Question

Sphingolipid storage diseases (sphingolipidoses) are inherited diseases caused by abnormal accumulation of membrane lipids. Elaborate on the molecular basis behind Tay-Sachs disease.

Answer 1

Gangliosides are anionic glycosphingolipid along with sialic acid linked on a chain of sugar (ceramide oligosaccharides).Gangliosides are found in most of the cell membranes but they are found more abundantly in axon and dendrites. They serve as receptor for several hormones (glycoproteins).

Tay sach disease is one of the main sphingolipidoses. The inheritance pattern is autosomal recessive. Therefore, both the alleles should be mutated for disease to be fully developed.

In tay sach disease one of the key sphingolipid degrading enzyme Hexosaminidase A is poorly functional or non functional. Hexosaminidase A enzyme has two subunits- alpha (coded by HEXA) and beta (coded by HEXB). Both these subunits with the help of an activator protein degrade the ganglioside. Mutation in alpha subunit (HEXA gene) causes Tay sach disease.

Hexosaminidase A enzyme is important for ganglioside (GM2) degradation by removal of N acetylgalactosamine. The mutation in HEXA gene leads to accumulation of ganglioside in lysosome of neurons. Therefore, disease materializes. Mutation in HEXA gene does not affects active site of the enzyme necessarily. But it affects folding of protein and thereby targeting of enzyme to lysosome is hindered.

The disease onset happens in infantile, juvenile stage or in Adults ( If some activity of hexosaminidase is present).

In infantile disease, death happens before reaching 4 years of age with neuron degradation starting from 6-8 month and visual loss after one year (Retinal cherry sput is common)..In case of juvenile disease deterioration of neurons starts after 2 years of age. This leads to poor coordination and ataxia. After 10 years of age seizures become frequent along with decerebrate rigidity and coma. afterwards, the characteristic cherry spot in retina becomes visible along with optic atrophy. Patient mostly dies before reaching 15 years of age

In adults, symptoms are more diverse.like various psychiatric abnormalities, spinocerebellar degeneration. However, in case of adults eye sight is not affected much.