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Stendel, C.* ; Neuhofer, C.* ; Floride, E.* ; Yuqing, S.* ; Ganetzky, R.D.* ; Park, J.* ; Freisinger, P.* ; Kornblum, C.* ; Kleinle, S.* ; Schöls, L.* ; Distelmaier, F.* ; Stettner, G.M.* ; Büchner, B.* ; Falk, M.J.* ; Mayr, J.A.* ; Synofzik, M.* ; Abicht, A.* ; Haack, T.B.* ; Prokisch, H. ; Wortmann, S.B. ; Murayama, K.* ; Fang, F.* ; Klopstock, T.*

Delineating MT-ATP6-associated disease.

Neurol. Genet. 6:e393 (2020)
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ObjectiveTo delineate the phenotypic and genotypic spectrum in carriers of mitochondrial MT-ATP6 mutations in a large international cohort.MethodsWe analyzed in detail the clinical, genetical, and neuroimaging data from 132 mutation carriers from national registries and local databases from Europe, USA, Japan, and China.ResultsWe identified 113 clinically affected and 19 asymptomatic individuals with a known pathogenic MT-ATP6 mutation. The most frequent mutations were m.8993 T > G (53/132, 40%), m.8993 T > C (30/132, 23%), m.9176 T > C (30/132, 23%), and m.9185 T > C (12/132, 9%). The degree of heteroplasmy was high both in affected (mean 95%, range 20%-100%) and unaffected individuals (mean 73%, range 20%-100%). Age at onset ranged from prenatal to the age of 75 years, but almost half of the patients (49/103, 48%) became symptomatic before their first birthday. In 28 deceased patients, the median age of death was 14 months. The most frequent symptoms were ataxia (81%), cognitive dysfunction (49%), neuropathy (48%), seizures (37%), and retinopathy (14%). A diagnosis of Leigh syndrome was made in 55% of patients, whereas the classic syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP) was rare (8%).ConclusionsIn this currently largest series of patients with mitochondrial MT-ATP6 mutations, the phenotypic spectrum ranged from asymptomatic to early onset multisystemic neurodegeneration. The degree of mutation heteroplasmy did not reliably predict disease severity. Leigh syndrome was found in more than half of the patients, whereas classic NARP syndrome was rare. Oligosymptomatic presentations were rather frequent in adult-onset patients, indicating the need to include MT-ATP6 mutations in the differential diagnosis of both ataxias and neuropathies.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Leigh-syndrome; Mitochondrial; Mutation; Ataxia; Neuropathy; Insights; Defects
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 2376-7839
e-ISSN 2376-7839
Journal Neurology Genetics
Quellenangaben Volume: 6, Issue: 1, Pages: , Article Number: e393 Supplement: ,
Publisher American Academy of Neurology
Publishing Place Minneapolis, Minn.
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500700-001
DOI 10.1212/NXG.0000000000000393
WOS ID WOS:000530284200013
Scopus ID 85081928779
Erfassungsdatum 2020-05-19
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