caused by a mutation on the CLN6 gene which leads to an accumulation of transmembrane proteins in the cells. The gene CLN6 provides the code for a protein known as linclin, which plays an important role in the function of cellular membranes and in providing energy to nerve cells. This mutation essentially eliminates the function of the CLN6 gene and gives rise to the symptoms of this disorder. More than 18 mutations on the CLN6 gene have been identified. This disorder causes nerve cells, found in the brain, retina, and in the central nervous system, to die.

Early juvenile CLN6 predominately affects those of Portuguese, Indian, Pakistani, or Czech origin, although the exact prevalence figures are not known. It is estimated that the NCLs affect two to four of every 100,000 live births in the United States.

Symptoms:

Symptoms of Early juvenile CLN6 begin to be present between ages four and eight, and include blindness, seizures, and loss of cognitive skills. A loss of motor skills typically occurs between four and 10 years of age. As this disorder progresses, the affected individual becomes increasingly incapacitated.

Inheritance Pattern:

Early juvenile CLN6 is an autosomal recessive disorder.

Life Expectancy:

Life Expectancy for Early juvenile CLN6 is between 10 and 30 years of age.

Diagnosis and Testing:

A DNA analysis confirming a mutation on the CLN6 gene is utilized to diagnose Early juvenile CLN6. For this test, blood or a tissue sample is examined from individuals who are suspected of having the disorder or from family members wherein a carrier of the CLN6 gene has been identified. Prenatal screening is also available.

Treatment:

There is no cure for Early juvenile CLN6. Treatment is limited to reducing or controlling the symptoms of this disorder by consulting regularly with neurologists, ophthalmologists and genetic. Neurologists can help to control seizures or nervous system complications. An ophthalmologist monitor vision loss, and physical and occupational therapists assist the affected individual to maintain muscle movement and reduce muscle discomfort.

Batten-Spielmeyer-Vogt/Juvenile NCL/CLN3 disease
Definition:

Batten-Spielmeyer-Vogt/Juvenile NCL/CLN3 disorder is part of a group of progressive degenerative neurometabolic disorders known as neuronal ceroid lipofuscinoses (NCLs). NCLs are characterized by an abnormal accumulation of lipopigaments, which are substances combined from fats and proteins within the brain’s nerve cells, eyes, skin, muscle, and within other tissues throughout the body.

Skin biopsy in these patients shows characteristic fingerprint inclusions when examined under the electron microscope. This disorder causes nerve cells, found in the brain, retina, and in the central nervous system, to die.

Research has located a mutated gene responsible for Batten-Spielmeyer-Vogt/Juvenile NCL/CLN3, although the protein that the gene codes has not been identified.

Batten Disease is the most common form of the NCLs. It is estimated that the NCLs affect two to four of every 100,000 live births in the United States.

Symptoms:

Symptoms of Batten-Spielmeyer-Vogt/Juvenile NCL/CLN3 disorder begin between five and 10 years of age, when visual problems or seizures begin to appear. Personality and behavior changes, as well as clumsiness and delayed learning, may also occur in children affected with this disorder. As the disorder progresses, mental impairment and vision worsen, and motor skills decline. In its final stages, the affected individual becomes blind, mentally retarded, and bedridden.

Inheritance Pattern:

Batten-Spielmeyer-Vogt/Juvenile NCL/CLN3 disorder is an autosomal recessive disorder.

Life Expectancy:

Life Expectancy for Batten-Spielmeyer-Vogt/Juvenile NCL/CLN3 disorder is between the late teens and early 20s.

Diagnosis and Testing:

A urine test is utilized to help diagnose Batten-Spielmeyer-Vogt/Juvenile NCL/CLN3. The test measures increased levels of a chemical called dolichol. A biopsy of a tissue or skin sample to look for particular cellular deposits unique to NCL disorders is often performed to confirm a diagnosis. Other diagnostic tests include electroencephalogram, or EEG, to locate seizure activity in the brain, eye examination for optical complications characteristic of NCL disorders, and brain scan to search for changes in the brain’s appearance.

As the mutation in the gene for Batten-Spielmeyer-Vogt/Juvenile NCL/CLN3 disorder has been identified, DNA analysis can confirm a diagnosis in families wherein there are known carriers. Prenatal DNA analysis is also available for families affected by this form of Batten Disease.

Treatment:

There is no cure for Batten-Spielmeyer-Vogt/Juvenile NCL/CLN3 disorder. Treatment is limited to reducing or controlling the symptoms of this disorder. Neurologists are able to help control seizures or nervous system complications. An ophthalmologist can monitor vision loss, and physical and occupational therapists can assist the affected individual to maintain muscle movement and reduce muscle discomfort.

Patient Groups:

Batten Disease Support and Research Association
166 Humphries Dr.
Reynoldsburg, OH 43068
www.bdsra.org
tel: (800) 448-4570
Lance Johnston, Executive Director
bdsral@bdsra.org

Finnish Variant Late Infantile CLN5
Definition:

Finnish Variant Late Infantile CLN5 disorder is part of a group of progressive degenerative neurometabolic disorders known as neuronal ceroid lipofuscinoses (NCLs). NCLs are characterized by an abnormal accumulation of lipopigaments, subtances combined of fats and proteins within the brain’s nerve cells, eyes, skin, muscle, and within other tissues throughout the body.

