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EBioMedicine. 2018 Apr;30:86-93. doi: 10.1016/j.ebiom.2018.02.010. Epub 2018 Feb 24.

MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load.

Author information

1
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
2
Department of Neurology, Queen's Medical Centre, Nottingham, UK.
3
Paediatric Neurology Department, Red Cross War Memorial Children's Hospital, Cape Town, South Africa.
4
Division of Chemical Pathology, Faculty of Health Sciences, University of Cape Town, South Africa; National Health Laboratory Service, Cape Town, South Africa.
5
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK; Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, UK.
6
Department of Inherited Metabolic Disease, Division of Women's and Children's Services, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
7
Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
8
Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, UK.
9
Institute of Human Development, University of Manchester, Manchester M13 9WL, UK; Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
10
Ophthalmic Genetics Unit, OMMA, Institute of Ophthalmology, Athens, Greece.
11
Pediatric Ophthalmology Department, MITERA Children's Hospital, Athens, Greece.
12
Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands.
13
Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.
14
Department of Pediatrics, Nara Medical University Hospital, Nara 634-8522, Japan.
15
Department of Pediatrics, Sapporo City General Hospital, Sapporo 060-8604, Japan.
16
Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan.
17
Department of Metabolism, Chiba Children's Hospital, Chiba 266-0007, Japan.
18
Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, UK.
19
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
20
Department of Pediatrics, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan.
21
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK. Electronic address: grainne.gorman@ncl.ac.uk.

Abstract

Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers. Ten patients were deceased at the time of analysis (median age of death was 10years (range: 5·4months-37years, IQR=17·9years). Nine patients manifested with LS, one with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and one with Leber hereditary optic neuropathy. The remaining nine patients presented with either overlapping syndromes or isolated neurological symptoms. Mitochondrial respiratory chain activity analysis was normal in five out of ten muscle biopsies. We confirmed maternal inheritance in six families, and demonstrated marked variability in tissue segregation, and phenotypic expression at relatively low blood mutant loads. Neuropathological studies of two patients manifesting with LS/MELAS showed prominent capillary proliferation, microvacuolation and severe neuronal cell loss in the brainstem and cerebellum, with conspicuous absence of basal ganglia involvement. These findings suggest that whole mtDNA genome sequencing should be considered in patients with suspected mitochondrial disease presenting with complex neurological manifestations, which would identify over 300 known pathogenic variants including the m.13094T>C.

KEYWORDS:

Heteroplasmy; Lactic acidosis and stroke-like episodes (MELAS); Leigh syndrome (LS); Mitochondrial DNA; Mitochondrial encephalomyopathy; Neuropathology

PMID:
29506874
PMCID:
PMC5952215
DOI:
10.1016/j.ebiom.2018.02.010
[Indexed for MEDLINE]
Free PMC Article

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