Pyruvate dehydrogenase complex deficiency in Sweden; Clinical spectrum, Genetics, Neuroimaging findings and Outcomes

Abstract

Pyruvate dehydrogenase complex deficiency (PDCD) is a rare and clinically heterogeneous neurometabolic disorder. Current knowledge is based largely on case reports and small case series, while nationwide population-based data remains scarce. This thesis aimed to define the epidemiology of PDCD in Sweden and to characterize its clinical spectrum, outcomes, neuroimaging findings, and genotype-phenotype correlations. The work comprised nationwide population-based studies with retrospective, longitudinal, and cross-sectional components. In total, 54 individuals with primary PDCD were identified in Sweden. The estimated birth prevalence was 2.43 per 100,000 live births and the point prevalence was 0.44 per 100,000 population. Survival was 85%: causes of death were congenital lactic acidosis, stroke, and infection. PDHA1-related disease accounted for 81% of cases; severe frameshift variants were identified in 23% of affected females but were not observed in males. A reduced pyruvate+malate/glutamate+malate oxidation ratio was present in almost all patients and emerged as a potential diagnostic marker (Paper I). The most frequent neuroradiological abnormalities were corpus callosum agenesis or hypoplasia, ventriculomegaly, and Leigh-like lesions with predominant involvement of the globi pallidi. Stroke-like lesions and leukoencephalopathy were identified as additional radiological features within the PDCD spectrum (Paper II). Among patients with PDHA1 variants, 86% had de novo variants and a substantial proportion of heterozygous female carriers were symptomatic (Paper III). Intellectual disability and impaired adaptive functioning were common, although socialization often represented a relative strength. A ketogenic diet was associated with reduced seizure frequency, prevention of relapses, and improvements in motor and communicative function (Paper IV). Overall, PDCD appears to represent a clinical continuum with a broader phenotypic spectrum than previously recognized.