Expanded Clinical Phenotype and Untargeted Metabolomics Analysis in RARS2-Related Mitochondrial Disorder: A Case Report

Authors

Ameya S Walimbe
Keren Machol
Stephen F Kralik
Elizabeth A Mizerik
Yoel Gofin
Mir Reza Bekheirnia
Charul Gijavanekar
Sarah H Elsea
Lisa T Emrick
Fernando Scaglia

Publication Date

3-4-2024

Journal

BMC Neurology

DOI

10.1186/s12883-024-03571-w

PMID

38438854

PMCID

PMC10910770

PubMedCentral® Posted Date

3-4-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Male, Child, Microcephaly, Muscle Hypotonia, Phenotype, Mitochondrial Diseases, Seizures, Arginine-tRNA Ligase, RARS2, Mitochondrial disease, Dysmorphic features, Lennox-Gastaut Syndrome, Untargeted metabolomics analysis

Abstract

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 catalyzes the transfer of L-arginine to its cognate tRNA during the translation of mitochondrially-encoded proteins. 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 epilepsy by three months of age, which consists of focal or generalized seizures that frequently become pharmacoresistant and lead to developmental and epileptic encephalopathy (DEE).

Case presentation

Here, we describe a six-year-old boy with developmental delay, hypotonia, and failure to thrive who developed an early-onset DEE consistent with Lennox-Gastaut Syndrome (LGS), which has not previously been observed in this disorder. He had dysmorphic features including bilateral macrotia, overriding second toes, a depressed nasal bridge, retrognathia, and downslanting palpebral fissures, and he did not demonstrate 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 T, a previously unpublished variant that is predicted to affect splicing and is, therefore, likely pathogenic and c.419 T > G (p.Phe140Cys), a known pathogenic variant. He exhibited significant, progressive generalized brain atrophy and ex vacuo dilation of the supratentorial ventricular system on brain MRI and did not demonstrate PCH. Treatment with a ketogenic diet (KD) reduced seizure frequency and enabled him to make 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 dysmorphic features and an absence of progressive microcephaly, which can help guide the diagnosis of this condition. Our case highlights the importance of appropriate seizure phenotyping in this condition and indicates that patients can develop LGS, for which a KD may be a viable therapeutic option. Our work further suggests that analytes of phospholipid metabolism may serve as biomarkers of mitochondrial dysfunction.

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