Tay-Sachs disease

All forms are characterised by neurological symptoms due to progressive accumulation of GM2 in central nervous system neurons, leading to neuronal loss and demyelination.

The classical form presents with progressive weakness, loss of motor skills from three to six months of age, decreased visual attention, increased startle response, and a cherry-red spot on the macula indicating macular cell loss. A developmental plateau and regression occur after eight to ten months, accompanied by progressive macrocephaly and proportional ventricular enlargement at around 18 months. Seizures typically appear at about 12 months, with further deterioration during the second year of life; death usually occurs between two and three years, although survival up to seven years has rarely been reported.

The subacute juvenile form shows normal development until about two years of age, followed between three and eleven years by motor impairment such as coordination difficulties, abnormal gait, and dysarthria. Additional features of the classical form develop, including a cherry-red macular spot, developmental plateau, and regression due to global cerebral atrophy. Progressive spasticity, dysphagia and seizures appear towards the end of the first decade, with death usually occurring in the second decade, often due to aspiration.

The late-onset form appears in older adolescents or young adults with slowly progressive neurological symptoms, including lower limb weakness with muscle atrophy, dysarthria, coordination impairment, tremor, mild spasticity and/or dystonia, as well as psychiatric manifestations including acute psychosis. CNS imaging shows isolated cerebellar atrophy. Clinical variability occurs even among affected members of the same family in both the juvenile and late-onset forms.

Tay-Sachs disease is a rare disease with a worldwide incidence of approximately 1:250,000–360,000, and about 100-fold higher incidence in Ashkenazi Jewish populations.

Tay-Sachs disease results from pathogenic variants in the HEXA gene causing reduced activity of β-N-acetylhexosaminidase isozyme A (HEX A). This leads to impaired lysosomal degradation of ganglioside GM2 and progressive accumulation in neurons of the central nervous system, resulting in neuronal loss and demyelination.

All forms of Tay-Sachs disease are inherited in an autosomal-recessive manner, meaning both alleles must be affected for clinical manifestation.

Prior to molecular genetic testing of the HEXA gene, enzyme activity determination of β-N-acetylhexosaminidase should be performed. Characteristically, isozyme A activity is absent or markedly reduced, while isozyme B activity is normal or increased. Molecular genetic testing can identify pathogenic variants in the HEXA gene, supporting the confirmation of suspected Tay-Sachs disease.

Therapy is primarily symptomatic and consists of adequate nutrition and hydration, treatment of infectious diseases, respiratory protection, and control of seizures. A number of drug therapies are currently being tested.

Tay-Sachs disease belongs to the sphingolipidoses, a subgroup of lysosomal storage diseases characterised by impaired degradation of sphingolipids. The clinical presentation varies according to disease form but consistently involves neurological manifestations due to GM2 accumulation in central nervous system neurons.

• Toro et al. 2020, GeneReviews®, HEXA Disorders, GeneReviews® [Internet]
• Solovyeva et al. 2018, Front Physiol 9:1663