Although this disorder has many clinical symptoms similar to other NCLs, it is distinct because its cause is known. The cause of many NCLs remains nebulous. Finnish Variant Late Infantile CLN5 disorder is caused by a mutation on the CLN5 gene, which leads to an accumulation of transmembrane proteins in the cells. This mutation essentially eliminates the function of the CLN5 gene and gives rise to the symptoms of this disorder. The disorder causes nerve cells, found in the brain, retina, and in the central nervous system, to die.

Finnish Variant Late Infantile CLN5 predominately affects individuals of Finnish origin. It is estimated that one in 100 individuals in Finland are gene carriers of an NCL disorder. The exact frequency of Finnish Variant Late Infantile CLN5 in Finland or in the United States is not known. It is estimated that the NCLs affect two to four of every 100,000 live births in the United States.

Symptoms:

Symptoms of Finnish Variant Late Infantile CLN5 begin between two and seven years of age. The loss of muscle coordination and progressive mental deterioration are symptoms typical of this disorder. Loss of vision and seizures are also common symptoms as this disorder progresses.

Inheritance Pattern:

Finnish Variant Late Infantile CLN5 is an autosomal recessive disorder.

Life Expectancy:

The life Expectancy for Finnish Variant Late Infantile CLN5 is between 13 and 30 years of age.

Diagnosis and Testing:

A DNA analysis can confirm a mutation on the CLN5 Gene, and therefore, a diagnosis of Finnish Variant Late Infantile CLN5. For this analysis, blood or tissue sample is tested from individuals who are suspected of having the disorder and/or from members of families wherein a carrier of the CLN5 gene has been identified. Prenatal screening is also available.

Treatment:

There is no cure for Finnish Variant Late Infantile CLN5. Treatment is limited to reducing or controlling the symptoms of this disorder with regular consultation with neurologists, ophthalmologists, and genetic counselors. Neurologists are able to help control seizures or nervous system complications. An ophthalmologist can monitor vision loss, and physical and occupational therapists can assist the affected individual to maintain muscle movement and reduce muscle discomfort.

Jansky-Bielschowsky/Late infantile CLN2/TPP1 Disease
Definition:

Jansky-Bielschowsky/Late Infantile CLN2/TPP1 disorder is part of a group of progressive degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses (NCLs). The NCLs are characterized by an abnormal accumulation of lipopigaments, which are subtances combined of fats and proteins within the brain’s nerve cells, eyes, skin, muscle, and other tissues throughout the body.

Skin biopsies in CLN2 show characteristic curvilinear bodies. The cause of CLN2 is mutations in the CLN 2 gene which lead to deficient activity of the TPP1 enzyme.

The disorder causes nerve cells, found in the brain, retina, and central nervous system, to die. The reason for this remains unknown.

It is estimated that the NCLs affect two to four of every 100,000 live births in the United States.

Symptoms:

Symptoms of Jansky-Bielschowsky/Late Infantile CLN2/TPP1 disorder begin between two and four years of age. The loss of muscle coordinatio, and progressive mental deterioration are symptoms typical of this disorder. Seizures are also a common symptom.

Inheritance Pattern:

Jansky-Bielschowsky/Late Infantile CLN2/TPP1 disorder is an autosomal recessive disorder.

Life Expectancy:

Life Expectancy for Jansky-Bielschowsky/Late Infantile CLN2/TPP1 disorder is between eight and 12 years of age.

Diagnosis and Testing:

CLN2 is diagnosed by showing corresponding mutations in the CLN2 gene and deficient activity of the TPP1 enzyme.

Treatment:

There is no cure for Jansky-Bielschowsky/Late Infantile CLN2/TPP1 disorder. Treatment is limited to reducing or controlling the symptoms of this disorder, by regular consultation with neurologists, ophthalmologists and genetic counselors. Neurologists are able to help control seizures or nervous system complications. An ophthalmologist can monitor vision loss, and physical and occupational therapists can assist the affected individual in maintaining muscle movement and reducing muscle discomfort.

Kufs/Adult-onset NCL/CLN4 disease
Definition:

Kufs/Adult-onset NCL/CLN4 Disorder is part of a group of progressive degenerative neurometabolic disorders known as neuronal ceroid lipofuscinoses (NCLs). NCLs are characterized by an abnormal accumulation of lipopigaments, which are substances combined from fats and proteins within the brain’s nerve cells, eyes, skin, muscle, and within other tissues throughout the body.

Skin biopsy shows characteristic inclusions in CLN4. This includes a variety of profiles that overlap other forms of neuronal ceroid lipofuscinoses.

Research has located a mutated gene responsible for Kufs/Adult-onset NCL/CLN4, although the protein that the gene codes has not been identified.

It is estimated that the NCLs affects two to four of every 100,000 live births in the United States.

Symptoms:

Symptoms of Kufs/Adult-onset NCL/CLN4 disorder begin before 40 years of age, when signs of dementia begin to appear. Motor skills decline and seizures are common. This disorder does not cause blindness as many other NCLs do.

Inheritance Pattern:

Both autosomal recessive and dominant inheritance patterns have been described in Kufs disease.

Life Expectancy:

Life expectancy is variably reduced in Kufs disease.

