MAN2B1 – alpha-Mannosidosis

Alpha-mannosidosis is an autosomal recessive lysosomal storage disorder caused by deficiency of lysosomal α-mannosidase encoded by MAN2B1. Clinically, it presents with intellectual disability, hearing impairment, coarse facial features, hepatosplenomegaly and recurrent infections. Diagnosis is confirmed by demonstration of biallelic pathogenic MAN2B1 variants or enzyme activity assays. Over 130 unrelated patients have been reported with diverse mutation types, supporting a definitive gene–disease relationship (PMID:22161967).

Genetic evidence encompasses autosomal recessive inheritance with segregation in multiple sib-pairs and consanguineous families. Molecular analysis in 43 patients from 39 families revealed missense and nonsense mutations across severe and attenuated forms (PMID:9915946), while a cohort of 130 patients from 30 countries yielded 96 unique variants including 83 novel alleles (PMID:22161967). The high number of unrelated probands and consistent segregation exceed thresholds for definitive classification.

The variant spectrum spans missense, nonsense, frameshift, splice-site and copy‐number changes. A recurrent founder allele, c.2248C>T (p.Arg750Trp), accounts for ~27% of disease alleles across European and global cohorts (PMID:22161967). Loss-of-function alleles such as c.1197dup (p.Arg400fs) and canonical splice variants are widespread, while deep-intronic and CNV events contribute to complex genotypes.

Phenotypic heterogeneity correlates poorly with genotype but centers on lysosomal dysfunction. Onset ranges from infancy to adulthood; severe infantile cases often result in early mortality, whereas late-onset forms exhibit progressive hearing loss and skeletal anomalies. In a multicenter study of 16 patients, 87.5% experienced recurrent infections and diagnostic delays averaged 58 months (PMID:38382588). Early recognition is critical for therapeutic interventions.

Functional studies demonstrate that missense variants (e.g., p.His72Leu, p.Pro356Arg, p.Arg750Trp) dramatically reduce enzyme activity in COS-7 cell assays (PMID:9758606). Cellular localization and structural analyses categorize mutations by lysosomal transport efficiency, linking mislocalization with more severe cognitive and motor phenotypes.

In conclusion, MAN2B1 has a definitive association with alpha-mannosidosis based on robust genetic and functional evidence. Genetic testing for MAN2B1 variants informs diagnosis, prognosis and management, enabling timely enzyme replacement therapy or hematopoietic stem cell transplantation to improve clinical outcomes.

References

• American journal of human genetics • 1998 • Missense and nonsense mutations in the lysosomal alpha-mannosidase gene (MANB) in severe and mild forms of alpha-mannosidosis. PMID:9758606
• American journal of human genetics • 1999 • Spectrum of mutations in alpha-mannosidosis. PMID:9915946
• Human mutation • 2012 • Identification of 83 novel alpha-mannosidosis-associated sequence variants: functional analysis of MAN2B1 missense mutations. PMID:22161967
• European journal of medical genetics • 2024 • Long-term clinical evaluation of patients with alpha-mannosidosis - A multicenter study. PMID:38382588

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