Daniella Nishri1, Hadassa Goldberg-Stern2, Iris Noyman3, Lubov Blumkin4, Sara Kivity5, Hirotomo Saitsu6, Mitsuko Nakashima6, Naomichi Matsumoto6, Esther Leshinsky-Silver7, Tally Lerman-Sagie4, Dorit Lev8. 1. Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Child Development Center, Central District, Maccabi Health Services, Tel Aviv, Israel. 2. Epilepsy Center, Schneider's Children Medical Center, Petah Tiqwa, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 3. Pediatric Neurology Unit, Soroka Medical Center, Beer-Sheba, Israel. 4. Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 5. Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Epilepsy Center, Schneider's Children Medical Center, Petah Tiqwa, Israel. 6. Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan. 7. Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Molecular Genetics Laboratory, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 8. Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: dorlev@post.tau.ac.il.
Abstract
INTRODUCTION: Early onset epileptic encephalopathies (EOEEs) are a group of devastating diseases, manifesting in the first year of life with frequent seizures and/or prominent interictal epileptiform discharges on the electroencephalogram, developmental delay or regression and usually a poor prognosis. There are numerous causes for EOEEs making the diagnostic workup time consuming and costly. METHODS: We describe two siblings with fatal EOEE, profound global developmental delay and post-natal microcephaly that underwent extensive biochemical and metabolic workup in vain. Neuro-imaging disclosed non-specific progressive cerebral atrophy. RESULTS: Whole-exome sequencing (WES) disclosed compound heterozygous mutations in the gene encoding for mitochondrial arginyl-transfer RNA synthetase, RARS2. This gene has been previously described as the cause of pontocerebellar hypoplasia type 6. CONCLUSION: We suggest that RARS2 gene mutations can cause a metabolic neurodegenerative disease manifesting primarily as EOEE with post-natal microcephaly, without the distinctive radiological features of pontocerebellar hypoplasia.
INTRODUCTION: Early onset epileptic encephalopathies (EOEEs) are a group of devastating diseases, manifesting in the first year of life with frequent seizures and/or prominent interictal epileptiform discharges on the electroencephalogram, developmental delay or regression and usually a poor prognosis. There are numerous causes for EOEEs making the diagnostic workup time consuming and costly. METHODS: We describe two siblings with fatal EOEE, profound global developmental delay and post-natal microcephaly that underwent extensive biochemical and metabolic workup in vain. Neuro-imaging disclosed non-specific progressive cerebral atrophy. RESULTS: Whole-exome sequencing (WES) disclosed compound heterozygous mutations in the gene encoding for mitochondrial arginyl-transfer RNA synthetase, RARS2. This gene has been previously described as the cause of pontocerebellar hypoplasia type 6. CONCLUSION: We suggest that RARS2 gene mutations can cause a metabolic neurodegenerative disease manifesting primarily as EOEE with post-natal microcephaly, without the distinctive radiological features of pontocerebellar hypoplasia.
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