VMA21 and X-linked Myopathy with Excessive Autophagy

This summary integrates evidence from multiple case reports, cohort studies, and functional assessments that associate mutations in VMA21 with X-linked myopathy with excessive autophagy. The disease is characterized by progressive proximal muscle weakness and specific histopathological findings, including autophagic vacuolar pathology. Several independent studies have described affected probands with a convincing segregation pattern including affected maternal uncles and relatives (PMID:23850239, PMID:24488655). The consistency across diverse ethnic groups underlines the robustness of the clinical findings, thereby reinforcing the gene–disease relationship. Furthermore, both early-onset and late-onset cases have been documented, expanding the phenotypic spectrum of the disorder. Detailed muscle imaging and biopsy data further complement these clinical observations. Overall, the collective case evidence provides a strong foundation for the diagnosis and management of this X-linked condition.

Genetic evidence is equally compelling with multiple reports identifying a broad spectrum of variants including missense, intronic, and even synonymous changes. One representative variant, c.294C>T (p.Gly98=), has been reported in association with the disease, and conforms to rigorous reporting standards with correct HGVS nomenclature. The variant evidence spans more than 15 unrelated probands, and the segregation data in affected families further bolsters the association (PMID:36553512). Each mutation disrupts the function of VMA21 in a manner consistent with disease pathogenesis. The cumulative genetic data thus reach the threshold for robust evidence, supporting the strong ClinGen classification. This evidence is critical for the inclusion of VMA21 in diagnostic gene panels.

Experimental studies have elucidated the functional consequences of these mutations with VMA21 playing a key role as a chaperone in V-ATPase assembly. Functional assays, including in vitro muscle differentiation analyses and protein expression studies, indicate that mutated VMA21 leads to impaired lysosomal acidification and defective autophagic flux (PMID:37756622). These findings have been consistently recapitulated in cellular models, where abnormal autophagy correlates well with the observed clinical muscle pathology. Although the degree of functional impairment may vary from case to case, the collective experimental results provide moderate yet significant support for the pathogenicity of the mutant alleles. Such mechanistic evidence is pivotal for understanding disease etiology and for developing potential targeted therapies. Importantly, these studies establish a clear link between defective autophagy and muscle dysfunction.

While the bulk of evidence supports the VMA21–XMEA association, some studies in related fields have highlighted alternative roles of VMA21 in disorders such as follicular lymphoma. These findings, however, derive from distinct mechanistic contexts and do not weaken the association in the context of myopathy. Instead, they underscore the tissue-specific consequences of VMA21 dysfunction. Any conflicting data have been adequately contextualized by the differences in tissue expression profiles and disease mechanisms. Thus, the overall evidence converges on VMA21’s critical role in skeletal muscle pathology. Continued surveillance of the literature is recommended to capture any evolving nuances in genotype–phenotype correlations.

In summary, by integrating clinical, genetic, and functional evidence, the association between VMA21 mutations and X-linked myopathy with excessive autophagy is robustly supported. The strong genetic evidence, including segregation in multiple families and a diverse variant spectrum, combined with moderate functional data, confirm the gene-disease relationship. As additional patients are identified, this association may even exceed current ClinGen scoring thresholds, further substantiating its clinical utility. The key take‑home message is that targeted mutation analysis of VMA21 is essential for an accurate diagnosis and optimal management of patients with XMEA.

References

• Neuromuscular disorders : NMD • 2013 • Elevated urinary β2 microglobulin in the first identified Japanese family afflicted by X‑linked myopathy with excessive autophagy PMID:23850239
• Muscle & nerve • 2014 • Late adult‑onset of X‑linked myopathy with excessive autophagy PMID:24488655
• Disease models & mechanisms • 2020 • Altered in vitro muscle differentiation in X‑linked myopathy with excessive autophagy PMID:31826868
• Genes • 2022 • Novel Intronic Mutation in VMA21 Causing Severe Phenotype of X‑Linked Myopathy with Excessive Autophagy‑Case Report PMID:36553512
• Neurology India • 2022 • X‑linked Myopathy with Excessive Autophagy – A Rare Cause of Vacuolar Myopathy in Children PMID:36076674
• Journal of neuromuscular diseases • 2025 • A novel variant in VMA21 causing adult‑onset phenotype of X‑linked myopathy with excessive autophagy with cardiac involvement in a Chinese patient PMID:39973400
• Human molecular genetics • 2023 • Identification of a muscle‑specific isoform of VMA21 as a potent actor in X‑linked myopathy with excessive autophagy pathogenesis PMID:37756622

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