Diagnosis and Testing:

A urine test may be utilized to diagnose Kufs/Adult-onset NCL/CLN4. The test measures increased levels of a chemical called dolichol. A biopsy of a tissue or skin sample to look for cellular deposits unique to NCL disorders often will confirm a diagnosis. Diagnostic tests include electroencephalogram, or EEG, to locate seizure activity in the brain, eye exams to look for optical complications characteristic of NCL disorders, and brain scans to search for changes in the brain’s appearance.

Linkage has been described for NCL4, but the precise gene and mutation has not yet been identified.

Treatment:

There is no cure for Kufs/Adult-onset NCL/CLN4 disorder. Treatment is limited to reducing or controlling the symptoms of this disorder. Neurologists can assist in keeping seizures or nervous system complications under control. Physical and occupational therapists can help the affected individual maintain muscle movement and reduce muscle discomfort.

Northern Epilepsy/variant late infantile CLN8
Definition:

Northern Epilepsy/variant late infantile CLN8 disease is part of a group of progressive degenerative neurometabolic disorders known as neuronal ceroid lipofuscinoses (NCLs). NCLs are characterized by an abnormal accumulation of lipopigaments; subtances combined of fats and proteins within the brain’s nerve cells, eyes, skin, muscle, and within other tissues throughout the body.

Although this disorder has clinical symptoms similar to other NCLs, it is distinct because its cause is known. The cause of many NCLs remains nebulous. Northern Epilepsy/variant late infantile CLN8 disorder is caused by a mutation on the CLN8 gene. The mutation results in an accumulation of transmembrane proteins in the cells. The gene CLN8 provides the code for a specific transmembrane protein, but its exact function is unknown. This mutation essentially eliminates the function of the CLN8 gene and gives rise to the symptoms of this disorder. Five mutations on the CLN8 gene have been identified. This disorder causes nerve cells, found in the brain, retina, and in the central nervous system, to die.

Northern Epilepsy/variant late infantile CLN8 has been found only in the Finnish population and its exact frequency is not known. It is therefore considered a unique clinical and genetic disorder among other NCLs.

It is estimated that the NCLs affect two to four of every 100,000 live births in the United States.

Symptoms:

Early development is normal for children affected by Northern Epilepsy/variant late infantile CLN8. Seizures begin to appear between the ages of five and 10 in affected children followed by progressive mental retardation. Decreased vision and slight motor skills problems are also symptoms.

Inheritance Pattern:

Northern Epilepsy/variant late infantile CLN8 is an autosomal recessive disorder.

Life Expectancy:

Life Expectancy for Northern Epilepsy/variant late infantile CLN8 is 50 years of age.

Diagnosis and Testing:

A DNA analysis may be utilized to diagnose Northern Epilepsy/variant late infantile CLN8. This analysis would be utilized to confirm a mutation on the CLN8 gene. Blood or a tissue sample is tested from individuals who are suspected of having the disorder or from family members wherein a carrier of the CLN8 gene has been identified. Prenatal screening is also available.

Treatment:

There is no cure for Northern Epilepsy/variant late infantile CLN8. Treatment is limited to reducing or controlling the symptoms of this disorder by consulting regularly with neurologists, ophthalmologists and genetic counselors. Neurologists assist in keeping seizures or nervous system complications under control. An ophthalmologist monitors vision loss, and physical and occupational therapists can assist the affected individual to maintain muscle movement and reduce muscle discomfort. Medication can control seizures that are characteristic to this disorder.

Santavuori-Haltia/Infantile CLN1/PPT disease
Definition:

Santavuori-Haltia/Infantile CLN1/PPT Disease is part of a group of progressive degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses (NCLs). The NCLs are characterized by an abnormal accumulation of lipopigaments, which are subtances combined of fats and proteins within the brain’s nerve cells, eyes, skin, muscle, and within other tissues throughout the body.

Examination of cells under the electron microscope shows accumulation of pigments in the form of granular osmoiphilic deposits (GRODs), also known as “Finnish snowballs.” This appearance is characteristic for this form of neuronal ceroid lipofuscinoses.

NCL I is known to result from deficient activity of an enzyme called palmitoyl—protein thioesterase-1 (PPT-10). The gene coding for this enzyme has been named CLN1. Mutations can be demonstrated and are useful in confirming the diagnosis and in performing prenatal diagnosis.

It is estimated that the NCLs affect two to four of every 100,000 live births in the United States.

Symptoms:

Symptoms of Santavuori-Haltia/Infantile CLN1/PPT Disease begin between six months and 19 months of age. During ages of six to 19 months, a delay in mental and muscular activities appears at the same time when the affected child begins to lose the mental and physical skills he/she had acquired. A small head, seizures, an inability to coordinate voluntary muscular movements, decreasing muscle tone, muscle spasms, and visual impairments are additional symptoms. As neurological complication progress, immobility, spastic and involuntary movements, and a lack of response may also occur.

Inheritance Pattern:

Santavuori-Haltia/Infantile CLN1/PPT disorder is an autosomal recessive disorder.

Life Expectancy:

Life Expectancy for Santavuori-Haltia/Infantile CLN1/PPT disorder is five years of age or younger.

Diagnosis and Testing:

The diagnosis of Santayouri-Haltia Disease is made by demonstrating reduced activity of PPT and by showing corresponding mutations in the CLN1 gene. Characteristic changes may be shown in skin biopsy on electron microscopy and the electro-retina-gram. An MRI scan of the brain typically shows severe atrophy of the cerebral hemispheres and cerebellum.

