Elsevier

Pediatric Neurology

Volume 87, October 2018, Pages 65-69
Pediatric Neurology

Original Article
Clinicopathologic Findings of CARS2 Mutation

https://doi.org/10.1016/j.pediatrneurol.2018.06.009Get rights and content

Abstract

Objectives

We describe a 13-year-old girl with a past medical history of epilepsy, intellectual impairment, dysphagia with gastric tube dependence, and autism spectrum disorder who presented with focal status epilepticus.

Methods

Video-electroencephalography revealed left occipital pseudoperiodic epileptiform discharges and frequent seizures originating from the left hemisphere. The seizure was refractory to antiepileptic medications and pharmacologic coma. Subsequently, left occipital lobectomy was done. Extensive evaluation including whole exome sequencing, histopathologic examination of brain and muscle samples, mitochondrial DNA content analysis of tissue sample was completed to detect the etiology.

Results

Skeletal muscle mitochondrial DNA content (qPCR) analysis showed approximately 37% of the mean value of age and tissue matched control group consistent with a mitochondrial depletion syndrome. Microscopic examination of the brain showed cortical abnormalities that largely consisted of infarct-like pathology in a laminar manner, abnormalities of neuronal distribution, and white matter changes. Compound heterozygous mutations of the CARS2 gene were identified by whole exome sequencing; V52G variant [p.Val52Gly (GTG>GGG):c.155 T>G in exon 1] was inherited from the mother and T188M variant[p.Thr188Met (ACG>ATG): c.563 C>T in exon 5] was inherited from the father.

Conclusion

This is the first detailed clinicopathologic description of the Alpers-Huttenlocher syndrome phenotype from CARS mutations.

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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