@article{9268b845-2a9a-4084-9f00-6ff7ec242b80,
  abstract     = {{<p>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 – 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 PDHA1-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 p &lt; 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 – This nationwide, population-based study reports on the occurrence and survival of PDHc deficiency. We demonstrate genotype–sex–phenotype differences in PDHA1-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.</p>}},
  author       = {{Savvidou, Antri and Sofou, Kalliopi and Thunström, Sofia and Ygberg, Sofia and Eklund, Erik A. and Naess, Karin and Kollberg, Gittan and Darin, Niklas}},
  issn         = {{0028-3878}},
  language     = {{eng}},
  number       = {{9}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Neurology}},
  title        = {{A Nationwide Study of Pyruvate Dehydrogenase Complex Deficiency in Sweden : Epidemiology, Genotype–Phenotype Correlations, and Survival}},
  url          = {{http://dx.doi.org/10.1212/WNL.0000000000214924}},
  doi          = {{10.1212/WNL.0000000000214924}},
  volume       = {{106}},
  year         = {{2026}},
}