MANBA – beta-mannosidosis

Beta-mannosidosis is a rare autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in MANBA, encoding the lysosomal enzyme β-mannosidase. Affected individuals present with intellectual disability, hearing impairment and dysostosis multiplex, with onset ranging from infancy to adulthood. Diagnosis is confirmed by deficient β-mannosidase activity in fibroblasts, leukocytes and plasma, and by identification of MANBA variants.

Genetic studies have identified over 30 affected individuals from more than 20 families worldwide (PMID:2079835, PMID:1623631, PMID:32847582). The inheritance is autosomal recessive, with homozygous or compound heterozygous LoF and missense alleles. A recurrent splice acceptor variant, c.2158-2A>G, accounts for multiple cases in Roma populations with a carrier frequency of 3.77% (PMID:32847582).

The variant spectrum includes 14 null alleles (nonsense, frameshift, canonical splice) and missense mutations that abolish enzymatic activity. Representative pathogenic variants include c.1513T>C (p.Ser505Pro) (PMID:1623631), c.693G>A (p.Trp231Ter) (PMID:17420068), c.1454_1455del (p.Tyr485fs) (PMID:12890191), and the splice defect c.960+1G>A (PMID:12890191).

Segregation analyses in multiple families demonstrate cosegregation of homozygous or compound heterozygous alleles with disease, while parents and unaffected siblings carry heterozygous alleles at heterozygote enzyme activity levels (PMID:2079835).

Functional assays corroborate pathogenicity: patient-derived cells show absent β-mannosidase activity (PMID:2079835), COS-7 expression of missense alleles (e.g., p.Ser505Pro, p.Arg182Trp, p.Gly392Glu) yields no enzymatic activity (PMID:18565776), and site-directed mutagenesis in HEK293T cells confirms residual activity (~7–14%) for p.Arg641His, suggesting pseudodeficiency (PMID:19728872).

Integration of genetic and experimental data supports a Definitive gene–disease relationship. No conflicting evidence has been reported. Genetic testing for MANBA and enzymatic assays enable accurate diagnosis and carrier screening, including ethnic-specific variants.

Key Take-home: Pathogenic LoF and missense variants in MANBA cause beta-mannosidosis, an autosomal recessive lysosomal disorder with multisystemic manifestations; comprehensive genetic and enzymatic testing is essential for diagnosis and family counseling.

References

• Journal of inherited metabolic disease • 1990 • Beta-mannosidase deficiency: heterogeneous manifestation in the first female patient and her brother. PMID:2079835
• Clinical Genetics • 1992 • Human beta-mannosidosis: a 3-year-old boy with speech impairment and emotional instability. PMID:1623631
• Molecular Genetics and Metabolism • 2008 • Identification of two novel beta-mannosidosis-associated sequence variants: biochemical analysis of beta-mannosidase (MANBA) missense mutations. PMID:18565776
• BMC Medical Genetics • 2009 • A MANBA mutation resulting in residual beta-mannosidase activity associated with severe leukoencephalopathy: a possible pseudodeficiency variant. PMID:19728872
• Orphanet Journal of Rare Diseases • 2020 • Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population– evidence for a new ethnic-specific variant. PMID:32847582
• The British Journal of Dermatology • 2003 • Morphological and biochemical studies of human beta-mannosidosis: identification of a novel beta-mannosidase gene mutation. PMID:12890191

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