A Nationwide Study of Pyruvate Dehydrogenase Complex Deficiency in Sweden: Epidemiology, Genotype-Phenotype Correlations, and Survival.

Abstract

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. 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. A total of 54 patients (35 female patients) were identified, corresponding to a birth prevalence of 2.43 per 100,000 live births (95% CI 1.86-3.17) and a point prevalence of 0.44 per 100,000 population (95% CI 0.40-0.65). Eight patients (15%) died during the study period. The primary causes of death were congenital lactic acidosis (n = 4), stroke (n = 2), and infection (n = 2). We identified 35 pathogenic variants, including 11 not previously reported. X-linked <i>PDHA1</i>-related disease was the most common subtype (n = 44; 30 female patients), accounting for 81% of patients. Prenatal onset occurred in 20 female and 2 male patients. All but 1 affected female survived (97%), whereas more than 40% of affected male patients died (log-rank <i>p</i> < 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. This nationwide, population-based study reports on the occurrence and survival of PDHc deficiency. We demonstrate genotype-sex-phenotype differences in <i>PDHA1</i>-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.