Tay-Sachs disease

Etiology and biochemical defect

• Caused by mutations in the HEXA gene on chromosome 15, encoding the α-subunit of Hex A.
• Hex A normally degrades GM2 ganglioside.
• Enzyme deficiency causes lysosomal accumulation of GM2 ganglioside, predominantly in neurons because the brain is rich in gangliosides.
• It is relatively frequent in people of Ashkenazi Jewish ancestry, with a reported carrier frequency of approximately 1 in 30.

Pathogenesis

Morphology

• Neurons are enlarged or ballooned with fine cytoplasmic vacuolation.
• The vacuoles are massively distended lysosomes containing ganglioside.
• Progressive neuronal loss, microglial proliferation, and lipid-laden phagocytes in brain tissue occur later.

• Characteristic lysosomal inclusions with concentric, laminated membrane layers, described as onion-skin or whorled membranous bodies.

• Retinal ganglion cells become swollen with GM2 ganglioside.
• This produces a cherry-red spot at the macula: the perifoveal retina becomes pale from swollen ganglion cells, contrasting with the normal red color of the underlying choroid at the fovea.

Clinical features

• Infant is usually normal at birth.
• Onset around 3 to 6 months of age, classically about 6 months.
• Progressive neurodegeneration with:
  • Developmental delay followed by loss of acquired milestones
  • Hypotonia progressing to weakness and flaccidity
  • Exaggerated startle response
  • Progressive blindness
  • Seizures may occur
  • Cherry-red macular spot
• Severe mental and motor deterioration progresses to a vegetative state.
• Death commonly occurs by 2 to 3 years in classic infantile disease.

Important negative feature

• No hepatosplenomegaly.
  This helps distinguish Tay-Sachs disease from Niemann-Pick disease, where hepatosplenomegaly is prominent.

Diagnosis

• Demonstration of markedly reduced or absent Hex A enzyme activity.
• Confirmation by HEXA molecular genetic testing.
• Carrier detection and antenatal diagnosis can be performed with enzyme assay and DNA-based testing.

One-line exam summary

Tay-Sachs disease is an autosomal recessive GM2 gangliosidosis due to HEXA mutation causing hexosaminidase A deficiency, with GM2 accumulation in neurons, ballooned vacuolated neurons with onion-skin lysosomal inclusions, cherry-red macula, progressive neurodegeneration, and no hepatosplenomegaly.

Tay-Sachs vs Niemann-Pick type A