Treatment:

There is no cure for Santavuori-Haltia/Infantile CLN1/PPT disorder. Treatment is limited to reducing or controlling the symptoms of this disorder by routine consultation with the patient’s neurologists, ophthalmologists and genetic counselors. Neurologists may assist in keeping seizures or nervous system complications under control. An ophthalmologist can monitor vision loss, and physical and occupational therapists can help the affected individual maintain muscle movement and reduce muscle discomfort.

Beta-Mannosidosis
Definition:

Beta-Mannosidosis results from deficient activity of the enzyme beta-mannosidase. This leads to accumulation of sugar chains (oligosaccharides) within the lysosomes. This lysosomal accumulation leads to general cellular dysfunction, the manifestations of Beta-Mannosidosis.

Symptoms:

Beta-Mannosidosis does not display some of the hallmark features of Lysosomal Disease. Therefore, it is believed that the prevalence of this disorder has been under diagnosed. The most typical features of Beta-Mannosidosis are mental retardation, recurrent respiratory infections, hearing loss, and angiokeratomas.

Diagnosis and Testing:

To determine if the patient has Beta-Mannosidosis, a urine test is performed measuring increased levels of oligosaccharides, the type of sugar chains in the lysosome that accumulate as a result of the malfunctioning enzyme. A urine test is then routinely followed by a blood test or skin biopsy which will show reduced activity of the enzyme, beta-mannosidase. Prenatal screening is also available to examine beta-mannosidase activity in the fetus. Genetic testing is availble in combination with these diagnostic tests to look for the mutation that causes Beta-Mannosidosis.

Life Expectancy:

Life expectancy is highly variable in Beta-Mannosidosis. Many adults with this disorder have been recognized.

Treatment:

There is no cure for Beta-Mannosidosis. Treatment is limited to reducing or controlling the symptoms of this disorder, by, for example, making sure to keep respiratory infections at a minimum and to monitor hearing loss.

Pompe disease/Glycogen storage disease II
Definition:

Pompe Disease/Glycogen Storage Disease II (also known as Acid Maltase Deficiancy) is a rare, neuromuscular genetic disorder resulting from a mutated gene that manufactures the enzyme acid alpha-glucosidase (GAA). The GAA enzyme is responsible for breaking down glycogen in the lysosome. In individuals afflicted with Pompe Disease, the GAA enzyme is either absent or present in a very low quantity and glycogen builds in the lysosome, resulting in symptoms associated with this disorder.

Pompe Disease is also known as acid maltase deficiency or acid alpha-glucosidase deficiency. It is a continuum of the types of glycogen storage diseases that vary in severity and in the age of onset of the first symptoms associated with this disorder. There are four primary forms of Pompe Disease: The classic infantile form, the non-classic infantile, the juvenile form, and the adult form. The classic infantile form is the most severe.

Pompe Disease is estimated to occur in about one in 40,000 births worldwide.

Symptoms:

Symptoms of the classical form of Pompe Disease begin within the first few months of life and include a severe loss of muscle tone, progressive muscle weakness, and an enlargement and thickening of the heart. Symptoms include feeding and respiratory problems as a result of congestive heart failure associated with this disease.

Symptoms of the non-classic infantile form are similar to the classic form, excluding an enlargement of the heart.

Symptoms of the juvenile form commonly begin after age two and are marked by a loss of muscle tone.

Symptoms of the adult form include slow, progressive muscle weakness and/or respiratory difficulties.

Inheritance Pattern:

Pompe Disease/Glycogen Storage Disease II is an autosomal recessive disorder.

Life Expectancy:

Life expectancy for the classic infantile form Pompe Disease/Glycogen Storage Disease II is two years of age or younger, resulting from respiratory or cardiac failure.

Life expectancy for the non-classic infantile form Pompe Disease/Glycogen Storage Disease II is early childhood.

Life expectancy for the juvenile form Pompe Disease/Glycogen Storage Disease II is 30 years of age or younger.

Life expectancy for the adult form Pompe Disease/Glycogen Storage Disease II is 50 years of age or younger.

Diagnosis and Testing:

An enzyme assay using blood or tissue samples measures reduced or absent levels of the GAA enzyme. Children afflicted with infantile-onset typically have lower than 1% of normal GAA enzyme activity levels. Individuals afflicted with later-onset have lower than 40% of normal GAA enzyme levels.

Treatment:

Enzyme replacement therapy is available for individuals affected by Pompe Disease. The FDA-approved Myozyme is a synthiszied form of the human enzyme GAA that replaces the missing enzyme in individuals with Pompe Disease. It works to break down glycogen that accumulates in the lysosome. This drug is given intravenously and the affected individal must take it throughout all of his or her life. Myozyme has shown to prolong the overall survival of affected individuals. The drug costs approximately $300,000 per year and some insurance companies do not cover the expense.

Patient Groups:

Acid Maltase Deficiency Association
P.O. Box 700248
San Antonio, TX 78270
www.amda-pompe.org
tel: (210) 494-6144
fax: (210) 490-7161
Tiffany House
tianrama@aol.com

National Tay-Sachs & Allied Diseases Association
2001 Beacon Street, Suite 204
Boston, MA 02135
www.ntsad.org
tel: (800) 906-8723
fax: (617) 277-0134
Sue R. Kahn, Executive Director
info@ntsad.org

Pycnodysostosis
Definition:

Pycnodysostosis is an inherited disorder of the bone caused by a mutation in the gene that codes the enzyme cathespin K. This enzyme is important for normal bone cells called osteoclasts, to reabsorb into the bone and build new bone. The normal functioning of osteoclasts in individuals with pycnodysostosis is disrupted by a lack of cathepsin K, rendering individuals afflicted with this disorder to be unable to adequately reabsorb the component of bone called the organic matrix. This process, also called remodeling, is vital for normal bone maintenance. The bones in individuals afflicted with pycnodysostosis are abnormally dense and brittle as a result of this insufficient re-absorption process.

