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Blickhaeuser, B. ; Stenton, S.L.* ; Neuhofer, C. ; Floride, E.* ; Nesbitt, V.* ; Fratter, C.* ; Koch, J.* ; Kauffmann, B.* ; Catarino, C.* ; Schlieben, L.D. ; Kopajtich, R. ; Carelli, V.* ; Sadun, A.A.* ; McFarland, R.* ; Fang, F.* ; La Morgia, C.* ; Paquay, S.* ; Nassogne, M.C.* ; Ghezzi, D.* ; Lamperti, C.* ; Wortmann, S.* ; Poulton, J.* ; Klopstock, T.* ; Prokisch, H.

Digenic Leigh syndrome on the background of the m.11778G>A Leber hereditary optic neuropathy variant.

Brain 147, 1967-1974 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Leigh syndrome spectrum (LSS) is a primary mitochondrial disorder defined neuropathologically by a subacute necrotizing encephalomyelopathy and characterised by bilateral basal ganglia and/or brainstem lesions. LSS is associated with variants in several mitochondrial DNA (mtDNA) genes and more than 100 nuclear genes, most often related to mitochondrial complex I (CI) dysfunction. Rarely, LSS has been reported in association with primary Leber hereditary optic neuropathy (LHON) variants of the mtDNA, coding for CI subunits (m.3460G>A in MT-ND1, m.11778G>A in MT-ND4, and m.14484T>C in MT-ND6). The underlying mechanism by which these variants manifest as LSS, a severe neurodegenerative disease, as opposed to the LHON phenotype of isolated optic neuropathy, remains an open question. Here, we analyse the exome sequencing of six probands with LSS carrying primary LHON variants, and report digenic co-occurrence of the m.11778G>A variant with damaging heterozygous variants in nuclear disease genes encoding CI subunits as a plausible explanation. Our findings suggest a digenic mechanism of disease for m.11778G>A-associated LSS, consistent with recent reports of digenic disease in individuals manifesting with LSS due to biallelic variants in the recessive LHON-associated disease gene DNAJC30 in combination with heterozygous variants in CI subunits.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Leber Hereditary Optic Neuropathy (lhon) ; Leigh Syndrome Spectrum (lss) ; Digenic Inheritance ; Mitochondrial Complex I (ci); Mutation; Pathogenicity
ISSN (print) / ISBN 0006-8950
e-ISSN 1460-2156
Journal Brain: A Journal of Neurology
Quellenangaben Volume: 147, Issue: 6, Pages: 1967-1974 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Great Clarendon St, Oxford Ox2 6dp, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants German Federal Ministry of Education and Research