Original ArticleClinicopathologic Findings of CARS2 Mutation
Introduction
Mitochondrial dysfunction is a common but under-recognized cause of human disease. It has been associated with mutations in 13 mitochondrial-encoded genes and many nuclear-encoded genes that encode mitochondrial targeted proteins. Exact genetic diagnosis is difficult due to the broad diversity in phenotypes and a large number of genes. With increasing availability of whole exome sequencing, significant progress has been possible in the identification of mutations of nuclear-encoded genes responsible for the mitochondrial disease.
Disorders of mitochondrial translation are a newly recognized cause of epileptic encephalopathy. In addition to the ribosomal and tRNAs encoded by mtDNA, mitochondrial translation requires nuclear-encoded proteins including aminoacyl tRNA synthetase (ARS). These enzymes catalyze the specific attachment of the amino acids to the corresponding tRNA. Pathogenic mutations in mitochondrial aminoacyl-tRNA synthetases produce broad clinical spectrums of mitochondrial disease such as encephalopathy, cardiomyopathy, renal failure, myopathy with sideroblastic anemia, premature ovarian failure, and hearing loss. Only FARS2 (phenylalanyl-tRNA synthetase) and CARS2 (cysteine-specific aminoacyl-tRNA synthetase) have been associated with an epileptic phenotype.
We describe a child with severe epileptic encephalopathy with compound heterozygous mutations in CARS2. We describe for the first time the pathologic findings of a patient with CARS2 mutation and expand the spectrum of pathologic findings previously described in mitochondrial tRNA synthetase mutations.
Section snippets
Patient Description
This 13-year-old girl with a past medical history of epilepsy, intellectual impairment, dysphagia with gastric tube dependence, and autism spectrum disorder presented with focal status epilepticus. She was born at term to a primigravida mother with a prenatal diagnosis of nonimmune hydrops. She had early onset infection/fever triggered focal seizures (right hemibody jerking), developmental delays, and diagnosed with autism at age three years. She also had experienced unexplained generalized
Discussion
Mitochondrial DNA (mtDNA) depletion syndrome is defined as a reduction in mtDNA copy number in different tissues, leading to impaired energy production in the affected tissues. Mutations in nuclear genes that function in either mitochondrial nucleotide synthesis or mtDNA replication can cause phenotypically heterogenous presentation with variable involvement of muscle, brain, or liver.1 Alpers-Huttenlocher syndrome (AHS) is a progressive hepatocerebral mitochondrial DNA depletion syndrome
Conflict of Interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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2022, Stem Cell ResearchCitation Excerpt :Pathogenic mutations in CARS2 (cysteinyl-tRNA synthetase 2), a rare gene causing COXPD-27, was a newly recognized cause of EOEE. Until now, only two families carrying CARS2 mutation had been reported (Kerstin et al., 2014; Debopam et al., 2018) and no research with iPSCs carrying CARS2 mutation was reported. CARS2 catalyze the specific attachment of cysteine to corresponding tRNA.
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