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

Abstract

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.

Keywords

VMA21-related myopathy - autophagy - muscle MRI

Prior Publication

None.

Publikationsverlauf

Artikel online veröffentlicht:
10. Mai 2024

• References

• 1 Kalimo H, Savontaus ML, Lang H. et al. X-linked myopathy with excessive autophagy: a new hereditary muscle disease. Ann Neurol 1988; 23 (03) 258-265
• 2 Ramachandran N, Munteanu I, Wang P. et al. VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy. Acta Neuropathol 2013; 125 (03) 439-457
• 3 Crockett CD, Ruggieri A, Gujrati M. et al. Late adult-onset of X-linked myopathy with excessive autophagy. Muscle Nerve 2014; 50 (01) 138-144
• 4 Mercier S, Magot A, Caillon F. et al. Muscle magnetic resonance imaging abnormalities in X-linked myopathy with excessive autophagy. Muscle Nerve 2015; 52 (04) 673-680
• 5 Munteanu I, Ramachandran N, Ruggieri A, Awaya T, Nishino I, Minassian BA. Congenital autophagic vacuolar myopathy is allelic to X-linked myopathy with excessive autophagy. Neurology 2015; 84 (16) 1714-1716
• 6 Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF. et al. Predicting splicing from primary sequence with deep learning. Cell 2019; 176 (03) 535-548.e24
• 7 Rajeshwari M, Dhiman N, Chakrabarty B. et al. X-linked myopathy with excessive autophagy—a rare cause of vacuolar myopathy in children. Neurol India 2022; 70 (04) 1643-1648
• 8 Rao S, Chandra SR, Narayanappa G. X-linked myopathy with excessive autophagy; a case report. Neurol India 2019; 67 (05) 1344-1346
• 9 Alon T, Sadeh M, Lev D, Dabby R. X-linked myopathy with excessive autophagy: First report of an Israeli family presenting with late onset lower limb girdle weakness. Neuromuscul Disord 2021; 31 (09) 854-858
• 10 Ruggieri A, Ramachandran N, Wang P. et al. Non-coding VMA21 deletions cause X-linked myopathy with excessive autophagy. Neuromuscul Disord 2015; 25 (03) 207-211
• 11 Cotta A, Carvalho E, da-Cunha-Junior AL. et al. Clinical, imaging, morphologic, and molecular features of X-linked VMA21-related myopathy in two unrelated Brazilian families. J Neurol Sci 2020; 415: 116977
• 12 Pegat A, Streichenberger N, Lacoste N. et al. Novel Intronic Mutation in VMA21 causing severe phenotype of X-Linked myopathy with excessive autophagy-case report. Genes (Basel) 2022; 13 (12) 2245
• 13 Blanco-Arias P, Medina Martínez I, Arrabal Fernández L. et al. Severe congenital X-linked myopathy with excessive autophagy secondary to an apparently synonymous but pathogenic novel variant. Neuromuscul Disord 2023; 33 (07) 557-561
• 14 Chabrol B, Figarella-Branger D, Coquet M. et al. X-linked myopathy with excessive autophagy: a clinicopathological study of five new families. Neuromuscul Disord 2001; 11 (04) 376-388
• 15 Villanova M, Louboutin JP, Chateau D. et al. X-linked vacuolated myopathy: complement membrane attack complex on surface membrane of injured muscle fibers. Ann Neurol 1995; 37 (05) 637-645
• 16 Kurashige T, Takahashi T, Yamazaki Y. et al. Elevated urinary β2 microglobulin in the first identified Japanese family afflicted by X-linked myopathy with excessive autophagy. Neuromuscul Disord 2013; 23 (11) 911-916
• 17 Fernandes SA, Almeida CF, Souza LS. et al. Altered in vitro muscle differentiation in X-linked myopathy with excessive autophagy. Dis Model Mech 2020; 13 (02) dmm041244
• 18 Louboutin JP, Villanova M, Lucas-Héron B, Fardeau M. X-linked vacuolated myopathy: membrane attack complex deposition on muscle fiber membranes with calcium accumulation on sarcolemma. Ann Neurol 1997; 41 (01) 117-120