Consensus Guidelines for Diagnosis and Management of Pyruvate Dehydrogenase Complex Deficiency

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.