Tay-Sachs disease

Tay-Sachs disease is a progressive neurodegenerative disease caused by defects in the lysosomal enzyme hexosaminidase-A, encoded by the HEXA gene. Defects in this enzyme lead to an accumulation of GM2 gangliosides that are toxic to neurons.

GM2 gangliosidosis or Tay-Sachs disease is among the best known autosomal recessive diseases and belongs to the group of lysosomal storage diseases. This condition is characterized by the accumulation of GM2 gangliosides (a type of lipid) due to a deficiency in the lysosomal enzyme hexosaminidase-A.

Tay-Sachs disease is caused by pathogenic variants in the HEXA gene coding for hexosaminidase-A. Depending on how the variant affects the enzyme and residual enzyme activity, symptoms may be more or less severe. Defects in hexosaminidase-A cause GM2-type gangliosides, which are important molecules in the membranes of neurons and are essential for neuronal development and function, not to degrade properly in the lysosomes and accumulate to levels that are toxic and ultimately trigger the disease.

The prevalence of gangliosidosis is 1 in 3,900 births among Ashkenazi Jews and 1 in 1,000,000 births in the general population. Although the incidence of the disease is very low, it is estimated that one in 250 people carry a Tay-Sachs-related variant.


Three variants have been described depending on the age of disease onset:

  • The early-onset or infantile form (enzyme activity 0-5%) is the most severe and has as its main symptoms gray matter degeneration beginning between 3 and 6 months of age with muscle weakness, irritability and increased sensitivity to sensory stimuli such as auditory stimuli. The appearance of a cherry-red spot on the ocular macula may be indicative of the disease.
  • In the juvenile form (enzyme activity 10-15%), the onset of the disease is between 2 and 6 years of age, with ataxia, behavioral disorders and a progressive loss of intellectual abilities that eventually compromise the survival of the patients.
  • The chronic adult form (enzyme activity 10-15%) may begin around the age of 10 years, although the disorder is often not diagnosed until adulthood. It presents with muscle weakness in the lower extremities, atrophy, incoordination, tremor, dystonia and psychiatric manifestations with cognitive impairment.

Disease management

There is no effective treatment for Tay-Sachs disease; medications are used to alleviate symptoms, such as antiepileptic drugs. Multiple strategies are currently being developed to treat the disease, including enzyme replacement therapy, chaperone therapy, substrate reduction therapy, gene therapy and hematopoietic stem cell replacement therapy.

Genes analyzed



Park JH, Ko JM, Kim MS, et al . Novel HEXA variants in Korean children with Tay-Sachs disease with regression of neurodevelopment from infancy. Mol Genet Genomic Med. 2021 Jun;9(6):e1677.

Ou L, Kim S, Whitley CB, Jarnes-Utz JR. Genotype-phenotype correlation of gangliosidosis mutations using in silico tools and homology modeling. Mol Genet Metab Rep. 2019 Jul 17;20:100495.

Ramani PK, Parayil Sankaran B. Tay-Sachs Disease. 2022 Mar 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

Toro C, Shirvan L, Tifft C. HEXA Disorders. 1999 Mar 11 [updated 2020 Oct 1]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.

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