OMIM ID:
Sandhoff Disease
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
Retinal ganglion cells are rendered dysfunctional from the toxic accumulation of intra-lysosomal GM2 ganglioside molecules causing early visual symptoms. These cells in high density around the fovea centralis create a grayish-white appearance. Since ganglion cells are absent in the foveolar region, this area retains the normal reddish appearance, producing the cherry-red spot. Axonal decay and loss of the ganglion cells leads to optic atrophy and blindness.
Systemic Features
Sandhoff disease may be clinically indistinguishable from Tay-Sachs disease even though the same enzyme is defective (albeit in separate subunits A and B that together comprise the functional enzymes). The presence of hepatosplenomegaly in Sandoff disease may be distinguishing. The infantile form of this lysosomal storage disease seems to be the most severe. Infants appear to be normal until about 3-6 months of age when neurological development slows and muscles become weak. Seizures, loss of interest, and progressive paralysis begin after this together with loss of vision and hearing. An exaggerated startle response is considered an early and helpful sign in the diagnosis. Among infants with early onset disease, death usually occurs by 3 or 4 years of age.
Ataxia with spinocerebellar degeneration, motor neuron disease, dementia, and progressive dystonia are more common in individuals with later onset of neurodegeneration. The juvenile and adult-onset forms of the disease also progress more slowly.
Genetics
Inheritance
Sandhoff disease results from mutations in the beta subunit of the hexosaminidase A and B enzymes. It is an autosomal recessive disorder caused by mutations in HEXB (5q13).
Tay-Sachs disease (272800) can be clinically indistinguishable from Sandoff disease and they are allelic disorders. However, the mutation in Tay-Sachs (272800) is in HEXA resulting in dysfunction of the alpha subunit of hexosaminidase A enzyme.
Pedigree
Autosomal recessive
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.