Sunday, September 11, 2016


Ackerley CA, Cooper MA, Munoz DG, Minassian BA. Fatal hepatic failure and pontine and extrapontine myelinolysis in XMEA. Neurology. 2016 Aug 26. pii:
10.1212/WNL.0000000000003155. [Epub ahead of print]

X-linked myopathy with excessive autophagy (XMEA) is a childhood-onset, slowly progressive myopathy leading to lost ambulation after age 50 years.  It is caused by mutations of the VMA21 gene, which encodes the assembly chaperone of the V-ATPase proton pump that acidifies organelles. Autophagosomal alkalinization impairs autophagy completion, which drives autophagosome proliferation and apparent damage to skeletal muscle.  All known XMEA mutations reduce but do not eliminate VMA21 expression. Some cause greater VMA21 reduction than in classic XMEA and lead to a severe course with congenital/neonatal onset, extreme muscle wasting, and ventilation dependence. However, even with these mutations, no overt extramuscular disease is present. Given the vital role of V-ATPases in all cells, absence of manifest disease outside muscle is surprising. Possibly, extramuscular pathology is actually present but subclinical. In fact, patients with congenital/neonatal onset do have increased liver function tests, suggesting latent hepatopathy. We report rapid fatal hepatic cirrhosis at age 52 in one of our cases with otherwise classic XMEA…

Just as the rapid liver collapse was unanticipated, presence of extensive pontine and extrapontine myelinolysis in the brain, unassociated with osmotic shifts, was unexpected. We raise the possibility that the underlying possible CNS V-ATPase deficiency combined with the rapid hepatic failure to subject myelin to acute metabolic challenge. The patient was one of our oldest XMEA cases. Based on his unexplained acute hepatic and neurologic decompensation, we recommend close clinical, including hepatic, monitoring of patients with this genetic disease, especially as they age.

Courtesy of Doximity

Ramachandran N, Munteanu I, Wang P, Ruggieri A, Rilstone JJ, Israelian N, Naranian T, Paroutis P, Guo R, Ren ZP, Nishino I, Chabrol B, Pellissier JF, Minetti C, Udd B, Fardeau M, Tailor CS, Mahuran DJ, Kissel JT, Kalimo H, Levy N, Manolson MF, Ackerley CA, Minassian BA. VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy. Acta Neuropathol. 2013 Mar;125(3):439-57.


X-linked Myopathy with Excessive Autophagy (XMEA) is a childhood onset disease characterized by progressive vacuolation and atrophy of skeletal muscle. We show that XMEA is caused by hypomorphic alleles of the VMA21 gene, that VMA21 is the diverged human ortholog of the yeast Vma21p protein, and that like Vma21p, VMA21 is an essential assembly chaperone of the vacuolar ATPase (V-ATPase), the principal mammalian proton pump complex. Decreased VMA21 raises lysosomal pH which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids which leads to downregulation of the mTORC1 pathway, and consequent increased macroautophagy resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge, and vacuolate the cell. Our results uncover a novel mechanism of disease, namely macroautophagic overcompensation leading to cell vacuolation and tissue atrophy.

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