Myopathy, X-linked, with excessive autophagy

Presentation

The prevalence of the disease is not precisely known but it is considered to be rare (less than one per million people). It has been reported in 15 families, mostly from Canada, Finland and France.

The disease usually presents between the ages of 5 and 10 years old. The usual symptom is weakness involving the upper legs and affecting activities such as running and climbing stairs. As the condition progresses, patients tend to experience weakness in their lower legs and arms. Some remain able to walk in advanced age, while others require assistance in adulthood.

Genetics

The disorder is inherited in a recessive, X-linked fashion. As a result, males are much more commonly affected than females. It is due to a mutation in the VMA21 genethe human homolog of the yeast Vma21p protein. This gene is located on the long arm of chromosome X (Xq28). It is an essential assembly chaperone of vacuolar ATPasethe principal mammalian proton pump complex. Mutations in this gene increase lysosomal pH. This in turn reduces lysosomal degradative ability and blocks autophagy.

Pathology

The muscle fibers are rarely necrotic but have evidence of excessive autophagic activity and exocytosis of the phagocytosed material. They have increased variation in size and are predominantly composed of round small and hypertrophic fibers. The vacuoles are strongly reactive for dystrophin and lysosome-associated membrane protein 2 (LAMP2). Membrane-bound vacuoles and balls of dense material under the basal lamina are present. Deposition of the C5b-9 complement attack complex, sub-sarcolemmal deposition of calcium and expression of the MHC1 complex also occur.

On electron microscopy, characteristic balls of dense material are commonly seen. The vacuoles may contain remains of mitochondria, membrane whorls and calcium apatite crystals.

Diagnosis

The diagnosis can be established by muscle biopsy.

Investigations

The serum creatinine is raised.

Differential diagnosis

• Acid maltase deficiency
• Danon disease

History

The disorder was described in 1988 by Kalimo et al in Finland in three brothers. The same condition affected their maternal grandfather and great-uncle.

References

References

1. Kalimo H, Savontaus M. L., Lang H., Paljärvi L., Sonninen V., Dean P. B., Katevuo K., Salminen A. (1988) X-linked myopathy with excessive autophagy: a new hereditary muscle disease. Ann Neurol 23(3): 258–265