Tay-Sachs Disease and Sandhoff Disease
Tay-Sachs disease and Sandhoff disease are sphingolipidoses, inherited disorders of metabolism, caused by hexosaminidase deficiency that causes severe neurologic symptoms and early death.
Gangliosides are complex sphingolipids present in the brain. There are 2 major forms, GM1 and GM2, both of which may be involved in lysosomal storage disorders; there are 2 main types of GM2 gangliosidosis, each of which can be caused by numerous different mutations.
For more information, see Table Sphingolipidosis.
Deficiency of hexosaminidase A results in accumulation of GM2 in the brain. Inheritance is autosomal recessive; the most common mutations are carried by 1/27 normal adults of Eastern European (Ashkenazi) Jewish origin, although other mutations cluster in some French-Canadian and Cajun populations.
Children with Tay-Sachs disease start missing developmental milestones after age 6 mo and develop progressive cognitive and motor deterioration resulting in seizures, intellectual disability, paralysis, and death by age 5 yr. A cherry-red macular spot is common.
Diagnosis of Tay-Sachs disease is clinical and can be confirmed by enzyme assay. (Also see testing for suspected inherited disorders of metabolism.)
In the absence of effective treatment, management is focused on screening adults of childbearing age in high-risk populations to identify carriers (by way of enzyme activity and mutation testing) combined with genetic counseling.
There is a combined hexosaminidase A and B deficiency. Clinical manifestations include progressive cerebral degeneration beginning at 6 mo, accompanied by blindness, cherry-red macular spot, and hyperacusis. It is almost indistinguishable from Tay-Sachs disease in course, diagnosis, and management, except that there is visceral involvement (hepatomegaly and bone change) and no ethnic association.