Niemann-Pick Disease

In 1914, Albert Niemann, A German pediatrician, described a young child with an enlarged liver and spleen, enlarged lymph glands, swelling, and a darkening of the skin of the face. The child had brain and nervous system impairment and died in less than six months, before the age of two years. Many organs were found to contain fatty deposits and individual cells within these organs had a characteristic foamy, swollen, appearance. A few years later, Ludwick Pick studied tissues of several other children who had died following a similar disease course and provided the evidence for this disease, now called Niemann-Pick disease, being a different and distinct disorder from those storage disorders previously described.
 
Today, there are three separate Lysosomal storage diseases that carry the name Niemann-Pick: Type A, Type B and Type C. The first two types are genetically related and are disorders of lipid (a type of fat) metabolism. Type C, however, is quite different and is a disorder of lipid transport. The majority of the infants affected with the acute infantile form of Niemann-Pick described above (now called Type A) are of Ashkenazi Jewish ancestry. The less common Niemann-Pick disease, Type B, a chronic non-neurological form, shows the same ethnic predilection as Type A. It has been estimated that about 1 in 90 Ashkenazi Jews is a carrier for one of these forms of Niemann-Pick disease.  Niemann-Pick Type C, a biochemically and genetically distinct form of the disease, does not show this ethnic predilection.
 
Infantile, or Type A, Niemann-Pick Disease occurs most frequently and it accounts for about 60% of all cases of the disease. Its effects begin in the first few months of life; by six months of age feeding difficulties, progressive loss of early motor skills and enlargement of the abdominal organs are usually present. Continued poor feeding causes children to take on an emaciated look accompanied by abdominal distension. Their skin may develop a brownish-yellow discoloration, and about one-third of affected children have a cherry-red spot in the eye similar to that found in children with Tay-Sachs Disease. There is progressive loss of motor and mental function and death usually occurs between two and three years of age.
 
Type B Niemann-Pick (NPD-B) has a more variable course with the first symptoms of disease usually being enlargement of the liver and/or spleen in early childhood. The child experiences progressive organ enlargement, poor growth and susceptibility to respiratory infections but rarely displays any neurological problems. Many of those diagnosed with Type B Niemann-Pick during childhood survive into adulthood.
 
Persons with Type C Niemann-Pick (NPD-C), on the other hand, exhibit normal development for two or more years; this then is followed by a slow loss of speech and other nervous system skills. The disease progresses with symptoms of increased clumsiness and lack of coordination, and eventually seizures, and a gradual failure of physical and mental function. Most children with Type C die between the ages of 5 and 15 years. There is also an infantile form of NPD-C in which children die before the age of two and an adult-onset form that is less severe.
 
All of these forms of Niemann-Pick Disease show evidence of fatty deposits in one or more organs of the body. These deposits contain a characteristic lipid called sphingomyelin, along with cholesterol, and they have a foamy, swollen appearance. They are usually found in the liver, spleen and bone marrow cells of affected persons and contribute to the liver and spleen enlargement so characteristic of Niemann-Pick Disease. The cellular malfunction is especially prominent in immune system cells called macrophages. In Types A and C, deposits also accumulate in cells of the central nervous system, causing damage to the cells and progressive neurological impairment.
 
Persons with Type A and Type B Niemann-Pick Disease are missing the enzyme sphingomyelinase which is necessary to metabolize and break down sphingomyelin, a component of cell membranes. Without sphingomyelinase, the sphingomyelin builds up abnormally and causes the cells to malfunction. The gene for the enzyme sphingomyelinase is located on Chromosome 11, and persons with Type A and Type B Niemann-Pick Disease carry mutations in both copies of the gene, making it impossible for tem to make adequate amounts of functional sphingomyelinase. Children with Type A are completely deficient in sphingomyelinase production and make less than 5% of normal levels, while persons with the less severe Type B form make 5-10% of the normal levels of sphingomyelinase. Diagnosis of individuals suspected of having Type A or B Niemann-Pick Disease is done by determining the levels of sphingomyelinase in samples of blood or skin cells.
 
Persons with Type C Niemann-Pick Disease have approximately normal levels of sphingomyelinase; they do not carry mutations in the sphingomyelinase gene but instead carry mutations in a different gene, located on a different chromosome, which interfere with cholesterol trafficking within the body. The cells of persons with NPD-C thus suffer from an excess of cholesterol in one compartment of the cell (the lysosomes) and a deficiency of cholesterol in other compartments (the cell membrane and another membranous compartment called the endoplasmic reticulum). This abnormal distribution of cholesterol inside cells damages the cells and causes disease.  Diagnosis of individuals with Type C is more complex but can be carried out in specialized laboratories.