RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

Tessa van Dijk; Fred van Ruissen; Bregje Jaeger; Richard J Rodenburg; Saskia Tamminga; Merel van Maarle; Frank Baas; Nicole I Wolf; Bwee Tien Poll-The

doi:10.1007/8904_2016_584

RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

JIMD Rep. 2017:33:87-92. doi: 10.1007/8904_2016_584. Epub 2016 Sep 29.

Authors

Tessa van Dijk¹, Fred van Ruissen¹, Bregje Jaeger², Richard J Rodenburg³, Saskia Tamminga⁴, Merel van Maarle¹, Frank Baas¹, Nicole I Wolf⁵, Bwee Tien Poll-The⁶

Affiliations

¹ Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
² Department of Pediatric Neurology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
³ Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
⁴ Department of Clinical Genetics, VU University Medical Center, 1081 HZ, Amsterdam, The Netherlands.
⁵ Department of Pediatric Neurology, VU University Medical Center, and Neuroscience Campus Amsterdam, 1081 HZ, Amsterdam, The Netherlands.
⁶ Department of Pediatric Neurology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands. b.t.pollthe@amc.uva.nl.

Abstract

Mutations in the mitochondrial arginyl tRNA synthetase (RARS2) gene are associated with Pontocerebellar Hypoplasia type 6 (PCH6). Here we report two patients, compound heterozygous for RARS2 mutations, presenting with early onset epileptic encephalopathy and (progressive) atrophy of both supra- and infratentorial structures. Early pontocerebellar hypoplasia was virtually absent and respiratory chain (RC) defects could not be detected in muscle biopsies. Both patients carried a novel missense mutation c.1544A>G (p.(Asp515Gly)) in combination with either a splice site (c.297+2T>G) or a frameshift (c.452_454insC) mutation. The splice site mutation induced skipping of exon 4.These two patients expand the phenotypical spectrum associated with RARS2 mutations beyond the first report of PCH6 by Edvardson and colleagues. We propose to classify RARS2-associated phenotypes as an early onset mitochondrial encephalopathy, since this is more in agreement with both clinical presentation and underlying genetic cause.