HEXA – Tay–Sachs Disease

Tay–Sachs disease is an autosomal recessive neurodegenerative disorder caused by loss‐of‐function mutations in the HEXA gene, leading to β-hexosaminidase A deficiency and neuronal GM2 ganglioside accumulation. Classic infantile Tay–Sachs presents with developmental regression, hypotonia, cherry-red macula, and death by age 4, whereas late-onset forms manifest in adolescence or adulthood with ataxia, spasticity, movement disorders, and psychiatric features. Diagnosis relies on enzymatic assays of leukocyte or fibroblast Hex A activity and confirmation via HEXA genetic testing.

Extensive case reports and series have described over 50 distinct HEXA alleles across more than 100 unrelated probands, including missense, nonsense, splice-site, small insertions/deletions, and intronic variants. For example, a novel c.1260G>C (p.Trp420Cys) mutation in exon 11 abolishes enzyme activity in COS I cells and was confirmed in a compound heterozygote with infantile Tay–Sachs disease ([PMID:2144098]). Other recurrent alleles include c.805G>A (p.Gly269Ser), prevalent in Ashkenazi Jewish late-onset patients, and the 1278insTATC founder insertion in exon 11 common in multiple ethnic groups.

Segregation in consanguineous and extended families further supports autosomal recessive inheritance; for instance, four affected siblings in a non-Jewish kindred all carried bi-allelic pathogenic HEXA mutations ([PMID:9073025]). Population studies have identified ethnic-specific alleles—such as c.754C>T (p.Arg252Cys) in Czech late-onset cases ([PMID:31076878]) and c.524A>C (p.Asp175Ala) in Indian patients ([PMID:33811753])—facilitating targeted carrier screening in those communities.

Functional assays across multiple studies demonstrate that pathogenic HEXA variants disrupt α-subunit folding, dimerization, and lysosomal trafficking. COS-cell expression of c.533G>A (p.Arg178His) and c.986+3A>G splice mutations yield misfolded protein subjected to endoplasmic reticulum–associated degradation, correlating with absent or residual enzyme activity in patient fibroblasts ([PMID:9090529]; [PMID:7551830]). Mouse and spontaneous animal models (e.g., flamingo Homozygotes for P469L) replicate GM2 accumulation and neurodegeneration, underscoring the mechanistic link.

No credible conflicting evidence has been reported; pseudodeficiency alleles (e.g., c.739C>T [p.Arg247Trp]) are biochemically and genetically distinguished from disease-causing alleles through combined enzyme and DNA analyses ([PMID:7902672]).

Overall, the gene–disease relationship between HEXA and Tay–Sachs disease is classified as Definitive based on decades of consistent clinical, genetic, and functional concordance. Genetic testing of HEXA is essential for diagnostic confirmation, carrier screening, prenatal or preimplantation genetic diagnosis, and informing clinical management of at-risk families.

Key Take-home: Comprehensive HEXA variant analysis alongside enzymatic assays enables accurate Tay–Sachs diagnosis and underpins effective genetic counseling and family planning.

References

• American journal of human genetics • 1990 • A new point mutation in the beta-hexosaminidase alpha subunit gene responsible for infantile Tay-Sachs disease in a non-Jewish Caucasian patient PMID:2144098
• Journal of the neurological sciences • 1997 • Progressive cerebellar ataxia, proximal neurogenic weakness and ocular motor disturbances: hexosaminidase A deficiency with late clinical onset in four siblings PMID:9073025
• Human mutation • 1997 • Novel HEXA mutation in a Bedouin Tay-Sachs patient associated with exon skipping and reduced transcript level PMID:9090529
• Biochemical and molecular medicine • 1995 • An A-to-G mutation at the +3 position of intron 8 of the HEXA gene is associated with exon 8 skipping and Tay-Sachs disease PMID:7551830
• Journal of neurology • 2019 • Amyotrophy, cerebellar impairment and psychiatric disease are the main symptoms in a cohort of 14 Czech patients with the late-onset form of Tay-Sachs disease PMID:31076878
• Molecular genetics & genomic medicine • 2021 • Novel HEXA variants in Korean children with Tay-Sachs disease with regression of neurodevelopment from infancy PMID:33811753

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