GLB1 – GM1 Gangliosidosis

GM1 gangliosidosis is an autosomal recessive neurodegenerative lysosomal storage disorder caused by biallelic pathogenic variants in the GLB1 gene encoding β-galactosidase. Affected individuals present across a continuum of severity—infantile (Type I), late-infantile/juvenile (Type II), and adult/chronic (Type III)—with hallmark findings of progressive motor and cognitive decline, dystonia, and characteristic radiologic changes. Early recognition relies on enzymatic assays complemented by molecular testing.

Genetic evidence supports a definitive association between GLB1 and GM1 gangliosidosis. Over 261 pathogenic variants have been described in more than 100 unrelated probands, with recurrent alleles such as c.601C>T (p.Arg201Cys) and c.1445G>A (p.Arg482His) and clear biallelic segregation in multiplex families ([PMID:34539759]). Large cohorts include 16 adult patients from 10 Japanese families ([PMID:1353343]) and 61 French patients spanning all clinical subtypes ([PMID:37381921]). Variants encompass missense (>200), splice-site (>20), small indels, and in-frame deletions such as c.1468_1470del (p.Asn490del) ([PMID:30187681]). Founder and population-specific alleles (e.g., p.Arg482His in Cyprus, p.Ile51Thr in Japan) have been documented, and uniparental disomy cases emphasize diverse inheritance mechanisms ([PMID:24777551]).

Functional studies corroborate pathogenicity and elucidate mechanism. Most missense mutations impair protein folding and trafficking, causing endoplasmic reticulum retention and rapid degradation. Enzyme kinetics demonstrate severely reduced Vmax for active-site residues (e.g., p.Asp332Asn) ([PMID:10839995]). Cellular and animal models, including iPSC-derived neurons and human cerebral organoids, recapitulate GM1 storage and are rescued by AAV9-GLB1 gene delivery ([PMID:39213692]; [PMID:31534909]). Small-molecule chaperone studies show that compounds like N-butyl-deoxygalactonojirimycin enhance residual activity in select variants, supporting enzyme enhancement therapy ([PMID:20409738]).

Conflicting and modifying evidence include pseudodeficiency alleles (e.g., p.Arg595Trp) that reduce in vitro activity without clinical disease, complicating carrier screening and enzymatic diagnosis ([PMID:17661814]). Complex alleles combining polymorphisms (e.g., p.Leu436Phe) can modulate phenotype severity, underscoring the need for comprehensive molecular and functional assessment ([PMID:12644936]).

Integration of robust genetic, biochemical, and animal/cellular model data yields a definitive gene–disease relationship. Early biomarkers (e.g., alkaline phosphatase elevation) and radiographic signs guide timely molecular testing. These insights facilitate accurate diagnosis, genetic counseling, and the design of therapeutic trials for GM1 gangliosidosis.

Key Take-home: GLB1 testing is clinically actionable, with definitive evidence supporting comprehensive molecular analysis and emerging therapies justified by concordant functional data.

References

• Annals of neurology • 1992 • GM1 gangliosidosis in adults: clinical and molecular analysis of 16 Japanese patients PMID:1353343
• Clinical genetics • 2010 • Phenotype determining alleles in GM1 gangliosidosis patients bearing novel GLB1 mutations PMID:20175788
• Frontiers in genetics • 2021 • GM1 Gangliosidosis-A Mini-Review. PMID:34539759
• Molecular genetics & genomic medicine • 2018 • Protein modeling and clinical description of a novel in-frame GLB1 deletion causing GM1 gangliosidosis type II. PMID:30187681
• Stem cell research • 2024 • Establishment of iPS cell line (SDQLCHi080-A) from a patient with GM1 gangliosidosis due to GLB1 mutation. PMID:39213692
• Molecular genetics and metabolism reports • 2019 • Human GLB1 knockout cerebral organoids: A model system for testing AAV9-mediated GLB1 gene therapy for reducing GM1 ganglioside storage in GM1 gangliosidosis. PMID:31534909

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