Myopathy, Lactic acidosis, and Sideroblastic Anemia 2

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Description from OMIM

Myopathy, lactic acidosis, and sideroblastic anemia-2 is an autosomal recessive disorder of the mitochondrial respiratory chain. The disorder shows marked phenotypic variability: some patients have a severe multisystem disorder from infancy, including cardiomyopathy and respiratory insufficiency resulting in early death, whereas others present in the second or third decade of life with sideroblastic anemia and mild muscle weakness (summary by Riley et al., 2013). For a discussion of genetic heterogeneity of MLASA, see MLASA1 (600462).

Prevalence of clinical parameters (%)

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List of symptoms

Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
Anemia circulatory 100 % 20598274 2011-10-19
Lactate accumulation circulatory 100 % 20598274 2011-10-19
Myopathy skeletal 100 % 20598274 2011-10-19
Exercise intolerance skeletal 100 % 20598274 2011-10-19
Muscle weakness skeletal 100 % 20598274 2011-10-19
Pallor circulatory 67 % 20598274 2011-10-19
Dysphagia digestive 67 % 20598274 2011-10-19
Short stature skeletal 67 % 20598274 2011-10-19
Weight loss multi 67 % 20598274 2011-10-19
Cardiomyopathy circulatory 33 % 20598274 2011-10-19
Lethargy circulatory 33 % 20598274 2011-10-19
Failure to thrive multi 33 % 20598274 2011-10-19
Developmental delay nervous 33 % 20598274 2011-10-19

List of references:

Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome.
Lisa G Riley, Sandra Cooper, Peter Hickey, Joëlle Rudinger-Thirion, Matthew McKenzie, Alison Compton, Sze Chern Lim, David Thorburn, Michael T Ryan, Richard Giegé, Melanie Bahlo, John Christodoulou,

Mitochondrial respiratory chain disorders are a heterogeneous group of disorders in which the underlying genetic defect is often unknown. We have identified a pathogenic mutation (c.156C>G [p.F52L]) in YARS2, located at chromosome 12p11.21, by using genome-wide SNP-based homozygosity analysis of a family with affected members displaying myopathy, lactic acidosis, and sideroblastic anemia (MLASA). We subsequently identified the same mutation in another unrelated MLASA patient. The YARS2 gene product, mitochondrial tyrosyl-tRNA synthetase (YARS2), was present at lower levels in skeletal muscle whereas fibroblasts were relatively normal. Complex I, III, and IV were dysfunctional as indicated by enzyme analysis, immunoblotting, and immunohistochemistry. A mitochondrial protein-synthesis assay showed reduced levels of respiratory chain subunits in myotubes generated from patient cell lines. A tRNA aminoacylation assay revealed that mutant YARS2 was still active; however, enzyme kinetics were abnormal compared to the wild-type protein. We propose that the reduced aminoacylation activity of mutant YARS2 enzyme leads to decreased mitochondrial protein synthesis, resulting in mitochondrial respiratory chain dysfunction. MLASA has previously been associated with PUS1 mutations; hence, the YARS2 mutation reported here is an alternative cause of MLASA.

American journal of human genetics - Jul 2010