Expanded Clinical Phenotype and Untargeted Metabolomics Analysis in RARS2-related Mitochondrial Disorder
Ameya Walimbe1, Keren Machol2, Stephen Kralik3, Elizabeth Mizerik2, Yoel Gofin4, Mir Reza Bekheirnia2, Charul Gijavanekar2, Sarah Elsea2, Lisa Emrick1, Fernando Scaglia2
1Division of Pediatric Neurology and Developmental Neurosciences, Department of Pediatrics, 2Department of Molecular and Human Genetics, 3Department of Radiology, Baylor College of Medicine, 4Sackler School of Medicine, Tel Aviv University
Objective:
To describe a novel clinical presentation and metabolomic findings of a patient with RARS2-related mitochondrial disorder.
Background:
RARS2-related mitochondrial disorder is an autosomal recessive mitochondrial encephalopathy caused by biallelic pathogenic variants in the gene encoding the mitochondrial arginyl-transfer RNA synthetase 2 (RARS2, MIM *611524, NM_020320.5). RARS2 transfers L-arginine to its cognate tRNA during mitochondrial protein translation. The classical presentation of RARS2-related mitochondrial disorder includes pontocerebellar hypoplasia (PCH), progressive microcephaly, profound developmental delay, feeding difficulties, and hypotonia. Most patients also develop severe, pharmacoresistant epilepsy that frequently leads to developmental and epileptic encephalopathy (DEE).
Results:
We describe a 6-year-old boy with developmental delay, hypotonia, and failure to thrive who developed an early-onset DEE consistent with Lennox-Gastaut Syndrome (LGS), previously unreported in this disorder. He had dysmorphic features including bilateral macrotia, overriding second toes, a depressed nasal bridge, retrognathia, and downslanting palpebral fissures, and he lacked progressive microcephaly. Whole genome sequencing identified two variants in RARS2, c.36+1G>T, a previously unpublished variant that is predicted to affect splicing, and is, therefore, likely pathogenic, and c.419T>G, (p.Phe140Cys), a known pathogenic variant. Brain MRI demonstrated significant, progressive generalized brain atrophy and ex vacuo dilation of the supratentorial ventricular system and an absence of PCH. Treatment with a ketogenic diet (KD) reduced seizure frequency and enabled developmental progress. Plasma untargeted metabolomics analysis showed increased levels of lysophospholipid and sphingomyelin-related metabolites.
Conclusions:
Our work expands the clinical spectrum of RARS2-related mitochondrial disorder, demonstrating that patients can present with dysmorphology and lack progressive microcephaly, which can help guide diagnosis of this condition. Our case highlights the importance of appropriate seizure phenotyping and indicates that patients with this disorder can develop LGS, for which a KD may be effective. Our work further suggests that analytes of phospholipid metabolism may serve as biomarkers of mitochondrial dysfunction.