Tay-Sachs Disease

An autosomal recessive inherited gangliosidosis characterized by the onset in the first 6 months of life of an exaggerated startle response, delay in psychomotor development, hypotonia (followed by spasticity), visual loss, and a macular cherry red spot.

Tay-Sachs disease and its variants are caused by absence or defects of the alpha subunit of Hexosaminidase A, leading to the accumulation of GM2 ganglioside in neurons of the central nervous system and retina, which causes progressive neurodegeneration and developmental delay. The disease is described by its age at presentation as:

• Infantile (classic)
• Juvenile
• Late-onset

• Tay-Sachs disease is an autosomal recessive inherited disorder.¹
• Strongly associated with Ashkenazy Jews (1 in 30 Ashkenazy Jews carry the gene).
• There are also isolated populations with increased risk around the world.
• Rare in the UK; 1 in 360,000 live births worldwide.
• Incidence is decreasing in affected population due to prenatal screening.

• Classic Tay-Sachs disease is characterized by the onset in infancy of developmental retardation, followed by paralysis, dementia and blindness, with death in the second or third year of life.
• An early and persistent extension response to sound ('startle reaction') is useful for recognizing the disorder.
• Examination of reflexes shows hyper-reflexia.
• Fundoscopy typically shows a grey-white area around the retinal fovea centralis, due to lipid-laden ganglion cells, leaving a central 'cherry-red' spot. The cherry-red central spot is seen in the macula of those affected with infantile and juvenile forms but not the late-onset form of Tay-Sachs disease.
• Infantile form:
  • Normal development until about 5 months when becomes apparent with excessive startle reaction and failure to reach landmarks for motor development.
  • After 8 months, the patient declines rapidly with increasing weakness leading to paralysis with difficulty in swallowing.
  • Other features include apathy, uncontrollable seizures, spasticity and dementia.
• Juvenile form:
  • At 3-10 years patient starts to lose motor and verbal skills.
  • May be impairment in cognitive ability and/or sight.
  • Patient declines to dementia with seizures, with death by age16 years.
• Late-onset form:
  • First presents in adolescence and shows progressive neurological deficits with cognitive loss, ataxia.²
  • 1 in 3 present with psychotic symptoms.

Any other cause of development delay, dementia, seizures or upper motor neurone disorder.

• Red blood cells: homozygotes and heterozygotes have a reduced concentration of sphingomyelin.
• Enzyme assay: deficient Hexosaminidase A activity in serum, white blood cells or tissue cultures (including amniocytes).
• Abnormal results should be followed by DNA analysis, which can also help to identify other carriers in the family for discussion of child-bearing options and prenatal diagnosis.
• CT or MRI to detect cerebellar atrophy.
• Electromyelogram: denervation and reinnervation may be seen in the adult chronic form.

• There is no effective treatment for Tay-Sachs disease.
• Supportive care, e.g. anti-epileptic drugs for seizures.
• Enzyme replacement has not yet been successful.

Severe difficulties with mobility and self-care lead to an enormous physical and emotional strain for the carer(s).

• Tay-Sachs disease is a progressive neurodegenerative disorder.¹
• The classic infantile form is usually fatal by age 2 or 3 years¹. Death usually occurs due to intercurrent infection.
• In the juvenile form, death usually occurs by age 10-15 years; preceded by several years of vegetative state with decerebrate rigidity. Death is usually due to infection.
• In the adult form, most patients have a normal life expectancy.

Screening for carriers in affected populations, especially in family members of affected patients, together with preconception counselling.