Non-coding VMA21 deletions cause X-linked myopathy with excessive autophagy

Neuromuscul Disord. 2015 Mar;25(3):207-11. doi: 10.1016/j.nmd.2014.11.014. Epub 2014 Nov 26.


X-linked Myopathy with Excessive Autophagy (XMEA) affects proximal muscles of the lower extremities and follows a progressive course reminiscent of muscular dystrophy. It is caused by mutations in VMA21 whose protein product assembles lysosomes' proton pumps. All XMEA mutations to date have been single-nucleotide substitutions that reduce VMA21 expression, which leads to modest lysosomal pH increase, the first step in the disease's pathogenesis. We now report a new class of XMEA mutations. We identified two VMA21 non-coding microdeletions, one intronic (c.54-16_54-8del), the other in the 3'UTR (c.*13_*104del). Both resulted in a relatively more severe (early ambulation loss), diffuse (extra-ocular and upper extremity involvement), and early (neonatal) onset disease compared to previously reported patients. Our cases highlight the importance of including non-coding regions of VMA21 in genetic testing panels of dystrophies and myopathies. Specific diagnosis of XMEA will be particularly important as therapies aimed at correcting the modest rise in lysosomal pH at the root of this disease are developed.

Keywords: Autophagy; Lysosomal ATPase; Microdeletions; VMA21; XMEA.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Autophagy / genetics
  • Brain / pathology
  • Brain / physiopathology
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / pathology
  • Genetic Diseases, X-Linked / physiopathology
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Muscle, Skeletal / pathology
  • Muscular Diseases / genetics*
  • Muscular Diseases / pathology
  • Muscular Diseases / physiopathology
  • RNA, Messenger / metabolism
  • Sequence Deletion*
  • Vacuolar Proton-Translocating ATPases / genetics*
  • Vacuolar Proton-Translocating ATPases / metabolism
  • Young Adult


  • RNA, Messenger
  • VMA21 protein, human
  • Vacuolar Proton-Translocating ATPases