X-linked myopathy with excessive autophagy: First report of an Israeli family presenting with late onset lower limb girdle weakness

Alon, Tayir; Sadeh, Menachem; Lev, Dorit; Dabby, Ron

doi:10.1016/j.nmd.2021.06.013

Cited by 3 publications

(2 citation statements)

References 19 publications

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“…F-1: The age of onset is quite variable, though typically described as childhood onset. There are various reports on adult-onset myopathy, as noted in our patient, 4,9,15 with the oldest being onset in the seventh decade, as reported by Crockett et al 3 It typically affects males and spares carrier females. The phenotypic spectrum extends from floppy infant delayed milestones to proximal limb-girdle and respiratory muscle weakness.…”

Section: Discussionsupporting

confidence: 62%

“…Though there are many case reports from Europe and America, there are only a few cases from Asia (Comparison with previous studies is given in ►Table 1). 1,3-5, [7][8][9][10][11][12][13][14][15][16][17] XMEA affects males and has a slowly progressive proximal limb muscle weakness and normal cardiac function with onset ranging from childhood to adulthood. 10 VMA21 is an assembly chaperone for the principal mammalian proton pump required for lysosome acidification.…”

Section: Discussionmentioning

confidence: 99%

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Identification of a Novel Intronic Mutation in VMA21 Associated with a Classical Form of X-Linked Myopathy with Autophagy

Bardhan,

Polavarapu,

Baskar

et al. 2024

Glob Med Genet

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Introduction VMA21-related myopathy is one of the rare forms of slowly progressive myopathy observed in males. Till now, there have been only a handful of reports, mainly from Europe and America, and two reports from India. Method Here, we describe a case of genetically confirmed VMA21-associated myopathy with clinical, histopathological, and imaging features with a list of known VMA21 mutations. Results A 29-year-old man had the onset of symptoms at 18 years of age with features of proximal lower limb weakness. Muscle magnetic resonance imaging showed the preferential involvement of vasti and adductor magnus. A biopsy of the left quadriceps femoris showed features of autophagic vacuolar myopathy with vacuoles containing granular eosinophilic materials. In targeted next-generation sequencing, hemizygous mutation in the 3′ splice site of intron 2 of the VMA21 gene (c.164–7 T > A) was identified and confirmed the diagnosis of X-linked myopathy with excessive autophagy. Conclusion This report expands the phenotypic and genotypic profile of VMA21-related myopathy, with a yet unreported mutation in India.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Intronic Mutation in VMA21 Associated with a Classical Form of X-Linked Myopathy with Autophagy

Bardhan,

Polavarapu,

Baskar

et al. 2024

Glob Med Genet

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Phenotype variability and natural history of X-linked myopathy with excessive autophagy

Fernández-Eulate,

Alfieri,

Spinazzi

et al. 2024

J Neurol

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Comprehensive genomic filtering algorithm to expose the cause of skewed X chromosome inactivation. The proof of concept in female haemophilia expression

Ziegler,

Abelleyro,

Marchione

et al. 2024

J Med Genet

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BackgroundExploring the expression of X linked disorders like haemophilia A (HA) in females involves understanding the balance achieved through X chromosome inactivation (XCI). Skewed XCI (SXCI) may be involved in symptomatic HA carriers. We aimed to develop an approach for dissecting the specific cause of SXCI and verify its value in HA.MethodsA family involving three females (two symptomatic with severe/moderate HA: I.2, the mother, and II.1, the daughter; one asymptomatic: II.2) and two related affected males (I.1, the father and I.3, the maternal uncle) was studied. The genetic analysis includedF8mutational screening, multiplex ligation-dependent probe amplification, SNP microarray, whole exome sequencing (WES) and Sanger sequencing. XCI patterns were assessed in ectoderm/endoderm and mesoderm-derived tissues usingAR-based andRP2-based systems.ResultsThe comprehensive family analysis identifies I.2 female patient as a heterozygous carrier ofF8:p.(Ser1414Ter) excluding copy number variations. A consistent XCI pattern of 99.5% across various tissues was observed. A comprehensive filtering algorithm for WES data was designed, developed and applied to I.2. A Gly58Arg missense variant inVMA21was revealed as the cause for SXCI.Each step of the variant filtering system takes advantage of publicly available genomic databases, non-SXCI controls and case-specific molecular data, and aligns with established concepts in the theoretical background of SXCI.ConclusionThis study acts as a proof of concept for our genomic filtering algorithm’s clinical utility in analysing X linked disorders. Our findings clarify the molecular aspects of SXCI and improve genetic diagnostics and counselling for families with X linked diseases like HA.

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X-linked myopathy with excessive autophagy: First report of an Israeli family presenting with late onset lower limb girdle weakness

Cited by 3 publications

References 19 publications

Identification of a Novel Intronic Mutation in VMA21 Associated with a Classical Form of X-Linked Myopathy with Autophagy

Identification of a Novel Intronic Mutation in VMA21 Associated with a Classical Form of X-Linked Myopathy with Autophagy

Phenotype variability and natural history of X-linked myopathy with excessive autophagy

Comprehensive genomic filtering algorithm to expose the cause of skewed X chromosome inactivation. The proof of concept in female haemophilia expression

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