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Tay-Sachs Disease and Sandhoff Disease

By

Matt Demczko

, MD, Sidney Kimmel Medical College of Thomas Jefferson University

Last full review/revision Apr 2020| Content last modified Apr 2020
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Tay-Sachs disease and Sandhoff disease are sphingolipidoses Sphingolipidoses Lysosomal enzymes break down macromolecules, either those from the cell itself (eg, when cellular structural components are being recycled) or those acquired outside the cell. Inherited defects... read more , 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.

Tay-Sachs disease

Deficiency of hexosaminidase A results in accumulation of GM2 in the brain. Inheritance is autosomal recessive Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more ; 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 months and develop progressive cognitive and motor deterioration resulting in seizures, intellectual disability, paralysis, and death by age 5 years. A cherry-red macular spot is common.

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.

Sandhoff disease

There is a combined hexosaminidase A and B deficiency. Clinical manifestations include progressive cerebral degeneration beginning at 6 months, 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.

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