Consensus Guidelines for Diagnosis and Management of Pyruvate Dehydrogenase Complex Deficiency.

Nandaki Keshavan, Julia Neugebauer, Marcello Bellusci, Enrico Bertini, Garry Brown, Niklas Darin, Suzanne DeBrosse, Lucy Drexler, Stefan Drexler, Gregory M Enns, Rebecca D Ganetzky, Kelly Gilbert, Austin Larson, Rebecca Legi, April N Lehman, Camile Newby, Manuel Schiff, Rachel Skeath, Peter W Stacpoole, Sarah Thompson, Emma Watt, Saskia B Wortmann, Jirair K Bedoyan, Shamima Rahman

Journal: Journal of inherited metabolic disease 2026;49(6):e70226

PMID: 42823914

View on PubMed

Abstract

Primary pyruvate dehydrogenase complex deficiency (PDCD) comprises a group of monogenic disorders caused by pathogenic variants in genes encoding subunits of, or regulatory components affecting, the pyruvate dehydrogenase complex. The clinical phenotype spans a broad continuum, ranging from early onset congenital lactic acidosis to infantile or childhood onset global developmental delay with epilepsy, through to more attenuated adult-onset neurological presentations. Reports from patients and advocacy groups indicate substantial variability in clinical management across both emergency and outpatient settings and between centres internationally. This variability underscores the need for systematic evaluation of the evidence base and the development of harmonised, consensus-driven clinical guidelines to standardise care and improve outcomes. An international consortium of experts from Europe and North America, including metabolic physicians, neurologists, dietitians, geneticists and patient representatives, was convened. The group undertook a structured review of the literature and developed guideline statements addressing disease classification, recognition, diagnostic evaluation, dietary and non-dietary management, surveillance for complications, genetic counselling and transition to adult services. Each recommendation was assigned a GRADE rating reflecting strength and quality of evidence. Consensus was achieved using a Delphi methodology. In total, 199 recommendations reached consensus and constitute the core of these guidelines. These recommendations provide a framework for consistent, high-quality, multidisciplinary care. The process also identified key evidence gaps, highlighting priorities for future research and the ongoing need to develop effective disease-modifying therapies.

Address: Metabolic Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK.; Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK.; Department of Paediatric Gastroenterology, Nephrology and Metabolic Medicine, Charité - Universitaetsmedizin Berlin, Berlin, Germany.; Center for Chronically Sick Children, Charité - Universitaetsmedizin Berlin, Berlin, Germany.; Reference Center for Inherited Metabolic Disorders MetabERN, Mitochondrial Disorders Research Group, '12 de Octubre' University Hospital, Madrid, Spain.; Research Unit of Neuromuscular and Neurodegenerative Disease, Translational Pediatrics and Clinical Genetics, Bambino Gesu Children's Hospital, IRCCS, Rome, Italy.; Oxford Medical Genetics Laboratories, the Churchill Hospital, Oxford, UK.; Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.; Center for Human Genetics, Department of Genetics and Genome Sciences, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.; Neurological Institute, Department of Neurology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.; Department of Pediatrics, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.; The Freya Foundation, Bristol, UK.; Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine and Lucille Packard Children's Hospital, Palo Alto, California, USA.; Department of Pediatrics, Division of Human Genetics, Mitochondrial Medicine Frontier Program, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.; Center for Computational Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.; Nutrition Services, Stanford University School of Medicine and Lucille Packard Children's Hospital, Palo Alto, USA.; Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.; Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.; Department of Nutrition and Dietetics, Bristol Royal Hospital for Children, Bristol, UK.; Reference Center for Mitochondrial Disorders (CARAMMEL) and Reference Center for Inborn Errors of Metabolism, Department of Pediatrics, Necker-Enfants-Malades Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris-Cité, MetabERN, Paris, France.; INSERM UMRS 1163, Institut Imagine, Paris, France.; Department of Dietetics, Great Ormond Street Hospital, London, UK.; Division of Endocrinology, Diabetes and Metabolism, Departments of Medicine and Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA.; The Elizabeth Watt PDCD Research Fund, Centennial, Colorado, USA.; University Children's Hospital, Expertise Centre for Mitochondrial Diseases (Mitohaus), Paracelsus Private Medical University (PMU), Salzburg, Austria.; UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

DOI: 10.1002/jimd.70226

MeSH Terms: Humans, Pyruvate Dehydrogenase Complex Deficiency Disease, Consensus, Genetic Counseling, Phenotype