Tay-Sachs disease

The GM2 gangliosidoses comprise three disorders that share a final pathway of GM2 ganglioside storage: Tay-Sachs disease (HEXA), Sandhoff disease (HEXB) and GM2 activator deficiency, the AB variant (GM2A). HEXA disorders and Sandhoff disease comprise a phenotypic continuum ranging from infantile to late-onset disease. GM2 activator deficiency most commonly presents as a severe infantile neurodegenerative disorder, although juvenile- and adult-onset cases have been reported. The acute infantile form typically manifests during the first year of life, often between ages 3 and 12 months, with progressive weakness, myoclonic jerks, an exaggerated startle reaction to sudden stimuli and decreasing visual attentiveness; a cherry-red macula is seen in virtually all affected infants. Untreated, death from respiratory complications historically occurs between ages two and three years. The subacute juvenile form presents between ages two and five years with progressive neurological decline. The late-onset form presents in older adolescents or young adults with slowly progressive neurogenic lower-limb weakness, dysarthria, incoordination, tremor and dystonia; psychiatric manifestations, including acute psychosis, are well recognised in late-onset HEXA disease. Acute infantile Sandhoff disease is clinically near-identical to acute infantile Tay-Sachs disease.

The estimated incidence of Tay-Sachs disease is 1/3,600 in Ashkenazi Jewish births in the pre-screening era, and is substantially lower in other populations. Sandhoff disease is panethnic, and GM2 activator deficiency is ultra-rare, with about two dozen cases reported.

The GM2 gangliosidoses are caused by biallelic germline pathogenic variants in one of three genes. HEXA (15q23) encodes the α-subunit of β-hexosaminidase A; HEXB (5q13) encodes the β-subunit shared by hexosaminidase A and B; and GM2A (5q33) encodes the GM2 activator protein that presents the substrate to the enzyme. Loss of any of these functions impairs degradation of GM2 ganglioside, which accumulates progressively within neuronal lysosomes and drives neuronal dysfunction, neuronal loss and neurodegeneration. In the AB variant the enzyme is intact, but the missing activator protein leaves the substrate inaccessible.

All three GM2 gangliosidoses are inherited in an autosomal recessive manner. Both parents of an affected individual are typically heterozygous carriers; each pregnancy of two carrier parents carries a 25% risk of an affected child, a 50% risk of a heterozygous carrier and a 25% risk of an unaffected non-carrier. Carrier testing for at-risk relatives and population-based carrier screening in high-risk founder populations are established practice. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

Diagnosis rests on β-hexosaminidase enzyme assay in serum or leucocytes, interpreted with the molecular finding. Tay-Sachs disease shows deficient HEX A with preserved HEX B; Sandhoff disease shows combined deficiency of HEX A and HEX B activity. In GM2 activator deficiency both HEX A and HEX B activities are normal, because the defect lies in the activator protein rather than the enzyme; molecular testing of GM2A is therefore required. Biallelic variant confirmation in HEXA, HEXB or GM2A establishes the diagnosis, because pseudodeficiency alleles can produce misleading enzyme results.

Main differential diagnoses include:

• GM1 gangliosidosis type 1: cherry-red spot and infantile neurological regression overlap with acute infantile presentations, distinguished by hepatosplenomegaly with coarse facies and skeletal disease; GLB1
• : infantile neurodegeneration with cherry-red spot and hepatosplenomegaly; SMPD1
• Other lysosomal and peroxisomal storage disorders presenting with infantile or juvenile neuroregression and visual loss

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant in HEXA, HEXB or GM2A, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive and carrier testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

• Toro C, Shirvan L, Tifft C. HEXA disorders. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: .
• Xiao C, Tifft C, Toro C. Sandhoff disease. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: .
• Xiao C, Toro C, Tifft C. GM2 activator deficiency. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: .