The genotypic and phenotypic landscape of <i>PDHA1</i> -related pyruvate dehydrogenase complex deficiency

This retrospective study on X-linked PDHA1-related pyruvate dehydrogenase complex (PDHc) deficiency combined a systematic literature review with a multicenter survey exploring genotypes, phenotypes, and survival. Data from 891 individuals (45% unpublished) were included. Of note, 53% of cases were females. Median age at last assessment was six years (range 0-80 years, n = 622). We detected 331 different (118 unpublished) PDHA1 variants of which 75% (305/405) had occurred de novo.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 - SCV006297345). The 10 most frequent variants accounted for 36% of the diagnoses. Sixty-nine percent 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 NMD-predicted region 3.9 (95% Confidence Interval (CI) 1.54-11.04) 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 1.279-7.616) when harboring FS/N variants in NMD-predicted region. The overall (n = 242) mean survival time was 10.9 (95% CI 9.9-11.9) years. On average, females survived 4.5 (95% CI 2.62-6.40) years longer than males despite presenting more severe phenotypes. Poor survival was associated with male sex (hazard ratio (HR) 3.3 (95% CI 1.95-5.62)), neonatal presentation (HR 5.5 (95% CI 2.17-14.09)), FS/N variants in 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 percent (36/891) were reported to have mild phenotypes with no DD nor ID (25/36 males). This is the largest dataset on a nuclear-encoded defect of mitochondrial energy metabolism. The genotypic and phenotypic details further defines disease landscape and can be used for variant interpretation. The correlations between genotypes, sex, phenotypes and survival, adds a substantial improvement to counselling.

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Brain
Published
2025-11-13
DOI
https://doi.org/10.1093/brain/awaf430
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1
Primary Topic
Biochemical Acid Research Studies
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article
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1.11

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The genotypic and phenotypic landscape of PDHA1 -related pyruvate dehydrogenase complex deficiency

Manuel Schiff, Huafang Jiang, Mahmut Çöker, Dominik S. Westphal et al.
1 citations
Brain
Biochemical Acid Research Studies
1.11
article

The genotypic and phenotypic landscape of PDHA1 -related pyruvate dehydrogenase complex deficiency

Manuel Schiff, Huafang Jiang, Mahmut Çöker, Dominik S. Westphal, Thomas Meitinger, Élise Lebigot, Giulia Ferrera, Ina Knerr, Rebecca D. Ganetzky, Kari Casas, Anna Baghdasaryan, Birutė Burnytė, Anna Ardissone, Joy Yaplito‐Lee, Dmitrii Smirnov, Sumit Parikh, Zhimei Liu, Saskia Brigitte Wortmann, Chiara Panicucci, Katrin Õunap, Çiğdem Seher Kasapkara, Galit Tal, Eva M. M. Hoytema van Konijnenburg, Thomas Klopstock, Mathias Woidy, Can Fıçıcıoğlu, Kajus Merkevičius, Ellen Crushell, Esther M. Maier, Heidi Peters, Amel Karaa, Danijela Petković Ramadža, Tomáš Honzík, Lea D. Schlieben, Oliver Heath, Dariusz Rokicki, Marie‐Cécile Nassogne, Julia Hoefele, Sabine Schröder, Wolfgang Sperl, Bader Alhaddad, Gabriela M. Repetto, Wendy E. Smith, Carlos R. Ferreira, Ivo Barić, Marni J. Falk, Kostas Tsiakas, Robert McFarland, Holger Prokisch, Ingo Borggraefe, Lama AlAbdi, Sema Kalkan Uçar, Matias Wagner, Mirian C. H. Janssen, Peter Freisinger, Johannes Häberle, Charlotte L. Alston, Elsebet Østergaard, Dorota Wesół‐Kucharska, Zita Krūmiņa, Gülden Gökçay, Isabel Rivera, Eugen Boltshauser, Barbara Plecko, Diana Bârcă, Tomohiro Ebihara, Katja Steinbrücker, Richard J. Rodenburg, René G. Feichtinger, Joerg Klepper, Alessandro Rossi, Johannes A. Mayr, Marcello Bellusci, Bryce A. Mendelsohn, Barbara Siri, Amy Calhoun, Yılmaz Yıldız, Peter O. Bauer, Aida M. Bertoli‐Avella, Juliette Bouchereau, Mária Judit Molnár, Jolanta Sykut‐Cegielska, Kathrin Seidemann, Kei Murayama, Fowzan Sami Alkuraya, Diego Martinelli, Patrícia Janeiro, Carlo Dionisi‐Vici, Georg F. Hoffmann, Omar Abouyousef, Fang Fang, Sérgia Soares, Johannes Koch, Martina Huemer, Pascal De Lonlay, Anabela Oliveira, Ana Cristina Ferreira, Ilse Kern, Claudio Bruno, Andrea Bevot, Garry K. Brown, Petra Zsidegh, Costanza Lamperti, Robert W. Taylor, Samia Pichard, Helen Mundy, Martin Zenker, Albrecht Hellenschmidt
article en
1 citations