In 1996, the defective gene responsible for pycnodysostosis was located, offering accurate diagnosis, carrier testing and a more thorough understanding of this disorder.

Pycnodysostosis affects one in every 200,000 individuals in the United States.

Symptoms:

Pycnodysostosis results in short stature and abnormally dense and brittle bones. Height in affected males may reach four feet, while in affected females, measures are shorter. The bones’ brittleness in affected individuals commonly results in fractures, particularly in their feet, legs, and jaw. The fontanelle, the soft spot on the skull which normally closes when an infant is a few months old, remains open in affected individuals. Coarse facial features, abnormally short fingers, wrinkled skin, a small jaw, undeveloped and irregular teeth, dental cavities, and scoliosis are also common characteristics of this disorder.

Inheritance Pattern:

Pycnodysostosis is an autosomal recessive disorder.

Life Expectancy:

Life expectancy for Pycnodysostosis is normal.

Diagnosis and Testing:

A mutation has been found for Pycnodysostosis, rendering genetic analysis a necessary diagnostic tool to confirm this disorder. Prenatal genetic screening is available. X-rays may be used in combination with genetic testing to examine skeletal abnormalities.

Treatment:

Since bone fractures are a primary threat to those affected by Pycnodysostosis, it is important that care is taken to prevent or minimize tendencies for a fracture to occur. Such precautions include careful handling of an affected child, along with exercise and activities that are safe and do not require too much impact. Growth hormones have been shown to increase the bone growth and, thereby, the stature of individuals afflicted with Pycnodysostosis. Dental hygiene is especially helpful for affected individuals . The use of crutches or wheelchairs may be necessary and depend upon the progression of the disorder.

Sandhoff Disease/Adult Onset/GM2 Gangliosidosis
Definition:

Adult Onset Sandhoff Disease/GM2 Gangliosidosis is a group of inherited neurodegenerative diseases caused by a deficiency of the enzymes Hexosaminidase A (Hex-A) and Hexosaminidase B (Hex-B), which results in the accumulation of certain fats, gangliosides, in the brain. The bodies of individuals affected with Sandhoff are unable to break down GM2 gangliosides, hence the gangliosides build in the lysosomes.

Since a low level of functional Hex-A and Hex-B enzymes are found in adult cases, the symptoms of this disorder present later than they present with the two forms of Sandhoff Disease that are characterized by virtually no Hex-A and Hex-B enzymes. Therefore, the amount of Hex-A and Hex-B enzymes dictates the age of symptom onset and also the classification of the type of Sandhoff Disease.

Symptoms:

Symptoms of the disease begin in adolescence and include muscle weakness, tremors and slurred speech. Leg cramps, particularly at night, and muscle twitching are also common symptoms. Although symptoms may vary from individual to individual, weakness in the trunk muscles is one symptom common to all affected with this disorder. Dementia, which often occurs with other neurologic disabilities, is also a common symptom of this form of the disease.

Inheritance Pattern:

Adult Onset Sandhoff Disease/GM2 Gangliosidosis is an autosomal recessive disorder.

Diagnosis and Testing:

Adult Onset Sandhoff Disease/GM2 Gangliosidosis is usually diagnosed by measuring Hexosaminidase A and B activity in the blood. The disease can also be detected in a liver tissue biopsy or an enzyme assay to determine whether abnormally low levels of the enzyme are present.

Individuals at risk of this disease can undergo genetic screening to determine their carrier status before they decide to have children. Some medical professionals highly recommend DNA testing for those parents who do not have a family history of Sandhoff Disease. More than 95% of the families that have children with this disorder had no known prior family history of the condition, due to the gene mutation’s silent or recessive nature and to its ability to pass from one generation to another without recognition. Genetic counseling is recommended for those who have the mutation.

Life Expectancy:

Life expectancy of patients with Adult Onset Sandhoff Disease is likely not affected or reduced from normal life expectancy. The uncertainty of the disorder’s progression along with its physical and psychological effects may adversely affect the social skills and academic performance of those who have this form of the disease.

Treatment:

There is no treatment for Adult Onset Sandhoff Disease. Preventive genetic counseling is highly encouraged. It is the hope that one day gene therapy will prove to be for a cure for Sandhoff Disease.

Patient Groups:

Sandhoff Disease
259 Majorca Road
St. Augustine, FL 32080
http://www.sandhoffdisease.webs.com/
tel: (904) 662-1840
Gina Watkins
gmwatkins74@yahoo.com

Sandhoff Disease/GM2 Gangliosidosis - Infantile
Definition:

Sandhoff Disease is a rare, genetic, lipid storage disorder resulting in the progressive deterioration of the central nervous system. It is caused by a deficiency of the enzymes Hexosaminidase A (Hex-A) and Hexosaminidase B (Hex-B), which results in the accumulation of certain fats, known as gangliosides in the brain and in other organs of the body.

