X-linked myopathy with excessive autophagy (XMEA) is a rare childhood onset disease characterized by slow progressive vacuolation and atrophy of skeletal muscle. There is no known cardiac or intellectual involvement.

Presentation

The incidence of this disease is not precisely known but it is considered to be rare (< 1/10⁶ population). It has been reported in 15 families to date mostly from

Canada Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...

Finland Finland ( fi, Suomi ; sv, Finland ), officially the Republic of Finland (; ), is a Nordic country in Northern Europe. It shares land borders with Sweden to the northwest, Norway to the north, and Russia to the east, with the Gulf of B ...

and

France France (), officially the French Republic ( ), is a country primarily located in Western Europe. It also comprises of Overseas France, overseas regions and territories in the Americas and the Atlantic Ocean, Atlantic, Pacific Ocean, Pac ...

. This disease usually presents between the ages of 5 and 10 years old. The usual picture is with weakness involving the upper legs and affects 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

This 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 VMA21 gene - the human homolog of the

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...

Vma21p protein. This gene is located on the long arm of chromosome X (Xq28). It is an essential assembly chaperone of the vacuolar

ATPase ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...

- the principal mammalian proton pump complex. Mutations in this gene increase lysosomal pH. This in turn reduces lysosomal degradative ability and blocks

autophagy Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...

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 Lysosome-associated membrane protein 2 (LAMP2), also known as CD107b (Cluster of Differentiation 107b) and Mac-3, is a human gene. Its protein, LAMP2, is one of the lysosome-associated membrane glycoproteins. The protein encoded by this gene is a ...

). Membrane bound vacuoles and balls of dense material under the

basal lamina The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often incorrectly referred to as the basement membrane, though it does constitute a portion of the basement membrane. The ba ...

are present. Deposition of the C5b-9 complement attack complex, sub sarcolemmal deposition of calcium and expression of MHC1 complex also occur. On

electron microscopy An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...

characteristic balls of dense material are commonly seen. The vacuoles may contain remains of

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

, 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 Glycogen storage disease type II, also called Pompe disease, is an autosomal recessive metabolic disorder which damages muscle and nerve cells throughout the body. It is caused by an accumulation of glycogen in the lysosome due to deficiency of th ...

Danon disease Danon disease (or glycogen storage disease Type IIb) is a metabolic disorder. Danon disease is an X-linked lysosomal and glycogen storage disorder associated with hypertrophic cardiomyopathy, skeletal muscle weakness, and intellectual disability. I ...

Treatment

History

This disorder was described in 1988 by Kalimo ''et al'' in Finland in three brothers. The same condition affected their maternal grandfather and great-uncle.Kalimo H, Savontaus ML, Lang H, Paljärvi L, Sonninen V, Dean PB, Katevuo K, Salminen A (1988) X-linked myopathy with excessive autophagy: a new hereditary muscle disease. Ann Neurol 23(3):258-265

References

External links

{{Myopathy Muscular disorders Rare diseases