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

Nevanlinna, V; Konovalova, S; Ceulemans, B; Muona, M; Laari, A; Hilander, T; Gorski, K; Valanne, L; Anttonen, A-K; Tyynismaa, H; et al. 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. Eur J Med Genet, 63 (3). p. 103766. ISSN 1878-0849 https://doi.org/10.1016/j.ejmg.2019.103766
SGUL Authors: Hilander, Taru

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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.

Item Type: Article
Additional Information: © 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: Atrophy, PEHO syndrome, Pontocerebellar hypoplasia type 6, Progressive cerebellar and cerebral, RARS2, 0604 Genetics, 1103 Clinical Sciences, Genetics & Heredity
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Eur J Med Genet
ISSN: 1878-0849
Language: eng
Dates:
DateEvent
March 2020Published
16 September 2019Published Online
15 September 2019Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
UNSPECIFIEDFolkhälsan Research FoundationUNSPECIFIED
PubMed ID: 31536827
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/111227
Publisher's version: https://doi.org/10.1016/j.ejmg.2019.103766

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