Since gangliosides are produced only by nervous tissue, they will accumulate only in nervous tissue, even though the enzyme is deficient in all cells. This deficiency gives rise to the clinical symptoms of this disorder.

Even though Sandhoff Disease is similar to Tay-Sachs disease in its symptom manifestation, it is less prevalent among the Eastern European Jewish population.

Symptoms:

Onset of the symptoms usually occurs at around six months of age. Typically, the earlier the onset of symptoms, the quicker the progression of the disorder.

Neurological symptoms may include motor weakness, a startled response to sound, early blindness, progressive mental and motor deterioration, an abnormally enlarged head, red spots in the eyes, seizures, and abrupt muscle contractions. Other symptoms may include respiratory infections, doll-like facial features, and an enlarged liver and spleen.

Inheritance Pattern:

Sandhoff Disease is an autosomal recessive disorder.

Diagnosis and Testing:

Sandhoff Disease can be detected through a liver tissue biopsy or an enzyme assay to determine whether abnormally low levels of the enzyme, beta-hexosaminidase, can be found in the body.

Genetic screening can determine an individual’s carrier status before he or she chooses to have children. Some medical professionals highly recommend DNA testing even for individuals who do not have a family history of Sandhoff Disease. More than 95% of the families that have children with this disorder had no known prior family history of the condition, due to the gene mutation’s silent or recessive nature and to its ability to pass from one generation to another without recognition. Genetic counseling is recommended for those who have the mutation.

Life Expectancy:

Life expectancy for Sandhoff Disease is three years of age or younger. The cause of death is usually a respiratory infection.

Treatment:

There is no cure for Sandhoff Disease. Treatments to manage symptoms of the disease include proper nutrition and hydration, and keeping the airway open. Anticonvulsant medication may help to control seizures. Transplantation of stem cells derived from umbilical cord blood has been attempted in some children with Sandhoff Disease. Although this potential treatment has not yet produced a cure or lessening of symptoms, medical professionals continue to study this and other approaches.

Patient Groups:

Sandhoff Disease
259 Majorca Road
St. Augustine, FL 32080
http://www.sandhoffdisease.webs.com/
tel: (904) 662-1840
Gina Watkins
gmwatkins74@yahoo.com

Sandhoff Disease/GM2 gangliosidosis - Juvenile
Definition:

Juvenile Onset Sandhoff Disease is an inherited neurodegenerative disease caused by a deficiency of the enzymes Hexosaminidase A (Hex-A) and Hexosaminidase B (Hex-B), which results in the accumulation of certain fats, gangliosides, in the brain. The bodies of individuals affected with Sandhoff are unable to break down GM2 gangliosides, hence the gangliosides build in the lysosomes. Clinical features of Sandhoff and Tay Sachs diseases are largely similar and are indistinguishable, except for the differences in their enzyme deficiency patterns and the hepatosplenomegaly that may occur in Sandhoff Disease. Hexosaminidase A alone is absent in Tay-Sachs disease, whereas both hexosaminidase A and B are absent in Sandhoff Disease. Unlike Tay-Sachs disease, Sandhoff Disease is less prevalent among the Jewish population of Eastern European decent.

Given the differences in the age of onset and the range in the severity of symptoms, physical appearance of this disorder varies greatly from case to case. A later age of onset of symptoms associated with Juvenile Onset Sandhoff Disease/GM2 Gangliosidosis results from extremely low levels of hexosaminidase A enzyme activity, but higher than the levels found in children affected with the classical infantile form.

Symptoms:

Symptoms of the disease present around five years of age and resemble the symptoms associated with the classic and infantile forms of Sandhoff Disease. The disease progression of Juvenile Onset Sandhoff Disease/ GM2 Gangliosidosis is slower than the infantile form of Sandhoff Disease and the end stages typically occur late in adolescence.

Around the age of five, an affected child’s cognition may deteriorate. Ataxia, slurred speech, muscle wasting muscle cramps, tremors, uncoordinated gait, and seizures may occur. Vision may remain intact or decline in the later stages of disease progression.

Inheritance Pattern:

Juvenile Onset Sandhoff Disease/GM2 Gangliosidosis is an autosomal recessive disorder.

Diagnosis and Testing:

Juvenile Onset Sandhoff Disease/GM2 Gangliosidosis is usually diagnosed by measuring Hexosaminidase A and B activity in the blood.

Individuals at risk can undergo genetic screening to determine their carrier status before they have children. Some medical professionals highly recommend DNA testing even for those parents who do not have a family history of Sandhoff Disease. More than 95% of the families that have children with this disorder had no known prior family history of the condition, due to the gene mutation’s silent or recessive nature and to its ability to pass from one generation to another without recognition. Genetic counseling is recommended for individuals who have the mutation.

Life Expectancy:

Life expectancy is 15 years of age or younger due to complications such as respiratory infection.

Treatment:

There is no cure for Juvenile Onset Sandhoff Disease/GM2 Gangliosidosis. Therapies that include enzyme replacement therapy, bone marrow transplants, and blood transfusions have been tried, but have not proven effective in curing this disorder. Preventive genetic counseling is highly encouraged. It is the hope that one day gene therapy will prove to be a cure for Sandhoff Disease.

