A.P.14: A new in/del in the critical splicing region of the VMA21 gene causing X-linked myopathy with excessive autophagy (XMEA)

Abstract

X-linked myopathy with excessive autophagy (XMEA) is an inherited, slowly progressive myopathy, characterized by membrane-bound sarcoplasmic vacuoles in muscle fibers. Proximal muscle weakness in early childhood is observed, but with no cardiac, nor cognitive impairment. Recent findings identified mutations in the vacuolar membrane ATPase activity 21 (VMA21), as causative of XMEA. Among Six different single-nucleotide substitutions in VMA21 (in 14 XMEA families), four were intronic, and in two of them, the IVS1–27A base is involved. These mutations result in a reduction in VMA21 mRNA, and protein, and a consequent elevated lysosomal pH with partial block the final degradation stage of autophagy. Only a few XMEA families have been worldwide identified. Here we describe the first XMEA Brazilian family carrying a small in/del in the VMA21 gene. The 5-year-old propositus presented a characteristic dystrophic phenotype. He walked at the age of 2 and showed difficulties for running, climbing stairs, and raising from the floor. No calf hypertrophy nor joint contractures were observed. CK level was 1330 U/l, and ECG showed altered conduction in the right branch. Muscle biopsy showed a dystrophic pattern and autophagic vacuoles. Emerin was normal. Family history revealed a recessive X-linked inheritance, with 5 affected males linked through asymptomatic females. The affected maternal grandfather, aged 48, was wheelchair bound since the age of 30, presenting also cardiac alterations and joint contractures in the upper limbs. Exome sequencing identified a small insertion-deletion, including the IVS1-27A base previously described. This new family/mutation reinforces the importance of this splice site branchpoint for the appropriate transcription/translation of VMA21, and normal lysosome function. Additionally, it expands the clinical variability, including cardiac involvement and joint contractures to the XMEA phenotype. X-linked myopathy with excessive autophagy (XMEA) is an inherited, slowly progressive myopathy, characterized by membrane-bound sarcoplasmic vacuoles in muscle fibers. Proximal muscle weakness in early childhood is observed, but with no cardiac, nor cognitive impairment. Recent findings identified mutations in the vacuolar membrane ATPase activity 21 (VMA21), as causative of XMEA. Among Six different single-nucleotide substitutions in VMA21 (in 14 XMEA families), four were intronic, and in two of them, the IVS1–27A base is involved. These mutations result in a reduction in VMA21 mRNA, and protein, and a consequent elevated lysosomal pH with partial block the final degradation stage of autophagy. Only a few XMEA families have been worldwide identified. Here we describe the first XMEA Brazilian family carrying a small in/del in the VMA21 gene. The 5-year-old propositus presented a characteristic dystrophic phenotype. He walked at the age of 2 and showed difficulties for running, climbing stairs, and raising from the floor. No calf hypertrophy nor joint contractures were observed. CK level was 1330 U/l, and ECG showed altered conduction in the right branch. Muscle biopsy showed a dystrophic pattern and autophagic vacuoles. Emerin was normal. Family history revealed a recessive X-linked inheritance, with 5 affected males linked through asymptomatic females. The affected maternal grandfather, aged 48, was wheelchair bound since the age of 30, presenting also cardiac alterations and joint contractures in the upper limbs. Exome sequencing identified a small insertion-deletion, including the IVS1-27A base previously described. This new family/mutation reinforces the importance of this splice site branchpoint for the appropriate transcription/translation of VMA21, and normal lysosome function. Additionally, it expands the clinical variability, including cardiac involvement and joint contractures to the XMEA phenotype.