RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?
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.
Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
Tessa
T
van Dijk
Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
Fred
F
van Ruissen
Department of Pediatric Neurology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
Bregje
B
Jaeger
Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
Richard J
RJ
Rodenburg
Department of Clinical Genetics, VU University Medical Center, 1081 HZ, Amsterdam, The Netherlands.
Saskia
S
Tamminga
Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
Merel
M
van Maarle
Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
Frank
F
Baas
Department of Pediatric Neurology, VU University Medical Center, and Neuroscience Campus Amsterdam, 1081 HZ, Amsterdam, The Netherlands.
Nicole I
NI
Wolf
Department of Pediatric Neurology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands. b.t.pollthe@amc.uva.nl.
Bwee Tien
BT
Poll-The
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