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.
The authors “Nicole I. Wolf” and “Bwee Tien Poll-The” contributed equally to this work and share last authorship.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Alkhateeb AM, Aburahma SK, Habbab W, Thompson RI (2016) Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disabilities. Metab Brain Dis 31:901–907
Barth PG (1993) Pontocerebellar hypoplasias. An overview of a group of inherited neurodegenerative disorders with fetal onset. Brain Dev 15(6):411–422
Barth PG, Vrensen GFKM, Uylings HBM, Oorthuys JWE, Stam FC (1990) Inherited syndrome of microcephaly, dyskinesia and pontocerebellar hypoplasia: a systematic atrophy with early onset. J Neurol Sci 97(1):25–42
Boom R, Sol CJA, Salimans MMM, Jansen CL, Wertheim-van Dillen PME, van der Noordaa J (1990) Rapid and simple method for the purification of nucleic acids. J Clin Microbiol 28:495–503
Cassandrini D, Cilio MR, Bianchi M et al (2013) Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients. J Inherit Metab Dis 36:43–53
Edvardson S, Shaag A, Kolesnikova O et al (2007) Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with Pontocerebellar Hypoplasia. Am J Hum Genet 81(4):857–862
Glamuzina E, Brown R, Hogarth K et al (2012) Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2. J Inherit Metab Dis 35:459–467
Joseph TJ, Innes AM, Smith AC et al (2014) Neuropathologic features of pontocerebellar hypoplasia. J Neuropathol Exp Neurol 73(11):1009–1025
Kastrissianakis K, Anand G, Quaghebeur G et al (2013) Subdural effusions and lack of early pontocerebellar hypoplasia in siblings with RARS2 mutations. Arch Dis Child 98:1004–1007
Lax NZ, Alston CL, Schon K et al (2015) Neuropathologic characterization of pontocerebellar hypoplasia type 6 associated with cardiomyopathy and hydrops fetalis and severe multisystem respiratory chain deficiency due to novel RARS2 mutations. J Neuropathol Exp Neurol 74(7):688–703
Li Z, Schonberg R, Guidugli L et al (2015) A novel mutation in the promotor of RARS2 causes pontocerebellar hypoplasia in two siblings. J Hum Genet 60(7):363–369
Namavar Y, Barth PG, Kasher PR et al (2011a) Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. Brain 134(1):143–156
Namavar Y, Chitayat D, Barth PG et al (2011b) TSEN54 mutations cause pontocerebellar hypoplasia type 5. Eur J Hum Genet 19:724–726
Neveling K, Feenstra I, Gilissen C et al (2013) A post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases. Hum Mutat 34:1721–1726
Ngoh A, Bras J, Guerreiro R et al (2016) RARS2 mutations in a sibship with infantile spasms. Epilepsia 57(5):95–102
Nishri D, Goldberg-Stern H, Noyman I et al (2016) RARS2 mutations cause early onset epileptic encephalopathy without ponto-cerebellar hypoplasia. Eur J Paediatr Neurol 20(3):412–417
Rankin J, Brown R, Dobyns WB et al (2010) Pontocerebellar Hypoplasia type 6: a British case with PEHO like features. Am J Med Genet A 152A:2079–2084
Wortmann SB, Koolen DA, Smeitink JA, van den Heuvel L, Rodenburg RJ (2015) Whole exome sequencing of suspected mitochondrial patients in clinical practice. J Inherit Metab Dis 38:437–443
Acknowledgments
We would like to thank the patients and their families for participation in this study. We are grateful to Ruud Wolterman for RNA isolation and Dr. Leonie Menke for participation in this study.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Garry Brown
Appendices
Synopsis
PCH6 is a mitochondrial encephalopathy.
Compliance with Ethics Guidelines
Conflict of Interest
Tessa van Dijk, Fred van Ruissen, Bregje Jaeger, Richard J. Rodenburg, Saskia Tamminga, Merel van Maarle, Frank Baas, Nicole I. Wolf, and Bwee Tien Poll-The declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki declaration of 1975, as revised in 2000. Informed consent was obtained from patients/patients’ parents for being included in the study.
Author Contributions
TvD collected data, performed the RT-PCR, and wrote the first draft of the manuscript. BTPT and NIW collected patient information and critically reviewed the manuscript. FvR and RjR performed diagnostic analysis and interpretation of results. BJ, ST, and MvM collected patient information. FB supervised the laboratory procedures and results, and critically reviewed the manuscript.
Rights and permissions
Copyright information
© 2016 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
van Dijk, T. et al. (2016). RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 33. JIMD Reports, vol 33. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_584
Download citation
DOI: https://doi.org/10.1007/8904_2016_584
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-55011-3
Online ISBN: 978-3-662-55012-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)