Tay-Sachs disease

What is Tay-Sachs disease?¹

Tay-Sachs disease is a fatal, recessively inherited neurodegenerative lysosomal sphingolipid storage disorder of infancy and early childhood. It is characterised by:

• An exaggerated startle response.

• Delay in psychomotor development.

• Hypotonia (followed by spasticity).

• Visual loss.

• A macular cherry-red spot.

Causes of Tay-Sachs disease (pathogenesis)¹

Tay-Sachs disease (and its variants) are caused by absence or defects of the alpha subunit of hexosaminidase A. This leads to the accumulation of GM2 ganglioside in neurons of the central nervous system and retina. This causes progressive neurodegeneration and developmental delay.

How common is Tay-Sachs disease? (Epidemiology)²

• Tay-Sachs disease is an autosomal recessive inherited disorder.³

• Tay-Sachs disease affects 1 in 100,000 live births.

• It is strongly associated with Ashkenazi Jews (1 in 30 Ashkenazi Jews carries the gene).

• There are also isolated populations with increased risk around the world.

• The incidence is decreasing in at-risk populations, due to prenatal screening.

Presentation of Tay-Sachs disease⁴

The disease is classified by its age at presentation as either infantile (classic), juvenile or late-onset.

• An early and persistent extension response to sound ('startle reaction') is useful for recognising the disorder.

• Examination of reflexes shows hyperreflexia.

• 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 it 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.

• Death follows in the second or third year of life.

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 age 16 years.

Late-onset form

• First presents in adolescence and shows progressive neurological deficits with cognitive loss, ataxia.⁵

• 1 in 3 affected patients present with psychotic symptoms.

Differential diagnosis

Any other cause of developmental delay:

• Dementia.

• Seizures.

• Upper motor neurone disorder.

Investigations⁴

• 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 scan (to detect cerebellar atrophy).

• Electromyogram - (denervation and reinnervation may be seen in the adult chronic form).

Management of Tay-Sachs disease^{2 6}

There is no effective treatment for Tay-Sachs disease. Enzyme replacement has not yet been successful.

Supportive care eg antiepileptic drugs for seizures, physiotherapy for spasticity. Speech and language services may offer support on airway protection and feeding.

Complications of Tay-Sachs disease

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

Prognosis

Tay-Sachs disease is a progressive neurodegenerative disorder.³

• The classic infantile form is usually fatal by age 2 or 3 years.³ 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.

Prevention of Tay-Sachs disease

Screening for carriers in affected populations, especially in family members of affected patients. This should be offered with preconception counselling.⁷