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(s)
Type
Journal Article
Abstract
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.1A9G, p.? variant predicted to abolish the initiator methionine, and a
deep intronic c.613-3927C9T variant causing skipping of exons 6Y8 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.
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.1A9G, p.? variant predicted to abolish the initiator methionine, and a
deep intronic c.613-3927C9T variant causing skipping of exons 6Y8 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.
Date Issued
2015-07-01
Date Acceptance
2015-07-01
Citation
Journal of Neuropathology and Experimental Neurology, 2015, 74 (7), pp.688-703
ISSN
1554-6578
Publisher
Lippincott, Williams & Wilkins
Start Page
688
End Page
703
Journal / Book Title
Journal of Neuropathology and Experimental Neurology
Volume
74
Issue
7
Copyright Statement
2015 American Association of Neuropathologists, Inc.This is an open access article distributed under the Creative Commons Attribution
License 4.0 (CCBY), which permits unrestricted use, distribution,
and reproduction in any medium, provided the original work is
properly cited.
License 4.0 (CCBY), which permits unrestricted use, distribution,
and reproduction in any medium, provided the original work is
properly cited.
License URL
Subjects
Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences
Pathology
Neurosciences & Neurology
Mitochondrial disease
Pontocerebellar hypoplasia type 6
RARS2
Respiratory chain deficiency
COMPLEX I DEFICIENCY
HYPERTROPHIC CARDIOMYOPATHY
LACTIC-ACIDOSIS
MITOCHONDRIAL
GENE
ATAXIA
ENCEPHALOPATHY
MODIFIER
FEATURES
DEFECTS
Publication Status
Published