Ketogenic diet therapy in pyruvate dehydrogenase deficiency: Global clinical practice from literature and survey data

BACKGROUND: Pyruvate dehydrogenase deficiency (PDHD) is a rare mitochondrial disorder characterized by impaired carbohydrate metabolism, resulting in lactic acidosis and neurological dysfunction. Ketogenic diet therapy (KDT) is commonly used to bypass defective glucose metabolism; however, evidence guiding clinical practice remains limited. OBJECTIVE: To evaluate global clinical practice and published evidence regarding the use of KDT in children and young people with PDHD. METHODS: A combined literature review and international clinician survey were conducted. A systematic search identified studies reporting KDT use in PDHD. Two international surveys targeting registered dietitians and medical doctors collected data on clinical practice, diet initiation, monitoring, outcomes, and adverse effects. RESULTS: Forty studies describing 129 patients were identified, predominantly case reports or series. Survey responses were obtained from 41 dietitians (142 patients) and 14 physicians (64 patients) across multiple regions. All physician respondents supported referral for KDT at diagnosis regardless of genotype. Classical ketogenic diets were most commonly prescribed, though modified approaches were frequently used in clinical practice to improve feasibility and palatability. Target β-hydroxybutyrate levels typically ranged between 2 and 4 mmol/L, although treatment was frequently individualized. Findings demonstrated improvements in seizure control, motor function, cognition, and quality of life. Adverse effects were primarily gastrointestinal. CONCLUSIONS: KDT is a widely used and generally well tolerated therapeutic strategy for PDHD across genotypes and age groups, with reported clinical benefits extending beyond seizure control. Clinical practice demonstrates variability, reflecting the limited high-quality evidence base. Development of standardized but flexible clinical guidelines and further longitudinal studies are needed to optimize patient outcomes.