Patient Groups:

Sandhoff Disease
259 Majorca Road
St. Augustine, FL 32080
http://www.sandhoffdisease.webs.com/
tel: (904) 662-1840
Gina Watkins
gmwatkins74@yahoo.com

Schindler disease
Definition:

Schindler Disease is caused by the deficient activity of the lysosomal enzyme, alpha-N-acetylgalactosaminidase (alpha-NAGA). A deficiency of the alpha-NAGA enzyme leads to an accumulation of glycosphingolipids throughout the body. This accumulation of sugars gives rise to the clinical features associated with this disorder.

There are three types of Schindler Disease, characterized by the age of onset and type of physical and mental symptoms. They are Type I (infantile), Type II (adult) and Type III (intermediate).

Symptoms:

In the Type I infantile form, infants will develop normally until about a year old. At this time, the affected infant will begin to lose previously acquired skills involving the coordination of physical and mental behaviors. Additional neurological and neuromuscular symptoms such as diminished muscle tone, weakness, involuntary rapid eye movements, visual loss, and seizures may become present. With time, the symptoms worsen and children affected with this disorder will experience a decreased ability to move certain muscles due to the muscles’ rigidity. The ability to respond to external stimuli will also decrease.

In Type II adult form, symptoms are milder and may not appear until the individual is in his or her 30s. Angiokeratomas, an increased coarsening of facial features, and mild intellectual impairment are likely symptoms.

In Type III intermediate form, symptoms vary and can include to be more severe with seizures and mental retardation, or less severe with delayed speech, a mild autistic-like presentation, and/or behavioral problems.

Inheritance Pattern:

All three forms of Schindler Disease are autosomal recessive disorders.

Diagnosis and Testing:

Schindler disease may be screened for by measuring oligosaccharides in the urine. If these are found to be increased, specific diagnosis is made by demonstrating reduced activity of the enzyme alpha-NAGA in the blood or a tissue biopsy. Genetic testing is available to show the mutations in the NAGA gene. Such molecular testing is the preferred means of making prenatal diagnosis.

Life Expectancy:

Life expectancy for Type I Schindler Disease is between three and four years of age.

Treatment:

There is no cure for Schindler Disease. Treatment is limited to reducing or controlling the symptoms of this disorder by making sure that neurologists, ophthalmologists, and genetic counselors are routinely seen. Neurologists will help to keep seizures or nervous system complications under control. An ophthalmologist can monitor vision loss and, in the case of Type I infantile Schindler Disease, physical and occupational therapists can help the affected individual maintain muscle movement and reduce muscle discomfort.

Patient Groups:

International Society for Mannosidosis & Related Diseases
P.O. Box 328
Dexter, MI 48130
www.mannosidosis.org
tel: (734) 449-8222
fax: (734) 449-2282
Terri Klein, Executive Directorinfo@ismrd.org

Salla disease/Sialic Acid Storage Disease
Definition:

Salla disease is caused by a mutation on a gene ,that codes a protein that transports a charged sugar known as sialic acid, out of the lysosome. The accumulation of sialic acid gives rise to the symptoms associated with this disorder.

Salla disease is one of 40 Finnish heritage diseases. Although its exact prevalence is unknown, Salla disease affects approximately 130 individuals, mainly from Finland and Sweden.

Symptoms:

Symptoms of this disorder present between six and nine months of age and are marked by involuntary eye movements, reduced muscle tone and strength, and mental retardation. Spastic muscle movements and seizures may present later in life. Some individuals affected with this disorder learn to walk and to understand speech, but speaking is often impaired or restricted.

Inheritance Pattern:

Salla disease is an autosomal recessive disorder.

Life Expectancy:

The life expectancy for individuals with Salla disease is between the ages of 50 and 60.

Diagnosis and Testing:

A diagnosis of this disorder can be made by measuring urine to look for elevated levels of free sialic acid. Prenatal testing is also available for known carriers of this disorder.

Treatment:

There is no cure for Salla Disease. Treatment is limited to controlling the symptoms of this disorder. Anti-convulsant medication may control seizure episodes. Physical therapists can assist an affected individual to build muscle strength and coordination, and speech therapists may assist the affected individual in improving his or her speech.

Tay-Sachs/GM2 gangliosidosis
Definition:

Tay-Sachs disease is a fatal genetic disorder that causes progressive destruction of the central nervous system in children.

Tay-Sachs disease is caused by the absence of a vital enzyme called hexosaminidase A (Hex-A). Without Hex-A, a fatty substance or lipid called GM2 ganglioside accumulates abnormally in cells, especially in the nerve cells of the brain. Gangliosides need to be biodegraded rapidly in early life as the brain develops. This ongoing accumulation causes progressive damage to the cells.

In the general population, about one out of every 320,000 babies born has Tay-Sachs disease and approximately one in 30 Ashkenazi Jews is a carrier of the gene that causes this disease. Even though there is a high incidence of this disease among people of Eastern European and Askhenazi Jewish descent, Tay-Sachs disease has been reported in children of virtually all ethnic, racial, and religious populations. French Canadians of the eastern St. Lawrence River Valley area of Quebec, Cajuns from Louisiana, and the Old Order Amish in Pennsylvania have been found to carry the mutation with frequencies equal to or even greater than those seen in the Ashkenazi Jewish population.

