title: A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.
abstract: Nuclear-encoded disorders of mitochondrial translation are clinically and genetically heterogeneous. Genetic causes include defects of mitochondrial aminoacyl-tRNA synthetases, and factors required for initiation, elongation and termination of protein synthesis as well as ribosome recycling. We report on a new case of myopathy, lactic acidosis and sideroblastic anemia (MLASA) syndrome caused by defective mitochondrial tyrosyl aminoacylation. The patient presented at 1 year with anemia initially attributed to iron deficiency. Bone marrow aspirate at 5 years revealed ringed sideroblasts but transfusion dependency did not occur until 11 years. Other clinical features included lactic acidosis, poor weight gain, hypertrophic cardiomyopathy and severe myopathy leading to respiratory failure necessitating ventilatory support. Long-range PCR excluded mitochondrial DNA rearrangements. Clinical diagnosis of MLASA prompted direct sequence analysis of the YARS2 gene encoding the mitochondrial tyrosyl-tRNA synthetase, which revealed homozygosity for a known pathogenic mutation, c.156C>G;p.F52L. Comparison with four previously reported cases demonstrated remarkable clinical homogeneity. First line investigation of MLASA should include direct sequence analysis of YARS2 and PUS1 (encoding a tRNA modification factor) rather than muscle biopsy. Early genetic diagnosis is essential for counseling and to facilitate appropriate supportive therapy. Reasons for segregation of specific clinical phenotypes with particular mitochondrial aminoacyl tRNA-synthetase defects remain unknown.
authors.affiliation: Mitochondrial Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK.
authors.forename: Rojeen
authors.initials: R
authors.lastname: Shahni
authors.forename: Yehani
authors.initials: Y
authors.lastname: Wedatilake
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Cleary
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Lindley
authors.forename: Keith R
authors.initials: KR
authors.lastname: Sibson
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
mesh_terms: D000140:Acidosis, Lactic / Q000175:diagnosis / Q000235:genetics*; D000756:Anemia, Sideroblastic / Q000175:diagnosis / Q000235:genetics*; D001853:Bone Marrow / Q000473:pathology; D004252:DNA Mutational Analysis; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D017240:Mitochondrial Myopathies / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D013577:Syndrome; D014448:Tyrosine-tRNA Ligase / Q000235:genetics*
chemical_list: D014448:Tyrosine-tRNA Ligase
keywords: MLASA; YARS2; lactic acidosis; mitochondrial disease; mitochondrial myopathy; sideroblastic anemia
references.citation: Neuromuscul Disord. 2013 Jun;23(6):506-15
references.pmid: 23582335
references.citation: Hematology Am Soc Hematol Educ Program. 2011;2011:525-31
references.pmid: 22160084
references.citation: J Biol Chem. 2005 May 20;280(20):19823-8
references.pmid: 15772074
references.citation: Am J Hum Genet. 2010 Jul 9;87(1):52-9
references.pmid: 20598274
references.citation: Neuromuscul Disord. 2012 Jul;22(7):577-86
references.pmid: 22578526
references.citation: Mol Genet Metab. 2013 Apr;108(4):206-11
references.pmid: 23433712
references.citation: Hum Mol Genet. 1995 Aug;4(8):1327-30
references.pmid: 7581370
references.citation: Neurology. 2000 Oct 24;55(8):1210-2
references.pmid: 11071502
references.citation: Biochim Biophys Acta. 2011 Sep;1807(9):1198-205
references.pmid: 21708121
references.citation: Pediatr Blood Cancer. 2010 Feb;54(2):273-8
references.pmid: 19731322
references.citation: Hum Mol Genet. 2002 Jul 1;11(14):1669-81
references.pmid: 12075011
references.citation: Am J Med Genet A. 2003 Dec 1;123A(2):172-8
references.pmid: 14598342
references.citation: Am J Hum Genet. 2004 Jun;74(6):1303-8
references.pmid: 15108122
references.citation: Am J Hum Genet. 1991 Jan;48(1):39-42
references.pmid: 1985462
references.citation: Annu Rev Genet. 2011;45:299-329
references.pmid: 21910628
references.citation: Hum Mutat. 2012 Aug;33(8):1201-6
references.pmid: 22504945
references.citation: J Inherit Metab Dis. 2000 Nov;23(7):753-4
references.pmid: 11117437