Send to

Choose Destination
J Neuropathol Exp Neurol. 2015 Jul;74(7):688-703. doi: 10.1097/NEN.0000000000000209.

Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to Novel RARS2 Mutations.

Author information

From the Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK (NZL, CLA, LH, GF, RM, RWT); East Anglian Medical Genetics Service, Cambridge University Hospital NHS foundations Trust, Cambridge Biomedical Campus, Cambridge, UK (KS, SP); Department of Paediatric Neurology, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge UK (DK); Neonatal Unit, The Rosie Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK (AO); The Centre for Fetal Care, Queen Charlotte's and Chelsea Hospital, Du Cane Road, London, UK (CL); Department of Clinical Neurosciences, Institute of Neurology, University College London, London, UK (RHK); Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK (IPH); Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Trust, Oxford, UK (GKB); and Department of Histopathology, Cambridge University Hospital NHS foundations Trust, Cambridge, UK (AFD).


Autosomal recessive mutations in the RARS2 gene encoding the mitochondrial arginyl-transfer RNA synthetase cause infantile-onset myoencephalopathy pontocerebellar hypoplasia type 6 (PCH6). We describe 2 sisters with novel compound heterozygous RARS2 mutations who presented perinatally with neurologic features typical of PCH6 but with additional features including cardiomyopathy, hydrops, and pulmonary hypoplasia and who died at 1 day and 14 days of age. Magnetic resonance imaging findings included marked cerebellar hypoplasia, gyral immaturity, punctate lesions in cerebral white matter, and unfused deep cerebral grey matter. Enzyme histochemistry of postmortem tissues revealed a near-global cytochrome c oxidase-deficiency; assessment of respiratory chain enzyme activities confirmed severe deficiencies involving complexes I, III, and IV. Molecular genetic studies revealed 2 RARS2 gene mutations: a c.1A>G, p.? variant predicted to abolish the initiator methionine, and a deep intronic c.613-3927C>T variant causing skipping of exons 6-8 in the mature RARS2 transcript. Neuropathologic investigation included low brain weights, small brainstem and cerebellum, deep cerebral white matter pathology, pontine nucleus neuron loss (in 1 sibling), and peripheral nerve pathology. Mitochondrial respiratory chain immunohistochemistry in brain tissues confirmed an absence of complexes I and IV immunoreactivity with sparing of mitochondrial numbers. These cases expand the clinical spectrum of RARS2 mutations, including antenatal features and widespread mitochondrial respiratory chain deficiencies in postmortem brain tissues.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center