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Research","doi-asserted-by":"publisher","award":["PRG2040"],"award-info":[{"award-number":["PRG2040"]}],"id":[{"id":"10.13039\/501100002301","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>This retrospective study on X-linked PDHA1-related pyruvate dehydrogenase complex (PDHc) deficiency combined a systematic literature review with a multicentre survey exploring genotypes, phenotypes and survival.<\/jats:p>\n                  <jats:p>Data from 891 individuals (45% unpublished) were included. Of note, 53% of cases were females. Median age at last assessment was 6 years (range 0\u201380 years, n = 622).<\/jats:p>\n                  <jats:p>We detected 331 different (118 unpublished) PDHA1 variants, of which 75% (305\/405) had occurred de novo. Variants in this study were uploaded to ClinVar (SCV006297015\u2014SCV006297345). The 10 most frequent variants accounted for 36% of the diagnoses. Sixty-nine per cent of the variants were private; missense (50%) and frameshift (20%) variants were most common. Frameshift\/nonsense (FS\/N) variants in males (44\/401, 11%) were confined to regions escaping nonsense-mediated decay (NMD) and were significantly less frequent than in females (151\/461, 33%). Neonatal or infantile (405\/529, 77%) presentations were most frequent, with pre\/perinatal abnormalities reported in 47% (159\/342). FS\/N variants in the NMD-predicted region 3.9 [95% confidence interval (CI) 1.54\u201311.04] times increased the odds of fetal findings. Females presented significantly earlier [2 months, interquartile range (IQR) 7.0, n = 224] than males (8 months, IQR 16.6, n = 233), with increased risk of neonatal presentation [odds ratio (OR) 3.01 (95% CI 1.279\u20137.616)] when harbouring FS\/N variants in the NMD-predicted region. The overall (n = 242) mean survival time was 10.9 (95% CI 9.9\u201311.9) years. On average, females survived 4.5 (95% CI 2.62\u20136.40) years longer than males despite presenting more severe phenotypes. Poor survival was associated with male sex [hazard ratio (HR) 3.3 (95% CI 1.95\u20135.62)], neonatal presentation [HR 5.5 (95% CI 2.17\u201314.09)], FS\/N variants in the NMD-predicted region [HR 4.0 (95% CI 1.78, 9.16)] and splice variants [HR 2.3 (95% CI 1.15, 4.59)]. More severe clinical phenotypes were predicted by neonatal or infantile presentations and by female sex. Developmental delay (DD), intellectual disability (ID), muscle hypotonia, abnormal movements, seizures, feeding difficulties and microcephaly were the most frequent phenotypes, all occurring in more than half. Corpus callosum or basal ganglia alterations and cerebral atrophy were common. Four per cent (36\/891) were reported to have mild phenotypes with no DD nor ID (25\/36 males).<\/jats:p>\n                  <jats:p>This is the largest dataset on a nuclear-encoded defect of mitochondrial energy metabolism. The genotypic and phenotypic details further defines the disease landscape and can be used for variant interpretation. The correlations between genotypes, sex, phenotypes and survival, adds substantial improvement to counselling.<\/jats:p>","DOI":"10.1093\/brain\/awaf430","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T13:04:03Z","timestamp":1763039043000},"page":"2344-2362","source":"Crossref","is-referenced-by-count":6,"title":["The genotypic and phenotypic landscape of\n                    <i>PDHA1<\/i>\n                    -related pyruvate dehydrogenase complex deficiency"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0480-3922","authenticated-orcid":false,"given":"Kajus","family":"Merkevicius","sequence":"first","affiliation":[{"name":"Expertise Centre for Mitochondrial Diseases (Mitohaus), University Children\u2019s Hospital, Paracelsus Medical University (PMU) Salzburg , Salzburg 5020 ,","place":["Austria"]},{"name":"Faculty of Medicine, Clinic of Paediatrics, Institute of Clinical Medicine, Vilnius University , Vilnius 03101 ,","place":["Lithuania"]},{"name":"Institute of Biosciences, Life Sciences Center, Vilnius University , Vilnius 10257 ,","place":["Lithuania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitrii","family":"Smirnov","sequence":"additional","affiliation":[{"name":"School of Medicine, Institute of Human Genetics, Klinikum Rechts der Isar, Technical University of Munich , Munich 81675 ,","place":["Germany"]},{"name":"Institute of Neurogenomics, Computational Health Centre, Helmholtz Zentrum M\u00fcnchen , Neuherberg 85764 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea D","family":"Schlieben","sequence":"additional","affiliation":[{"name":"School of Medicine, Institute of Human Genetics, Klinikum Rechts der Isar, Technical University of Munich , Munich 81675 ,","place":["Germany"]},{"name":"Institute of Neurogenomics, Computational Health Centre, Helmholtz Zentrum M\u00fcnchen , Neuherberg 85764 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6238-8109","authenticated-orcid":false,"given":"Rebecca","family":"Ganetzky","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Human Genetics, Mitochondrial Medicine Frontier Program, Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 ,","place":["USA"]},{"name":"Department of Pediatrics, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 ,","place":["USA"]},{"name":"Center for Computational Genomic Medicine, Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9 