Sandhoff Disease

Sandhoff disease is similar to Tay-Sachs disease, but is much less common and occurs with approximately equal frequency in all ethnic groups. Infants with Sandhoff are usually found to have a cherry-red spot in the retina and exhibit an exaggerated startle response. By one year of age, most children with Sandhoff will have completely lost their ability to see – and often to hear. Their faces gradually take on a “doll-like” appearance and their heads enlarge. Eventually children with Sandhoff become unable to swallow or cough and many will experience seizures. The disease is progressive and most children with Sandhoff die between the ages of two and six.
 
Sandhoff disease is a recessive genetic disorder and is caused by a lack of the beta subunit of the hexosaminidase A enzyme (Hex-A), rather than the absence of the alpha subunit of Hex-A as in Tay-Sachs. Since both the alpha and beta subunits are needed for Hex-A function, children with Sandhoff are also deficient in Hex-A activity. However, the beta subunit is also essential for the functioning of another kind of hexosaminidase called Hex-B. As a result, children with Sandhoff disease lack normal levels of both Hex-A and Hex-B.
 
While Hex-A and Hex-B differ in the kinds of subunits they contain, both play a role in the degradation of GM2 gangliosides, specific substances containing fat and sugar that are made predominantly in the neurons of the brain. Individuals with Sandhoff are unable to degrade these GM2 gangliosides and they accumulate in special compartments of the cells called lysosomes. Lysosomes contain many enzymes that degrade different kinds of molecules and can be thought of as the recycling centers of the cell. If one of the Lysosomal enzymes is deficient then the molecule it degrades accumulates in the cell, eventually resulting in cell death. Since GM2 is found mainly in neurons, its accumulation leads to the progressive loss of neurons in the brains of children with Sandhoff disease – and the progressive loss of function that results. Since the accumulation of GM2 gangliosides is the root of Sandhoff disease, it is classified at a GM2 gangliosidosis – to distinguish it from other Lysosomal storage diseases.
 
The severity of Sandhoff disease depends on the amount of residual enzyme that is produced. Children with virtually no hexosaminidase activity will have the infantile (acute onset) form of the disease. Those born with a small amount of hexosaminidase activity will have the juvenile, subacute form and those with still more activity will have a later onset adult (chronic) form of Sandhoff disease.  The infantile form is the most severe and, unfortunately, the most common.  The juvenile and adult forms of Sandhoff disease occur later and tend to be much more variable in their clinical features. The amount of residual enzyme, and therefore the clinical course, is determined by the specific mutation(s) in the beta subunit of Hex-A.