Natural history of X-linked myopathy with excessive autophagy

X-linked myopathy with excessive autophagy (XMEA) is a little-known disease linked to the VMA21 gene. It leads to autophagy failure with progressive vacuolation and atrophy of skeletal muscles. The aim of this retrospective study, conducted by French teams including researchers and clinicians from the Institut de Myologie, was to define the clinical, radiological and natural history of XMEA.

The authors gathered clinical, genetic, muscle imaging and biopsy data from patients followed in France for XMEA. They also reviewed the literature to find other cases.

The results of the study carried out on 18 men with genetically confirmed XMEA in France showed that :

  • they carried four different variants of VMA21,
  • the average age of onset of the disease was 9.4 ± 9.9 years (from 1 to 40 years),
  • in 14 of the 18 patients (77.8%), the disease appeared during childhood (< 15 years).

In addition, the patients showed :

  • muscle weakness in the anterior and medial compartments of the thigh, 
  • distal contractures (56.3%), 
  • high levels of CK (1,287.9 ± 757.8 U/l),
  • autophagic vacuoles with sarcolemmal features on muscle histopathology. 

The authors also observed that :

  • muscle MRI in 10 patients showed a characteristic pattern of lower limb muscle involvement, 
  • in 11 patients, evaluation criteria were available for a mean follow-up period of 10.6 ± 9.8 years,
  • 6 of these patients showed disease progression,
  • 7 of 16 patients (43.8%) required walking aids,
  • 3 of 16 (18.8%) were wheelchair-bound,
  • one of the variants was associated with a later onset of symptoms,
  • respiratory failure was common (57.1%) but cardiac involvement rare (12.5%).

These results suggest that, while the age of onset of XMEA is variable, its clinical, histopathological and muscle imaging presentation is characteristic, which guides the diagnosis. The authors conclude that, although slow, motor disability progresses over time, and the relevant genotype-phenotype correlations may help to design future clinical trials.


Fernández-Eulate G, Alfieri G, Spinazzi M, Ackermann-Bonan I, Duval F, Solé G, Caillon F, Mercier S, Pereon Y, Magot A, Pegat A, Salort-Campana E, Chabrol B, Gorokhova S, Krahn M, Biancalana V, Evangelista T, Behin A, Metay C, Stojkovic T. Phenotype variability and natural history of X-linked myopathy with excessive autophagy. J Neurol. 2024 Mar 22. doi: 10.1007/s00415-024-12298-0. Epub ahead of print. PMID: 38517523.