OP5 – 2696: Pyruvate dehydrogenase complex deficiency: Phenotype–genotype, phenotype–neuroimaging associations and treatment outcomes

Abstract

Objectives To assess the phenotypic and genotypic spectrum of patients with pyruvate dehydrogenase complex (PDHc) deficiency, identify phenotype–genotype correlations and evaluate the effect of ketogenic diet. Methods All patients investigated at the Queen Silvia Children's Hospital and found to have genetically verified PDHc deficiency were included in this study. Results 18 patients (5 males: 13 females) were included; all but one patients were alive at a median follow-up period of 7.5 years. All patients were born at full term. Eleven patients (1 male: 10 females) presented with perinatal onset, consisting mainly of hypotonia, microcephaly and congenital lactic acidosis. These patients developed progressive microcephaly, severe mental retardation, while epilepsy was also seen in some patients. Brain neuroimaging in these patients revealed hypoplasia or complete agenesis of the corpus callosum, enlargement of the ventricles – often asymmetrical – and of the subarachnoid spaces and accompanying atrophy of the periventricular white matter. Genetic investigation showed variable genetic defects of the PDHA1 and PDHX genes. The remaining seven patients had later disease onset, at a median age of 1.5 years. The disease course in these patients pertained mainly to recurrent episodes of hypotonia, ataxia, dysarthria and hyperlactatemia, often following infections. All seven patients were found to have genetic defects in the PDHA1 gene. Brain neuroimaging showed bilateral lesions in the basal ganglia and the midbrain, while neuroimaging was normal in two patients. Thirteen patients were treated with ketogenic diet with positive effect, in the majority of treated patients, on the recurrent episodes of ataxia and dysarthria, speech development, mood and cognition. Conclusions We show that pediatric patients with PDHc deficiency express two different clinical phenotypes, each one correlated to specific neuroimaging features. The genetic background and the effect of ketogenic diet are assessed.