A Nationwide Study of Pyruvate Dehydrogenase Complex Deficiency in Sweden

BACKGROUND AND OBJECTIVES: Pyruvate dehydrogenase complex (PDHc) deficiency is a potentially treatable neurodegenerative genetic disorder. It represents a common cause of mitochondrial disease. Most published reports are limited to single cases, and population-based data are lacking. The objective of this study was to investigate the prevalence, incidence, and life expectancy and to explore genotype-phenotype correlations, clinical onset, and disease course. METHODS: We conducted a nationwide, population-based epidemiologic cohort study with retrospective, longitudinal, and cross-sectional components. The cohort included all individuals residing in Sweden who were diagnosed between 2003 and 2022. RESULTS: < 0.001). Severe frameshift variants were detected in 23% of female patients but were absent in male patients. The clinical presentation was heterogeneous. Facial dysmorphism occurred in 76% of patients, polyneuropathy in 54%, stroke-like episodes or lesions in 15%, and perinatal leukoencephalopathy in 11%. CSF lactate was elevated in all 23 patients who underwent lumbar puncture. Mitochondrial functional studies using polarography or ATP production rate assessment in 34 individuals revealed a reduced pyruvate + malate/glutamate + malate oxidation ratio in all but 1 patient. DISCUSSION: -related disease and describe a wider spectrum of clinical features than previously recognized. The broader detection likely reflects the study's population-based and cross-sectional design. Furthermore, we show that the discrepancy between pyruvate and glutamate oxidation in muscle mitochondrial investigations may serve as a diagnostic clue.