HEXB – Sandhoff Disease

Biallelic mutations in HEXB (HGNC:4879) disrupt the β-subunit of lysosomal β-hexosaminidase, leading to Sandhoff disease (MONDO:0010006), a GM2 gangliosidosis with progressive neurodegeneration. Disease manifestations range from infantile onset with psychomotor regression, seizures and cherry-red macular spots to adult presentations with motor neuron and cerebellar phenotypes.

Extensive case series and cohort studies have established a robust genetic association: over 100 unrelated probands across diverse populations, including 14 Italian patients (PMID:22848519), 31 UK cases (PMID:22115551), and 22 Indian patients (PMID:26582265), harbor pathogenic HEXB variants, with consistent enzyme deficiency and clinical correlation.

Inheritance is autosomal recessive, confirmed by segregation analyses in multiple families. For example, three adult siblings sharing compound heterozygous mutations exhibited early and severe sensory neuropathy and lower motor neuron signs (PMID:8530938). Segregation of pathogenic alleles in consanguineous pedigrees further supports causality.

The variant spectrum includes loss-of-function alleles (nonsense, frameshift, large deletions), splicing mutations, and missense changes. A recurrent founder frameshift, c.115del (p.Val39TrpfsTer25), has been identified in several affected individuals and used for targeted screening (PMID:22191674). Missense variants such as p.Pro417Leu and p.Arg505Gln associate with juvenile and adult phenotypes, respectively, whereas null alleles underlie infantile disease.

Functional studies demonstrate that HEXB mutations abrogate hexosaminidase activity and disrupt neuronal development. A Greek-Cypriot splice variant at IVS8 nt5 (c.1082+5G>C) causes exon skipping and premature termination in CHO cells (PMID:9888387). In Hexb−/− mice, reduced Sox2 expression, delayed neuronal migration, and altered cortical layering mirror human neurodevelopmental defects (PMID:31340161). These data confirm haploinsufficiency as the primary mechanism.

No studies have refuted this gene–disease link. The convergence of genetic, biochemical, and model organism evidence supports a Strong ClinGen classification.

Key Take-home: HEXB mutations cause autosomal recessive Sandhoff disease; molecular diagnosis informs carrier screening, newborn testing, and guides enrollment in emerging substrate reduction and gene therapy trials.

References

• PloS one • 2012 • Sequence and copy number analyses of HEXB gene in patients affected by Sandhoff disease: functional characterization of 9 novel sequence variants. PMID:22848519
• Genetic testing and molecular biomarkers • 2012 • A polymerase chain reaction-based genotyping assay for detecting a novel Sandhoff disease-causing mutation. PMID:22191674
• Developmental medicine and child neurology • 2012 • GM2 gangliosidosis in a UK study of children with progressive neurodegeneration: 73 cases reviewed. PMID:22115551
• Journal of human genetics • 2016 • Clinical, biochemical and mutation profile in Indian patients with Sandhoff disease. PMID:26582265
• Metabolic brain disease • 2016 • Clinical, biochemical and molecular analysis of five Chinese patients with Sandhoff disease. PMID:27021291
• Neuroscience research • 2020 • Abnormal organization during neurodevelopment in a mouse model of Sandhoff disease. PMID:31340161
• Human mutation • 1999 • Novel splice site mutation at IVS8 nt 5 of HEXB responsible for a Greek-Cypriot case of Sandhoff disease. PMID:9888387
• Journal of neurology, neurosurgery, and psychiatry • 1995 • Early and severe sensory loss in three adult siblings with hexosaminidase A and B deficiency (Sandhoff disease). PMID:8530938

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