G","family":"Feichtinger","sequence":"additional","affiliation":[{"name":"Expertise Centre for Mitochondrial Diseases (Mitohaus), University Children\u2019s Hospital, Paracelsus Medical University (PMU) Salzburg , Salzburg 5020 ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huafang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Weifang Maternal and Children Health Hospital , Weifang 261000 ,","place":["China"]},{"name":"Department of Neurology, Beijing Children\u2019s Hospital, Capital Medical University, National Center for Children\u2019s Health , Beijing 100005 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children\u2019s Hospital, Capital Medical University, National Center for Children\u2019s Health , Beijing 100005 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Ebihara","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics, Computational Health Centre, Helmholtz Zentrum M\u00fcnchen , Neuherberg 85764 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3923-8636","authenticated-orcid":false,"given":"Kei","family":"Murayama","sequence":"additional","affiliation":[{"name":"Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University , Tokyo 113-842 ,","place":["Japan"]},{"name":"Department of Metabolism, Chiba Children\u2019s Hospital , Chiba City 266-0007 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Ferrera","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurosciences, Child Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta , Milan 20133 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1969-0147","authenticated-orcid":false,"given":"Anna","family":"Ardissone","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurosciences, Child Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta , Milan 20133 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dariusz","family":"Rokicki","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Nutrition and Metabolic Diseases, The Children\u2019s Memorial Health Institute , Warsaw 04-730 ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Wesol-Kucharska","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Nutrition and Metabolic Diseases, The Children\u2019s Memorial Health Institute , Warsaw 04-730 ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Schr\u00f6der","sequence":"additional","affiliation":[{"name":"CENTOGENE GmbH , Rostock 18055 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Bauer","sequence":"additional","affiliation":[{"name":"CENTOGENE GmbH , Rostock 18055 ,","place":["Germany"]},{"name":"Department of Medicine, Clinic III, Hematology, Oncology, Palliative Medicine, University of Rostock , Rostock 18051 ,","place":["Germany"]},{"name":"Department of Pediatrics, Rare Diseases and Metabolic Medicine, Pomeranian Medical University, 171-252 Szczecin ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida","family":"Bertoli-Avella","sequence":"additional","affiliation":[{"name":"CENTOGENE GmbH , Rostock 18055 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsebeth","family":"\u00d8stergaard","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet , Copenhagen 2100 ,","place":["Denmark"]},{"name":"Department of Clinical Medicine, University of Copenhagen , Copenhagen 2200 ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Freisinger","sequence":"additional","affiliation":[{"name":"Klinikum am Steinenberg, Children\u2019s Hospital Reutlingen , Reutlingen 72764 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirian C H","family":"Janssen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Internal Medicine, Radboudumc Amalia Childrens Hospital, Radboud Center for Mitochondrial Medicine , Nijmegen 6525 ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4454-8823","authenticated-orcid":false,"given":"Matias","family":"Wagner","sequence":"additional","affiliation":[{"name":"School of Medicine, Institute of Human Genetics, Klinikum Rechts der Isar, Technical University of Munich , Munich 81675 ,","place":["Germany"]},{"name":"Institute of Neurogenomics, Computational Health Centre, Helmholtz Zentrum M\u00fcnchen , Neuherberg 85764 ,","place":["Germany"]},{"name":"Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Hauner Children\u2019s Hospital, Ludwig-Maximilian University (LMU) Munich , Munich 80337 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Abouyousef","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center , Riyadh 11211 ,","place":["Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bader","family":"Alhaddad","sequence":"additional","affiliation":[{"name":"School of Medicine, Institute of Human Genetics, Klinikum Rechts der Isar, Technical University of Munich , Munich 81675 ,","place":["Germany"]},{"name":"Institute of Neurogenomics, Computational Health Centre, Helmholtz Zentrum M\u00fcnchen , Neuherberg 85764 ,","place":["Germany"]},{"name":"Lifera Omics , Riyadh 11452 ,","place":["Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lama","family":"AlAbdi","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center , Riyadh 11211 ,","place":["Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4158-341X","authenticated-orcid":false,"given":"Fowzan","family":"Alkuraya","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center , Riyadh 11211 ,","place":["Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte L","family":"Alston","sequence":"additional","affiliation":[{"name":"Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["UK"]},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne