{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:47:42Z","timestamp":1791222462168,"version":"4.1.0"},"reference-count":23,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T00:00:00Z","timestamp":1710288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"German Federal Ministry of Education and Research"},{"DOI":"10.13039\/100013143","name":"Manton Center for Orphan Disease Research, Boston Children's Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013143","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Early Career Award from the Thrasher Research Fund"},{"name":"UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children"},{"name":"Austrian Science Funds"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Leigh syndrome spectrum (LSS) is a primary mitochondrial disorder defined neuropathologically by a subacute necrotizing encephalomyelopathy and characterized by bilateral basal ganglia and\/or brainstem lesions. LSS is associated with variants in several mitochondrial DNA 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 mitochondrial DNA, coding for CI subunits (m.3460G&amp;gt;A in MT-ND1, m.11778G&amp;gt;A in MT-ND4 and m.14484T&amp;gt;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 &amp;gt; A variant with damaging heterozygous variants in nuclear disease genes encoding CI subunits as a plausible explanation.<\/jats:p>\n               <jats:p>Our findings suggest a digenic mechanism of disease for m.11778G&amp;gt;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.<\/jats:p>","DOI":"10.1093\/brain\/awae057","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T20:09:52Z","timestamp":1710360592000},"page":"1967-1974","source":"Crossref","is-referenced-by-count":14,"title":["Digenic Leigh syndrome on the background of the m.11778G&amp;gt;A Leber hereditary optic neuropathy variant"],"prefix":"10.1093","volume":"147","author":[{"given":"Beryll","family":"Blickh\u00e4user","sequence":"first","affiliation":[{"name":"Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum M\u00fcnchen , 85764 Neuherberg , Germany"},{"name":"Friedrich-Baur-Institute, Department of Neurology, LMU University Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen , 80336 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L","family":"Stenton","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital , Boston, MA 02115 , USA"},{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard , Cambridge, MA 02142 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane M","family":"Neuhofer","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum M\u00fcnchen , 85764 Neuherberg , Germany"},{"name":"Institute of Human Genetics, School of Medicine, Technical University of Munich , 81675 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Floride","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics, Paracelsus Medical University (PMU) , 5020 Salzburg , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Nesbitt","sequence":"additional","affiliation":[{"name":"NHS Highly Specialised Services for Rare Mitochondrial Disorders, Oxford University Hospitals NHS Foundation Trust , Oxford, OX3 7HE , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"Fratter","sequence":"additional","affiliation":[{"name":"NHS Highly Specialised Services for Rare Mitochondrial Disorders, Oxford University Hospitals NHS Foundation Trust , Oxford, OX3 7HE , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Koch","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital, Department of Neuropediatrics, Paracelsus Medical University (PMU) , 5020 Salzburg , Austria"},{"name":"Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children\u2019s Hospital, Radboudumc , 6525 Nijmegen , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Kauffmann","sequence":"additional","affiliation":[{"name":"Klinikum Bremen Mitte, Department of Pediatrics, Neuropediatrics , 28205 Bremen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Catarino","sequence":"additional","affiliation":[{"name":"Friedrich-Baur-Institute, Department of Neurology, LMU University Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen , 80336 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea Dewi","family":"Schlieben","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum M\u00fcnchen , 85764 Neuherberg , Germany"},{"name":"Institute of Human Genetics, School of Medicine, Technical University of Munich , 81675 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Kopajtich","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum M\u00fcnchen , 85764 Neuherberg , Germany"},{"name":"Institute of Human Genetics, School of Medicine, Technical University of Munich , 81675 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerio","family":"Carelli","sequence":"additional","affiliation":[{"name":"IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica , 40139 Bologna , Italy"},{"name":"Department of Biomedical and Neuromotor Sciences, University of Bologna , 40127 Bologna , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo A","family":"Sadun","sequence":"additional","affiliation":[{"name":"Doheny Eye Institute , Pasadena, CA 91105 , USA"},{"name":"Department of Ophthalmology, David Geffen School of Medicine , UCLA, Los Angeles, CA 10833 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"McFarland","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne, NE2 4HH , UK"},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne, NE2 4HH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Beijing Children\u2019s Hospital, Capital Medical University, National Center for Children\u2019s Health , 100005 Beijing , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"La Morgia","sequence":"additional","affiliation":[{"name":"IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica , 40139 Bologna , Italy"},{"name":"Department of Biomedical and Neuromotor Sciences, University of Bologna , 40127 Bologna , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Paquay","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, University Hospital St Luc, UCLouvain , 1200 Bruxelles , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie C\u00e9cile","family":"Nassogne","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, University Hospital St Luc, UCLouvain , 1200 Bruxelles , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6564-3766","authenticated-orcid":false,"given":"Daniele","family":"Ghezzi","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Neurologico Carlo Besta , 20133 Milan , Italy"},{"name":"Department of Pathophysiology and Transplantation, University of Milan , 20122 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costanza","family":"Lamperti","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Neurologico Carlo Besta , 20133 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Wortmann","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital, Department of Neuropediatrics, Paracelsus Medical University (PMU) , 5020 Salzburg , Austria"},{"name":"Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children\u2019s Hospital, Radboudumc , 6525 Nijmegen , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo","family":"Poulton","sequence":"additional","affiliation":[{"name":"Nuffield Department of Women\u2019s and Reproductive Health University of Oxford, The Women\u2019s Centre , Oxford, OX3 9DU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Klopstock","sequence":"additional","affiliation":[{"name":"Friedrich-Baur-Institute, Department of Neurology, LMU University Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen , 80336 Munich , Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE) , 81377 Munich , Germany"},{"name":"Munich Cluster for Systems Neurology (SyNergy) , 81377 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2379-6286","authenticated-orcid":false,"given":"Holger","family":"Prokisch","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum M\u00fcnchen , 85764 Neuherberg , Germany"},{"name":"Institute of Human Genetics, School of Medicine, Technical University of Munich , 81675 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,3,13]]},"reference":[{"key":"2024060314264239900_awae057-B1","doi-asserted-by":"crossref","first-page":"e402","DOI":"10.1212\/NXG.0000000000000402","article-title":"Mitochondrial diseases in North America: An analysis of the NAMDC 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