Novel NARS2 variant causing leigh syndrome with normal lactate levels

Abstract

Leigh syndrome is the most genetically heterogenous phenotype of mitochondrial disease. We describe a patient with Leigh syndrome whose diagnosis had not been confirmed because of normal metabolic screening results at the initial presentation. Whole-exome sequencing identified pathogenic variants in NARS2, the gene encoding a mitochondrial asparaginyl-tRNA synthetase. One of the biallelic variants was novel. This highlights the essential role of genetic testing for a definite diagnosis of Leigh syndrome.

Postinspiratory complex acts as a gating mechanism regulating swallow-breathing coordination and other laryngeal behaviors

“…The identification of PiCo as an important region in swallow-breathing coordination will also be critical for better understanding the mechanisms underlying diseases and disorders with prevalent swallow-breathing discoordination. Leigh Syndrome, Stroke and Parkinson Disease, as well as obstructive sleep apnea and chronic obstructive pulmonary disease all have high incidences of aspiration pneumonia (Armstrong & Mosher, 2011; Cvejic & Bardin, 2018; Su et al, 2014; Tanaka et al, 2022; Won, Byun, Oh, Park, & Seo, 2021). Aspiration is the result of a discoordination of laryngeal closure during swallow that allows foreign material to enter into the airway instead of the esophagus.…”

Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations

“…We searched 14 articles related to neural performance affected by NARS2 mutations ( Simon et al, 2015 ; Sofou et al, 2015 ; Vanlander et al, 2015 ; Mizuguchi et al, 2017 ; Souza et al, 2017 ; Seaver et al, 2018 ; Han et al, 2019 ; Lee et al, 2020 ; Štěrbová et al, 2021 ; Tanaka et al, 2022 ; Vafaee-Shahi et al, 2022 ; Yagasaki et al, 2022 ; Yang et al, 2022 ; Zhang et al, 2022 ). A total of 21 patients and 23 NARS2 mutations were reported in 16 families, most of which were missense mutations (91%, 21/23), followed by nonsense and frameshift mutations.…”

“…The antiepileptic treatment combining multiple antiepileptic drugs could not effectively control seizures in most patients. Some patients developed pentobarbital-induced burst suppression ( Seaver et al, 2018 ) or Fanconi syndrome induced by valproic acid sodium ( Tanaka et al, 2022 ). In addition, almost all patients showed developmental abnormalities to varying degrees, including growth retardation, severe intellectual disability, and mental and motor retardation.…”

“…MRI shows white matter lesions, mainly involving the frontal and parietal lobes and the deep white matter, and features of agenesis of the corpus callosum or diffuse brain atrophy ( Simon et al, 2015 ; Sofou et al, 2015 ; Vanlander et al, 2015 ; Mizuguchi et al, 2017 ; Souza et al, 2017 ; Seaver et al, 2018 ; Han et al, 2019 ; Lee et al, 2020 ; Štěrbová et al, 2021 ; Tanaka et al, 2022 ; Vafaee-Shahi et al, 2022 ; Yagasaki et al, 2022 ; Yang et al, 2022 ; Zhang et al, 2022 ). The characteristics of Leigh syndrome can be observed in some patients’ brain MRI or autopsy results, including symmetric long T2 abnormal signals in the brain stem or the putamen or atrophy of the corpus callosum with lamellar necrosis and vacuolization ( Simon et al, 2015 ; Tanaka et al, 2022 ). In addition, a few cases may be accompanied by renal dysfunction or elevated liver enzymes, possibly leading to a clinical misdiagnosis of Alpers syndrome ( Seaver et al, 2018 ).…”

“…The reported cases have shown a mortality rate of approximately 26%. The survivors may gradually lose their ability to take care of themselves and usually develop chronic progressive ataxia, severe psychomotor retardation or regression, loss of head control, and dysphagia ( Souza et al, 2017 ; Tanaka et al, 2022 ). More rare phenotypes also include neonatal diabetes mellitus and metabolic acidosis ( Yagasaki et al, 2022 ).…”