Abstract

This retrospective study on X-linked PDHA1-related pyruvate dehydrogenase complex (PDHc) deficiency combined a systematic literature review with a multicenter survey exploring genotypes, phenotypes, and survival. Data from 891 individuals (45% unpublished) were included. Of note, 53% of cases were females. Median age at last assessment was six years (range 0-80 years, n = 622). 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 - SCV006297345). The 10 most frequent variants accounted for 36% of the diagnoses. Sixty-nine percent 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 NMD-predicted region 3.9 (95% Confidence Interval (CI) 1.54-11.04) 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 1.279-7.616) when harboring FS/N variants in NMD-predicted region. The overall (n = 242) mean survival time was 10.9 (95% CI 9.9-11.9) years. On average, females survived 4.5 (95% CI 2.62-6.40) years longer than males despite presenting more severe phenotypes. Poor survival was associated with male sex (hazard ratio (HR) 3.3 (95% CI 1.95-5.62)), neonatal presentation (HR 5.5 (95% CI 2.17-14.09)), FS/N variants in 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 percent (36/891) were reported to have mild phenotypes with no DD nor ID (25/36 males). This is the largest dataset on a nuclear-encoded defect of mitochondrial energy metabolism. The genotypic and phenotypic details further defines disease landscape and can be used for variant interpretation. The correlations between genotypes, sex, phenotypes and survival, adds a substantial improvement to counselling.

Brain
Semmelweis University (HU), University of Copenhagen (DK), University of Iowa (US), Hôpital Necker-Enfants Malades (FR), National Institutes of Health (US), Ministry of Health (TR), Sanford Health (US), Cliniques Universitaires Saint-Luc (BE), Cleveland Clinic (US), Royal Children's Hospital (AU), Maine Medical Center (US), Children's Hospital of Philadelphia (US), Universidad del Desarrollo (CL), University Hospital Centre Zagreb (HR), University of Lisbon (PT), Radboud University Nijmegen (NL), Universität Hamburg (DE), Carol Davila University of Medicine and Pharmacy (RO), Vilnius University (LT), Technion – Israel Institute of Technology (IL), Medical University of Graz (AT), Université Paris Cité (FR), Charles University (CZ), Heidelberg University (DE), Paracelsus Medical University (AT), King Faisal Specialist Hospital & Research Centre (SA), Churchill Hospital (GB), Rambam Health Care Campus (IL), Istituto Giannina Gaslini (IT), German Center for Neurodegenerative Diseases (DE), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), Kaiser Permanente Oakland Medical Center (US), University Hospital Heidelberg (DE), Tartu University Hospital (EE), Copenhagen University Hospital (DK), TUM Klinikum (DE), Rigshospitalet (DK), Radboud University Medical Center (NL), Children's Health Ireland at Crumlin (IE), Helmholtz Zentrum München (DE), Juntendo University (JP), Medizinische Hochschule Hannover (DE), University of Oxford (GB), Ege University (TR), Vilnius University of Applied Sciences (LT), Massachusetts General Hospital (US), Düsseldorf University Hospital (DE), Städtisches Klinikum Karlsruhe (DE), Assistance Publique – Hôpitaux de Paris (FR), Memorial Ankara Hospital (TR), Klinikum Aschaffenburg (DE), Hospital Universitario 12 De Octubre (ES), MaineHealth (US), Saudi Heart Association (SA), University Hospital of Geneva (CH), Hospital Pedro Hispano (PT), University Medical Center Hamburg-Eppendorf (DE), Radboud Institute for Molecular Life Sciences (NL), Administração Regional de Saúde de Lisboa e Vale do Tejo (PT), Munich Cluster for Systems Neurology (DE), Amalia Kinderziekenhuis (NL), Children's Memorial Health Institute (PL), German Center for Infection Research (DE), Rappaport Family Institute for Research in the Medical Sciences (IL), IVF Centers Prof. Zech (AT), Institute of Human Genetics (PL), München Klinik (DE), Bambino Gesù Children's Hospital (IT), National Children’s Research Centre (IE), University Children's Hospital Tübingen (DE), Riga Stradiņš University (LV), Kreiskliniken Reutlingen (DE), German Centre for Cardiovascular Research (DE), University Children's Hospital Zurich (CH), Sanford Medical Center (US), Sanford Medical Center (US), Mother and Child Foundation (GB), Friedrich Baur Stiftung (DE), Chiba Hospital (JP), Centogene (Germany) (DE), University Hospital Magdeburg (DE), Wellcome Centre for Mitochondrial Research (GB), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), Beijing Children’s Hospital (CN), Evelina London Children's Healthcare (GB), Oxford University Hospitals NHS Trust (GB), Hospital de Santa Maria (PT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Barbara Bush Children’s Hospital (US), Weifang Maternity and Child Care Hospital (CN), General University Hospital in Prague (CZ), Institute of Child and Mother Health (BD), Wilhelmina Children's Hospital (NL), Bicêtre Hospital (FR), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Heinrich Heine University Düsseldorf (DE), University of Rostock (DE), Life University (US), University of Tartu (EE), Technical University of Munich (DE), Hacettepe University (TR), Istanbul University (TR), University of Naples Federico II (IT), University of Pennsylvania (US), Pomeranian Medical University (PL), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), University of Genoa (IT), Newcastle University (GB)
Japan Agency for Medical Research and Development, E-Rare, European Commission, Bundesministerium für Bildung und Forschung, Austrian Science Fund, Ministero della Salute, Technische Universität München, Všeobecná Fakultní Nemocnice v Praze, Agencia Nacional de Investigación y Desarrollo
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Biochemical Acid Research Studies
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