FARS2 mutation and epilepsy: Possible link with early-onset epileptic encephalopathy

Cho, Jae So; Kim, Seung Hyo; Kim, Ha Young; Chung, Taesu; Kim, Dongsup; Jang, Sesong; Lee, Seungbok; Shin, Jong-Yeon; Kim, Jong il; Kim, Hunmin; Chae, Jong Hee; Choi, Jieun; Kim, Ki Joong; Lim, Byung Chan

doi:10.1016/j.eplepsyres.2016.11.022

Cited by 22 publications

(22 citation statements)

References 20 publications

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“…Overall, approximately 21 subjects with FARS2 ‐related disease have been reported, with most cases (12 of 21; see Table S1) presenting with a severe phenotype consisting of epileptic encephalopathy and diffuse cortical dysfunction (lower extremity spasticity, motor delays, and cognitive disability). Many of these severe cases were also associated with lactic acidosis or liver disease . Several moderate phenotypes have also been reported with diffuse cortical dysfunction, but had more functional capabilities .…”

Section: Discussionmentioning

confidence: 99%

“…mtPheRS contains four major domains: a mitochondrial localization signal (residues 1–37) in the N‐terminal region (residues 1–83), a catalytic domain (residues 84–325), a linker region (residues 326–358), and an anticodon‐binding domain (359–451) . Similar to many mt‐aaRSs, FARS2 has been linked with a severe mitochondrial syndrome associated with an infantile‐onset epileptic encephalopathy and/or fatal Alpers‐like syndrome . More moderate phenotypes consisting of cognitive disability, motor delays, and epilepsy have also been reported .…”

Section: Introductionmentioning

confidence: 99%

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FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei

Sahai

Steiner

et al. 2018

Ann Clin Transl Neurol

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Mutations in FARS2, the gene encoding the mitochondrial phenylalanine‐tRNA synthetase (mtPheRS), have been linked to a range of phenotypes including epileptic encephalopathy, developmental delay, and motor dysfunction. We report a 9‐year‐old boy with novel compound heterozygous variants of FARS2, presenting with a pure spastic paraplegia syndrome associated with bilateral signal abnormalities in the dentate nuclei. Exome sequencing identified a paternal nonsense variant (Q216X) lacking the catalytic core and anticodon‐binding regions, and a maternal missense variant (P136H) possessing partial enzymatic activity. This case confirms and expands the phenotype related to FARS2 mutations with regards to clinical presentation and neuroimaging findings.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei

Sahai

Steiner

et al. 2018

Ann Clin Transl Neurol

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“…The charging of tRNA molecules with phenylalanine in the cytoplasm is accomplished via a tetrameric enzyme that contains two catalytic subunits encoded by phenylalanyl‐tRNA synthetase alpha ( FARSA ; MIM# 602918) and two regulatory subunits encoded by phenylalanyl‐tRNA synthetase beta ( FARSB ; MIM# 609690) (Rodova, Ankilova, & Safro, ). To date, no variants in FARSA or FARSB have been implicated in human disease; however, loss‐of‐function mutations in the gene encoding mitochondrial phenylalanyl‐tRNA synthetase ( FARS2 ) have been implicated in recessive phenotypes including hereditary spastic paraplegia, Alpers syndrome, early onset epilepsy, global delay, dysarthria, and tremor (Almalki et al., ; Cho et al., ; Elo et al., ; Raviglione et al., ; Shamseldin et al., ; Vernon, McClellan, Batista, & Naidu, ; Walker et al., ; Yang et al., ). Here, we describe a patient with a severe, lethal, multisystem, developmental phenotype associated with compound heterozygosity for loss‐of‐function FARSB variants.…”

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confidence: 99%

Compound heterozygosity for loss-of-function FARSB variants in a patient with classic features of recessive aminoacyl-tRNA synthetase-related disease

et al. 2018

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Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes that ligate amino acids onto tRNA molecules. Genes encoding ARSs have been implicated in phenotypically diverse dominant and recessive human diseases. The charging of tRNA with phenylalanine is performed by a tetrameric enzyme that contains two alpha (FARSA) and two beta (FARSB) subunits. To date, mutations in the genes encoding these subunits (FARSA and FARSB) have not been implicated in any human disease. Here, we describe a patient with a severe, lethal, multisystem, developmental phenotype who was compound heterozygous for FARSB variants: p.Thr256Met and p.His496Lysfs*14. Expression studies using fibroblasts isolated from the proband revealed a severe depletion of both FARSB and FARSA protein levels. These data indicate that the FARSB variants destabilize total phenylalanyl-tRNA synthetase levels, thus causing a loss-of-function effect. Importantly, our patient shows strong phenotypic overlap with patients that have recessive diseases associated with other ARS loci; these observations strongly support the pathogenicity of the identified FARSB variants and are consistent with the essential function of phenylalanyl-tRNA synthetase in human cells. In sum, our clinical, genetic, and functional analyses revealed the first FARSB variants associated with a human disease phenotype and expand the locus heterogeneity of ARS-related human disease.

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“…Despite all 3 Alpers‐Huttenlocher disease patients having mitochondrial complex I deficiency, it was not inherited in any of them. Among 11 reported cases with FARS2 mutations, 3 (27%) had WS and hypsarrhythmia . No reports of patients with POLG mutations and IS are known to the authors.…”

Section: Metabolic Errors In Organellesmentioning

confidence: 99%

Metabolic etiologies in West syndrome

2018

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SummaryWest syndrome (WS) is an early life epileptic encephalopathy associated with infantile spasms, interictal electroencephalography (EEG) abnormalities including high amplitude, disorganized background with multifocal epileptic spikes (hypsarrhythmia), and often neurodevelopmental impairments. Approximately 64% of the patients have structural, metabolic, genetic, or infectious etiologies and, in the rest, the etiology is unknown. Here we review the contribution of etiologies due to various metabolic disorders in the pathology of WS. These may include metabolic errors in organic molecules involved in amino acid and glucose metabolism, fatty acid oxidation, metal metabolism, pyridoxine deficiency or dependency, or acidurias in organelles such as mitochondria and lysosomes. We discuss the biochemical, clinical, and EEG features of these disorders as well as the evidence of how they may be implicated in the pathogenesis and treatment of WS. The early recognition of these etiologies in some cases may permit early interventions that may improve the course of the disease.

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FARS2 mutation and epilepsy: Possible link with early-onset epileptic encephalopathy

Cited by 22 publications

References 20 publications

FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei

FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei

Compound heterozygosity for loss-of-function FARSB variants in a patient with classic features of recessive aminoacyl-tRNA synthetase-related disease

Metabolic etiologies in West syndrome

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