Expanding the Phenotype: Neurodevelopmental Disorder, Mitochondrial, With Abnormal Movements and Lactic Acidosis, With or Without Seizures (NEMMLAS) due to WARS2 Biallelic Variants, Encoding Mitochondrial Tryptophanyl-tRNA Synthase
Journal Articles
Overview
Research
Identity
Additional Document Info
View All
Overview
abstract
Background: WARS2 encodes a tryptophanyl tRNA synthetase, which is involved in mitochondrial protein synthesis. Biallelic mutations in WARS2 are rare and have been associated with a spectrum of clinical presentations, including neurodevelopmental disorder with abnormal movements, lactic acidosis with or without seizures (NEMMLAS). Case Presentation: Here we present the case of an 8-year-old girl with ataxia and parkinsonism with periventricular white matter abnormalities on magnetic resonance imaging (MRI) and global developmental delay. The initial investigations revealed an elevated lactate level. Extensive metabolic testing, including a muscle biopsy, was inconclusive. Cerebrospinal fluid (CSF) neurotransmitter levels were low; however, a trial of levodopa was unremarkable. The chromosomal microarray and initial ataxia gene panel was normal. Zinc supplementation for a heterozygous variant of unknown significance in the CP gene on the ataxia exome panel was not effective in treating her symptoms. Reanalysis of the ataxia exome panel highlighted biallelic mutations in WARS2, which lead to the diagnosis of neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (NEMMLAS). This lead to parental genetic testing, redirected therapy, and helped to expand the symptomology of this rare condition. Conclusion: Here we emphasize the importance of imminent and repeat expanded genetic testing to ensure early diagnosis and treatment for rare pediatric disorders. The patient is being trialed on a mitochondrial cocktail in an attempt to compensate for defects in mitochondrial protein synthesis associated with this variant. Longitudinal monitoring of disease manifestation will help establish the currently unknown natural history of this condition.
