WARS2 – Neurodevelopmental Disorder, Mitochondrial, with Abnormal Movements and Lactic Acidosis, With or Without Seizures

Biallelic variants in WARS2 underlie an autosomal recessive neurodevelopmental disorder characterized by global developmental delay, ataxia, parkinsonism and lactic acidosis, designated NEMMLAS (MONDO:0060578). An 8-year-old girl presented with progressive ataxia, parkinsonism, periventricular white matter changes on MRI, elevated lactate and delayed milestones. Reanalysis of an ataxia exome panel identified homozygous NM_015836.4:c.938A>T (p.Lys313Met) in WARS2, confirmed by parental testing and prompting mitochondrial cocktail therapy, thereby expanding the phenotypic spectrum of NEMMLAS (PMID:31282308).

Functional assessment of c.938A>T in patient-derived neuroepithelial stem cells revealed mild combined complex I and IV defects, while modeling in yeast demonstrated severe respiration and viability impairment and Drosophila silencing caused lethality, consistent with a partial loss-of-function mechanism (PMID:30920170). Further reports of a recurrent hypomorphic p.Trp13Gly variant in four unrelated patients with early-onset tremor-parkinsonism responsive to levodopa support variable expressivity within WARS2-related NEMMLAS (PMID:37107582).

Key Take-home: Early and comprehensive genetic testing for WARS2 is critical for diagnosis, genotype-guided therapy, and prognosis in patients with suspected NEMMLAS.

References

• Journal of child neurology • 2019 • 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. PMID:31282308
• Molecular genetics & genomic medicine • 2019 • Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy. PMID:30920170
• Genes • 2023 • The Expanding Phenotypical Spectrum of WARS2-Related Disorder: Four Novel Cases with a Common Recurrent Variant. PMID:37107582

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