Brain & development · 2021
A case of QARS1 associated epileptic encephalopathy and review of epilepsy in aminoacyl-tRNA synthetase disorders.
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Chan Denise L, Rudinger-Thirion Joëlle, Frugier Magali, Riley Lisa G, Ho Gladys, Kothur Kavitha, Mohammad Shekeeb S
Аннотация
INTRODUCTION: Mutations in QARS1, which encodes human glutaminyl-tRNA synthetase, have been associated with epilepsy, developmental regression, progressive microcephaly and cerebral atrophy. Epilepsy caused by variants in QARS1 is usually drug-resistant and intractable. Childhood onset epilepsy is also reported in various aminoacyl-tRNA synthetase disorders. We describe a case with a milder neurological phenotype than previously reported with QARS1 variants and review the seizure associations with aminoacyl-tRNA synthetase disorders.
CASE REPORT: The patient is a 4-year-old girl presenting at 6 weeks of age with orofacial dyskinesia and hand stereotypies. She developed focal seizures at 7 months of age. Serial electroencephalograms showed shifting focality. Her seizures were controlled after introduction of carbamazepine. Progress MRI showed very mild cortical volume loss without myelination abnormalities or cerebellar atrophy. She was found to have novel compound heterozygous variants in QARS1 (NM_005051.2): c.[1132C > T];[1574G > A], p.[(Arg378Cys)];[(Arg525Gln)] originally classified as "variants of uncertain significance" and later upgraded to "likely pathogenic" based on functional testing and updated variant database review. Functional testing showed reduced solubility of the corresponding QARS1 mutants in vitro, but only mild two-fold loss in catalytic efficiency with the c.1132C > T variant and no noted change in tRNAGln aminoacylation with the c.1574G > A variant.
CONCLUSION: We describe two QARS1 variants associated with overall conserved tRNA aminoacylation activity but characterized by significantly reduced QARS protein solubility, resulting in a milder clinical phenotype. 86% of previous patients reported with QARS1 had epilepsy and 79% were pharmaco-resistant. We also summarise literature regarding epilepsy in aminoacyl-tRNA synthetase disorders, which is also often early onset, severe and drug-refractory.
CASE REPORT: The patient is a 4-year-old girl presenting at 6 weeks of age with orofacial dyskinesia and hand stereotypies. She developed focal seizures at 7 months of age. Serial electroencephalograms showed shifting focality. Her seizures were controlled after introduction of carbamazepine. Progress MRI showed very mild cortical volume loss without myelination abnormalities or cerebellar atrophy. She was found to have novel compound heterozygous variants in QARS1 (NM_005051.2): c.[1132C > T];[1574G > A], p.[(Arg378Cys)];[(Arg525Gln)] originally classified as "variants of uncertain significance" and later upgraded to "likely pathogenic" based on functional testing and updated variant database review. Functional testing showed reduced solubility of the corresponding QARS1 mutants in vitro, but only mild two-fold loss in catalytic efficiency with the c.1132C > T variant and no noted change in tRNAGln aminoacylation with the c.1574G > A variant.
CONCLUSION: We describe two QARS1 variants associated with overall conserved tRNA aminoacylation activity but characterized by significantly reduced QARS protein solubility, resulting in a milder clinical phenotype. 86% of previous patients reported with QARS1 had epilepsy and 79% were pharmaco-resistant. We also summarise literature regarding epilepsy in aminoacyl-tRNA synthetase disorders, which is also often early onset, severe and drug-refractory.