A patient with pontocerebellar hypoplasia type 6 : Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome

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Nevanlinna , V , Konovalova , S , Ceulemans , B , Muona , M , Laari , A , Hilander , T , Gorski , K , Valanne , L , Anttonen , A-K , Tyynismaa , H , Courage , C & Lehesjoki , A-E 2020 , ' A patient with pontocerebellar hypoplasia type 6 : Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome ' , European Journal of Medical Genetics , vol. 63 , no. 3 , 103766 . https://doi.org/10.1016/j.ejmg.2019.103766

Title: A patient with pontocerebellar hypoplasia type 6 : Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome
Author: Nevanlinna, Viivi; Konovalova, Svetlana; Ceulemans, Berten; Muona, Mikko; Laari, Anni; Hilander, Taru; Gorski, Katarin; Valanne, Leena; Anttonen, Anna-Kaisa; Tyynismaa, Henna; Courage, Carolina; Lehesjoki, Anna-Elina
Contributor: University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, Folkhälsan Research Center
University of Helsinki, Molecular and Integrative Biosciences Research Programme
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, HUS Medical Imaging Center
University of Helsinki, Medicum
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, HUSLAB
University of Helsinki, Department of Medical and Clinical Genetics
Date: 2020-03
Language: eng
Number of pages: 7
Belongs to series: European Journal of Medical Genetics
ISSN: 1769-7212
URI: http://hdl.handle.net/10138/326958
Abstract: Pontocerebellar hypoplasia type 6 (PCH6) is a rare infantile-onset progressive encephalopathy caused by biallelic mutations in RARS2 that encodes the mitochondrial arginine-tRNA synthetase enzyme (mtArgRS). The clinical presentation overlaps that of PEHO syndrome (Progressive Encephalopathy with edema, Hypsarrhythmia and Optic atrophy). The proband presented with severe intellectual disability, epilepsy with varying seizure types, optic atrophy, axial hypotonia, acquired microcephaly, dysmorphic features and progressive cerebral and cerebellar atrophy and delayed myelination on MRI. The presentation had resemblance to PEHO syndrome but sequencing of ZNHIT3 did not identify pathogenic variants. Subsequent whole genome sequencing revealed novel compound heterozygous variants in RARS2, a missense variant affecting a highly conserved amino acid and a frameshift variant with consequent degradation of the transcript resulting in decreased mtArgRS protein level confirming the diagnosis of PCH6. Features distinguishing the proband's phenotype from PEHO syndrome were later appearance of hypotonia and elevated lactate levels in blood and cerebrospinal fluid. On MRI the proband presented with more severe supratentorial atrophy and lesser degree of abnormal myelination than PEHO syndrome patients. The study highlights the challenges in clinical diagnosis of patients with neonatal and early infantile encephalopathies with overlapping clinical features and brain MRI findings.
Subject: Pontocerebellar hypoplasia type 6
RARS2
PEHO syndrome
Progressive cerebellar and cerebral atrophy
PROGRESSIVE ENCEPHALOPATHY
OPTIC ATROPHY
EDEMA
TBCD
3111 Biomedicine
1184 Genetics, developmental biology, physiology
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