Tay-Sachs Disease

Tay-Sachs disease is an autosomal recessive GM2 gangliosidosis due to deficiency of the alpha subunit of beta hexosaminidase A (HEXA, 15q23-q24), which leads to accumulation of GM2 ganglioside in neurons. Carrier frequency is about 1 in 27 to 30 in Ashkenazi Jews, French Canadians (Quebec), Cajun and Old Order Amish populations, and about 1 in 250 in the general population. Sandhoff disease (HEXB) causes a similar picture with visceral involvement.

Phenotypes: infantile (classic, onset 3 to 6 months), juvenile (subacute, onset 2 to 10 years) and late onset/adult (onset in adolescence or adulthood, with ataxia, dystonia, psychosis and motor neuron disease features).

• Infantile form: normal development to 3 to 6 months, followed by loss of motor skills, hypotonia, exaggerated startle response to noise (hyperacusis), visual inattentiveness, and a cherry red spot on the macula (in over 90%); progresses to spasticity, seizures, macrocephaly (after 18 months), blindness, decerebrate rigidity, bulbar failure, and death by 2 to 5 years
• Juvenile form: ataxia, dysarthria, cognitive decline, spasticity, seizures; death in teenage years
• Late onset: cerebellar ataxia, lower motor neuron disease, dystonia, psychiatric disease (psychosis, bipolar like illness), and survival into adulthood
• No hepatosplenomegaly (distinguishes from Niemann-Pick and Sandhoff)

1. Beta hexosaminidase A enzyme assay (serum, leucocytes or dried blood spots; absent or very low HexA activity with normal HexB; total hexosaminidase normal or elevated).
2. HEXA molecular analysis (common variants such as 1278insTATC, IVS12+1G>C and G269S), and sequencing and deletion analysis to confirm.
3. Fundoscopy (cherry red spot), brain MRI (hypomyelination, thalamic hyperintensity on T1 and hyperdensity on CT), and EEG.
4. Carrier screening in high risk populations by enzyme assay and DNA analysis; prenatal diagnosis by CVS or amniocentesis, or preimplantation genetic testing.

• No curative treatment. Care is palliative and supportive: seizure control (levetiracetam, valproate, clonazepam, with benzodiazepines for acute seizures), management of feeding and aspiration (gastrostomy), respiratory physiotherapy, antibiotic treatment of aspiration pneumonia, spasticity treatment (baclofen 0.5 to 2 mg/kg/day divided, botulinum toxin), pain relief, glycopyrronium or hyoscine for drooling, skin care, and palliative care with family support.
• Late onset patients: antiepileptics, antipsychotics and antidepressants with careful tolerance (avoid agents that exacerbate; some patients are sensitive to neuroleptics), physiotherapy, and speech therapy.
• Experimental: substrate reduction (miglustat; venglustat), pyrimethamine pharmacological chaperone, and AAV gene therapy in early trials; bone marrow transplantation and enzyme replacement were not effective.
• Genetic counselling: 25% recurrence risk; carrier screening programmes in high risk communities have reduced incidence by over 90%.