Novel Intronic Mutation in VMA21 Causing Severe Phenotype of X-Linked Myopathy with Excessive Autophagy-Case Report.
Antoine PegatNathalie StreichenbergerNicolas LacosteMarc HermierRita MenassaLaurent CoudertJulian TheurietRoseline FroissartSophie TerroneFrancoise BouhourLaurence Michel-CalemardLaurent SchaefferArnaud JacquierPublished in: Genes (2022)
X-linked Myopathy with Excessive Autophagy (XMEA) is a rare autophagic vacuolar myopathy caused by mutations in the Vacuolar ATPase assembly factor VMA21 gene; onset usually occurs during childhood and rarely occurs during adulthood. We described a 22-year-old patient with XMEA, whose onset was declared at 11 through gait disorder. He had severe four-limb proximal weakness and amyotrophy, and his proximal muscle MRC score was between 2 and 3/5 in four limbs; creatine kinase levels were elevated (1385 IU/L), and electroneuromyography and muscle MRI were suggestive of myopathy. Muscle biopsy showed abnormalities typical of autophagic vacuolar myopathy. We detected a hemizygous, unreported, intronic, single-nucleotide substitution c.164-20T>A (NM_001017980.4) in intron 2 of the VMA21 gene. Fibroblasts derived from this patient displayed a reduced level of VMA21 transcripts (at 40% of normal) and protein, suggesting a pathogenicity related to an alteration of the splicing efficiency associated with an intron retention. This patient with XMEA displayed a severe phenotype (rapid weakness of upper and lower limbs) due to a new intronic variant of VMA21 , related to an alteration in the splicing efficiency associated with intron retention, suggesting that phenotype severity is closely related to the residual expression of the VMA21 protein.
Keyphrases
- case report
- late onset
- cell death
- early onset
- skeletal muscle
- muscular dystrophy
- drug induced
- endoplasmic reticulum stress
- magnetic resonance imaging
- binding protein
- signaling pathway
- genome wide
- poor prognosis
- copy number
- oxidative stress
- photodynamic therapy
- depressive symptoms
- myasthenia gravis
- computed tomography
- physical activity
- contrast enhanced
- long non coding rna
- young adults
- tyrosine kinase
- ultrasound guided
- weight loss
- biofilm formation
- cerebral palsy