The phenotypic variability and natural history of NARS2 associated disease

Abstract

Introduction:The phenotypic variability of NARS2 associated disease is vast, yet not thoroughly explored. We present the phenotypic and genetic features of 2 siblings with early-onset mitochondrial encephalopathy due to pathogenic variant in NARS2, along with the results from a systematic literature review. Aims: To better delineate the phenotypic variability and natural history of NARS2 associated disease. Methods: The clinical and radiological phenotype, along with the results from the morphological and biochemical investigations from the muscle biopsy as well as the postmortem investigations, where applicable, are presented. Genetic analysis was performed with next-generation sequencing.Results: Together with these 2 patients, we have diagnosed and followed 3 Scandinavian patients with the same homozygous p. Pro214Leu variant in NARS2 who presented with phenotypic features of earlyonset mitochondrial encephalopathy and variable disease course. Another 14 patients with pathogenic variants in NARS2 were identified in the literature. We found that sensorineural hearing impairment is a cardinal feature of early-onset NARS2 associated disease, either isolated or in combination with central nervous system disease. Early-onset mitochondrial encephalopathy due to NARS2 variants shared phenotypic features of Alpers or Leigh syndrome and was characterized by more severe disease course and poorer survival compared to the other NARS2 associated phenotypes. Conclusion: NARS2 variants present with a spectrum of clinical severity from a severe, infantile-onset, progressive disease to a mild, non-progressive disease, without strong association between the genotype and the disease outcome.

Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome

“…The pathogenic NARS2 variant (p.S264C) maps in the catalytic domain of the mitochondrial asparaginyl-tRNA synthase protein, which catalyzes the binding of asparagine to its cognate mt-tRNA ( Bonnefond et al, 2005 ). Several studies reported NARS2 variants in LS patients ( Simon et al, 2015 ; Sofou et al, 2015 ; Mizuguchi et al, 2017 ; Lee et al, 2020 ; Sofou et al, 2021 ). More relevant is the sensorineural hearing impairment, as a hallmark of NARS2 -associated LS phenotype, which is consistent with the proband’s symptoms ( Sofou et al, 2021 ).…”

Clinical Attributes and Electroencephalogram Analysis of Patients With Varying Alpers’ Syndrome Genotypes

“…Only 1 truncation variant in POLG was identified (Wolf et al, 2009). Variants in PARS2, CARS2, GABRB2, FARS2, and NARS2 were also reported in Alpers' syndrome patients (Sofou et al, 2015;Walker et al, 2016;Samanta et al, 2018;Sofou et al, 2021). All the variations were consistent with the autosomal recessive inheritance pattern, except for that in GABRB2.…”

“…Next-generation sequencing has significantly broadened our understanding of the genetic causes of mitochondrial disease (Jin et al, 2019;Li et al, 2019;Shen and Shi, 2019). In recent years, an increasing number of genes have been related to Alpers' syndrome, many pathogenic mutations in the mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs), such as FARS2, CARS2, NARS2, and PARS2, etc, are a novel cause of mitochondrial translation disorder, leading to Alpers' syndrome (Elo et al, 2012;Sofou et al, 2015;Walker et al, 2016;Samanta et al, 2018;Sofou et al, 2021). This study demonstrated the pathogenic mechanism of gene variants resulting in the loss of receptor function (Nishikawa et al, 2020).…”

“…Recent studies have identified molecular genetic causes of Alpers' syndrome, including pathogenic mutations in the gene encoding the catalytic subunit of polymerase gamma (POLG), PARS2 which encodes prolyl-tRNA synthetase, FARS2 which encodes phenylalanyl-tRNA synthetase, and NARS2 which encodes asparaginyl-tRNA synthetase, etc, POLG gene variation is the most common (Sofou et al, 2015;Walker et al, 2016;Samanta et al, 2018;Sofou et al, 2021).…”

Mutational Analysis and mtDNA Haplogroup Characterization in Three Serbian Cases of Mitochondrial Encephalomyopathies and Literature Review

“…LS is characterized by psychomotor regression with progressive loss of mental and movement abilities and may result in fatal encephalopathy [14,15]. The disorder could be associated with mutations in more than 75 genes that have been identified in both the nuclear and mitochondrial genome; about 20% of LS cases are caused by mtDNA mutations [16][17][18]. Point mutations at m.8993T>G or the less severe m.8993T>C in MT-ATP6 gene in the complex V are the most frequent LS-associated mtDNA changes.…”