NE1 4LP ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Baghdasaryan","sequence":"additional","affiliation":[{"name":"Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz , Graz 8010 ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Barca","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Department, Carol Davila University of Medicine and Pharmacy, Alexandru Obregia Clinical Hospital , Bucharest 050474 ,","place":["Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivo","family":"Bari\u0107","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Hospital Centre, Zagreb and University of Zagreb, School of Medicine , Zagreb 10000 ,","place":["Croatia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Bellusci","sequence":"additional","affiliation":[{"name":"Centro de Referencia Nacional (CSUR) y Europeo (MetabERN) en Enfermedades Metab\u00f3licas, Hospital Universitario 12 de Octubre, Instituto de Investigaci\u00f3n i+12, CIBERER , Madrid 28041 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9482-9447","authenticated-orcid":false,"given":"Andrea","family":"Bevot","sequence":"additional","affiliation":[{"name":"Neuropediatrics, General Pediatrics, Diabetology, Endocrinology and Social Pediatrics, University of Tuebingen, University Hospital T\u00fcbingen , T\u00fcbingen 72016 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugen","family":"Boltshauser","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, University Children\u2019s Hospital Zurich , Zurich 8008 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Borggraefe","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Hauner Children\u2019s Hospital, Ludwig-Maximilian University (LMU) Munich , Munich 80337 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliette","family":"Bouchereau","sequence":"additional","affiliation":[{"name":"Reference Center for Inherited Metabolic Diseases and Reference Center for Mitochondrial Disorders (CARAMMEL), Hopital Necker-Enfants Malades, AP-HP, University Paris Cit\u00e9 , Paris 75015 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Bruno","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa , Genoa 16132 ,","place":["Italy"]},{"name":"Paediatric Neurology and Muscle Disease Unit, IRCCS Istituto Giannina Gaslini , Genoa 16147 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birute","family":"Burnyte","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University , Vilnius 03101 ,","place":["Lithuania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Calhoun","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa , Iowa City, IA 52242 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari","family":"Casas","sequence":"additional","affiliation":[{"name":"Sanford Health, Medical Genetics, Fargo , North Dakota 58103 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmut","family":"Coker","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Nutrition, Department of Pediatrics, Faculty of Medicine, Ege University , Izmir 35100 ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Crushell","sequence":"additional","affiliation":[{"name":"National Centre for Inherited Metabolic Disorders, Children\u2019s Health Ireland , Dublin D01 XD99 ,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"De Lonlay","sequence":"additional","affiliation":[{"name":"Reference Center for Inherited Metabolic Diseases, Hopital Necker Enfants Malades, Institut Imagine, INEM, AP-HP, University Paris Descartes , Paris 75015 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Dionisi-Vici","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases and Hepatology, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS , Rome 00165 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4304-7848","authenticated-orcid":false,"given":"Felix","family":"Distelmaier","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Children\u2019s Hospital, Heinrich-Heine-University , D\u00fcsseldorf 40225 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1723-6728","authenticated-orcid":false,"given":"Marni J","family":"Falk","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Human Genetics, Mitochondrial Medicine Frontier Program, Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 ,","place":["USA"]},{"name":"Department of Pediatrics, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Cristina","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Reference Center of Inherited Metabolic Disease, Unidade Local de Sa\u00fade de S\u00e3o Jos\u00e9, Lisbon Clinical Academic Center , Lisboa 1169-045 ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos R","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Ficicioglu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 ,","place":["USA"]},{"name":"Section of Metabolic Disease, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gulden Fatma","family":"Gok\u00e7ay","sequence":"additional","affiliation":[{"name":"Division of Nutrition and Metabolism, Istanbul Medical Faculty Children\u2019s Hospital, Istanbul University , Istanbul 34390 ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"H\u00e4berle","sequence":"additional","affiliation":[{"name":"Division of Metabolism & Children\u2019s Research Center, University Children\u2019s Hospital , Z\u00fcrich 8032 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