Because of the increased occurrence of the disease among Ashkenazi Jews, along with the availability of genetic counseling and prenatal diagnosis, population screening was initiated in 1970 for Jewish individuals of reproductive age and is recommended in published guidelines of the American College of Obstetrics and Gynecology and the American College of Medical Genetics [Kaback et al 1993]. This screening program educates couples in which both partners are carriers, regarding their status and the risks associated with giving birth to affected children. Genetic counseling and the option of prenatal testing allows such families the choice to bring to term only those pregnancies in which the fetus is unaffected. This program has reduced the incidence of Tay-Sachs among the Ashkenazi population by more than 90 percent.

Tay-Sachs disease has a continuum of severity based on the amount of residual Hexosaminidase A activity present in the cells. The amount of residual activity depends on the particular mutation in the Tay-Sachs gene. This dynamic is expressed through two variations of Tay-Sachs disease. These two variants are Juvenile Hexosaminidase A deficiency and Chronic Hexosaminidase A deficiency.

Symptoms:

A baby with Tay-Sachs disease appears normal at birth and seems to develop normally until about six months of age. The first signs can vary and are evident at different ages in affected children. Initially, development slows, there is a loss of peripheral vision, and the affected child exhibits an abnormal, startled response to noise. By about two years of age, most affected children experience recurrent seizures and diminishing mental function. The affected child regresses gradually, loses skills one by one, and is eventually unable to crawl, turn over, sit or reach out. Other symptoms include increasing loss of coordination, progressive inability to swallow and breathing difficulties. Eventually, the affected child becomes blind, mentally retarded, paralyzed, and unresponsive to his or her environment.

Inheritance Pattern:

Tay-Sachs disease is an autosomal recessive disorder.

Diagnosis and Testing:

Patients and carriers of Tay-Sachs disease can be identified by a simple blood test that measures the enzymatic activity of beta-hexosaminidase A. Both parents must carry the mutated gene to have an affected child. In these instances, there is a 25% chance with each pregnancy that the child will be affected with Tay-Sachs disease. Prenatal diagnosis is also available if the pregnant mother knows that both she and the father of her unborn child carry the gene mutation.

Life Expectancy:

Life expectancy for Tay-Sachs disease is four years of age or younger. The cause of death is typically pneumonia.

Treatment:

Currently, there is no cure or effective treatment for Tay-Sachs disease. Anticonvulsant medicine can help to control seizures. Other treatment options include adequate nutrition and hydration as well as techniques to keep the airway open. A feeding tube may also be necessary for some children.

Enzyme replacement therapy using a synthetic version of the enzyme Hex-A, which is missing in babies with Tay-Sachs disease, has been explored. Although this approach is promising, scientists face obstacles since the disease affects brain cells protected by the blood-brain barrier. Enzymes like Hex-A are blocked from entering the brain from the blood.

Bone marrow transplantation has been attempted, but to date has not been successful in reversing or slowing damage to the central nervous system in babies with TSD. The National Institute of Neurological Disorders and Stroke, which is part of the National Institutes of Health, is conducting research to find additional therapies and treatments for this disease. There is hope that other treatments such as gene therapy targeted to cells in the central nervous system and/or the introduction of functional neural stem cells into the brains of affected children will help to reverse the symptoms of this disorder.

Patient Groups:

National Tay-Sachs & Allied Diseases Association
2001 Beacon Street, Suite 204
Boston, MA 02135
www.ntsad.org
tel: (800) 906-8723
fax: (617) 277-0134
Sue R. Kahn, Executive Director
info@ntsad.org

Wolman Disease
Definition:

Wolman Disease, also known as acid lipase deficiency, is a severe lipid storage disease that is usually fatal by age one. Wolman Disease involves the accumulation of both triglycerides and cholesteryl ester, that results from an inherited deficiency of lysosomal acid lipase, the enzyme used to break down triglycerides and cholesteryl esters in lysosomes. Because of the complete absence of lysosomal acid lipase activity, triglycerides and cholesteryl esters progressively accumulate in the affected tissues.

Males and females are affected by this disorder. Infants born with this genetic disease are normal and active at birth but quickly develop deteriorating symptoms.

Symptoms:

Infants develop an enlarged liver and spleen, also known as hepatosplenomegaly. A distended abdomen and gastrointestinal problems including steatorrhea (excessive amounts of fats in the stools), jaundice, anemia, vomiting, and adrenal-calcification are also symptoms of Wolman Disease.

Inheritance Patterns:

Wolman’s Disease is an autosomal recessive disorder.

Diagnosis and Testing:

Diagnosis can be difficult because there are no general laboratory tests that point specifically to this disorder. Infants with hepatosplenomegaly and evidence of malnutrition should have a careful neurological examination and x-rays of the abdomen to check for calcium deposits in the adrenal glands. If Wolman Disease is suspected on the basis of these tests, acid lipase activity can be measured in the laboratory using white blood cells or skin cells. An absence of acid lipase activity confirms the diagnosis.

Carrier status:

Wolman Disease can be confirmed by measuring acid lipase activity in the white blood cells. Carriers will typically demonstrate 50% of normal enzyme activity.

Life Expectancy:

Life expectancy is one year of age or younger.

Treatment:

Currently there is no disease modifying treatment for Wolman Disease although one case in 2000 (Krivit W, Peters C, Dusenbery K, et al) was successfully treated with a bone marrow transplant. Patients with anemia may receive blood transfusions, and removal of the spleen may be performed to improve cardiopulmonary function. Reducing the amount of fat in the affected infant’s diet does not prevent the progression of this disorder.