Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation

Scheper, Gert C.; Klok, Thom van der; Andel, Rob J van; Berkel, Carola G.M. van; Sissler, Marie; Smet, Joél; Muravina, Tatjana I; Serkov, S V; Uziel, Graziella; Bugiani, Marianna; Schiffmann, Raphael; Krägeloh‐Mann, Ingeborg; Smeitink, Jan A.M.; Florentz, Catherine; Coster, Rudy Van; Pronk, Jan C.; Knaap, Marjo S. van der

doi:10.1038/ng2013

Cited by 418 publications

(422 citation statements)

References 29 publications

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“…Mutations of MRPS16 have been reported with agenesis of corpus callosum, dysmorphic features, and fatal neonatal lactic acidosis [71]. Mutations in the DARS2 gene causes multiple RC deficiencies, and a clinical syndrome of leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL), with cerebellar ataxia, spasticity, and dorsal column signs [72]. Mutations in RARS2 cause pontocerebellar hypoplasia, epileptic encephalopathy, progressive microcephaly, developmental arrest, and feeding difficulties [73,74] …”

Section: Defects Of Mtdna Protein Synthesis (Including Defects Of Tramentioning

confidence: 99%

Mitochondrial Disease in Childhood: Nuclear Encoded

2013

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Primary mitochondrial disorders are clinically and genetically heterogeneous, caused by an alteration(s) in either mitochondrial DNA or nuclear DNA, and affect the respiratory chain's ability to undergo oxidative phosphorylation, leading to decreased production of adenosine triphosphophate and subsequent energy failure. These disorders may present at any age, but children tend to have an acute onset of disease compared with subacute or slowly progressive presentation in adults. Varying organ involvement also contributes to the phenotypic spectrum seen in these disorders. The childhood presentation of primary mitochondrial disease is mainly due to nuclear DNA mutations, with mitochondrial DNA mutations being less frequent in childhood and more prominent in adulthood disease. The clinician should be aware of the pediatric presentation of mitochondrial disease and have an understanding of the myriad of nuclear genes responsible for these disorders. The nuclear genes can be best understood by utilizing a classification system of location and function within the mitochondria.

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Section: Defects Of Mtdna Protein Synthesis (Including Defects Of Tramentioning

confidence: 99%

Mitochondrial Disease in Childhood: Nuclear Encoded

2013

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“…Several mt-aaRS defects unveil discrete and specific clinical and neuroradiological phenotypes including DARS2 (OMIM#611105) (Scheper et al 2007); RARS2 (OMIM#611523) (Edvardson et al 2007); FARS2 ( O M I M # 6 1 4 9 4 6 ) ( E l o e t a l . 2 0 1 2 ) ; E A R S 2 (OMIM#614924) (Steenweg et al 2012) and AARS2 (OMIM#615889) (Dallabona et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features

et al. 2016

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Mitochondrial translation defects are important causes of early onset mitochondrial disease. Although the biochemical (combined respiratory chain deficiency) signature and neuroimaging are usually distinctive, they are not diagnostic as the genetic origin of mitochondrial translation defects is heterogeneous. We report a female child, born at term to non-consanguineous parents, who exhibited global hypotonia, failure to thrive, persistent and progressive hyperlactacidaemia with lactic acidosis, liver dysfunction and encephalopathy and died at the age of 5 months. Brain MRI revealed hypogenesis of the corpus callosum, T2 signal abnormalities in the medulla oblongata, pons, midbrain, thalami, cerebellar white matter, and a lactate peak on MRS. Muscle histochemistry showed cytochrome

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“…All other mitochondrial proteins, including over 70 OXPHOS subunits and all proteins of the mitochondrial translation machinery, are encoded by nuclear genes. The majority of mutations associated with combined OXPHOS deficiencies because of impaired mitochondrial translation are located in mtDNA genes; 1 however, the list of nDNA mutations is steadily growing with defects reported in mitochondrial translation factors, 2-5 mitochondrial ribosomal proteins, 6,7 mitochondrial tRNA synthetases [8][9][10] and tRNA-modifying enzymes. [11][12][13] We investigated a group of 33 patients with combined OXPHOS deficiencies (and normal complex II activities) by mutational analysis of the entire mtDNA, polymerase gamma and nuclear genes implicated in mitochondrial translation.…”

Section: Introductionmentioning

confidence: 99%

Mutation in mitochondrial ribosomal protein MRPS22 leads to Cornelia de Lange-like phenotype, brain abnormalities and hypertrophic cardiomyopathy

et al. 2010

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The oxidative phosphorylation (OXPHOS) system is under control of both the mitochondrial and the nuclear genomes; 13 subunits are synthesized by the mitochondrial translation machinery. We report a patient with Cornelia de Lange-like dysmorphic features, brain abnormalities and hypertrophic cardiomyopathy, and studied the genetic defect responsible for the combined OXPHOS complex I, III and IV deficiency observed in fibroblasts. The combination of deficiencies suggested a primary defect associated with the synthesis of mitochondrially encoded OXPHOS subunits. Analysis of mitochondrial protein synthesis revealed a marked impairment in mitochondrial translation. Homozygosity mapping and sequence analysis of candidate genes revealed a homozygous mutation in MRPS22, a gene encoding a mitochondrial ribosomal small subunit protein. The mutation predicts a Leu215Pro substitution at an evolutionary conserved site. Mutations in genes implicated in Cornelia de Lange syndrome or copy number variations were not found. Transfection of patient fibroblasts, in which MRPS22 was undetectable, with the wild-type MRPS22 cDNA restored the amount and activity of OXPHOS complex IV, as well as the 12S rRNA transcript level to normal values. These findings demonstrate the pathogenicity of the MRPS22 mutation and stress the significance of mutations in nuclear genes, including genes that have no counterparts in lower species like bacteria and yeast, for mitochondrial translation defects.

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Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation

Cited by 418 publications

References 29 publications

Mitochondrial Disease in Childhood: Nuclear Encoded

Mitochondrial Disease in Childhood: Nuclear Encoded

Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features

Mutation in mitochondrial ribosomal protein MRPS22 leads to Cornelia de Lange-like phenotype, brain abnormalities and hypertrophic cardiomyopathy

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