GMPPB – Congenital Myasthenic Syndrome

Clinical Validity

GMPPB (HGNC:22932) is definitively associated with autosomal recessive congenital myasthenic syndrome (CMS) (MONDO:0018940). Seven unrelated probands with biallelic GMPPB variants were first described in five kinships [PMID:26133662], followed by five additional probands in a Chinese cohort [PMID:28433477] and two further patients in a genetic registry [PMID:33756069]. Segregation in these five families and consistent functional and animal model concordance support a definitive gene–disease relationship.

Genetic Evidence

Inheritance is autosomal recessive, with pathogenic GMPPB variants leading to fatigable limb‐girdle weakness and neuromuscular transmission defects. The spectrum includes missense (e.g., c.578T>C (p.Ile193Thr) [PMID:26133662], c.79G>C (p.Asp27His) [PMID:23768512]) and truncating alleles. Recurrent hypomorphic alleles such as p.Arg357His have been noted in Chinese patients [PMID:28433477]. Muscle biopsies show myopathic features, elevated serum creatine kinase, and decrement on repetitive nerve stimulation.

Functional Evidence

GMPPB mutations impair α-dystroglycan glycosylation in patient muscle and fibroblasts, restored by wild-type overexpression [PMID:23768512]. In vitro, mutant GMPPB forms cytoplasmic aggregates that colocalize with LC3-II and undergo lysosomal degradation reversible by leupeptin [PMID:31211170]. Zebrafish knockdown of gmppb recapitulates muscle defects, motility impairment, and hypoglycosylated α-dystroglycan, confirming pathogenicity [PMID:23768512].

Conflicting Evidence

No studies to date have refuted the GMPPB–CMS association or described alternative phenotypes for the same biallelic variants.

Integration & Conclusion

Genetic and experimental data converge on a mechanism of GMPPB deficiency leading to defective glycosylation of neuromuscular junction components and myofiber instability. The definitive association enables targeted genetic testing of GMPPB in suspected CMS cases, particularly those with limb-girdle weakness and elevated creatine kinase, and suggests enzyme supplementation or autophagy modulation as potential therapeutic strategies.

Key take-home: Biallelic GMPPB variants cause autosomal recessive CMS through hypoglycosylation of α-dystroglycan and autophagy-lysosome–mediated enzyme loss, supporting GMPPB screening in CMS diagnostics.

References

• Brain | 2015 | Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies. PMID:26133662
• American Journal of Human Genetics | 2013 | Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan PMID:23768512
• Neuromuscular Disorders | 2017 | Novel mutations in the C-terminal region of GMPPB causing limb-girdle muscular dystrophy overlapping with congenital myasthenic syndrome. PMID:28433477
• Annals of Clinical and Translational Neurology | 2019 | Lysosomal degradation of GMPPB is associated with limb-girdle muscular dystrophy type 2T. PMID:31211170
• Annals of Clinical and Translational Neurology | 2021 | Congenital myasthenic syndrome in China: genetic and myopathological characterization. PMID:33756069

Evidence Based Scoring (AI generated)