Clinical Information

The pyruvate dehydrogenase complex (PDHC) catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA, a critical step in the production of cellular energy. PDHC is a multienzyme complex located in the inner mitochondrial membrane, consisting of 6 different components: pyruvate decarboxylase (E1, with alpha and beta subunits), dihydrolipoic transacetylase (E2), dihydrolipoyl dehydrogenase (E3), 2 regulatory enzymes (PDH kinase and PDH phosphatase), and E3-binding protein.

PDHC deficiency is a mitochondrial disorder with a variable clinical presentation ranging from fatal congenital lactic acidosis to relatively mild ataxia or neuropathy. In infants and children with PDHC deficiency, the most common features are delayed development and hypotonia. Seizures and ataxia are also frequent features. Less common manifestations include congenital brain malformations, particularly ventriculomegaly and agenesis of the corpus callosum, or degenerative changes, including Leigh disease. Facial dysmorphism is seen in a small portion of patients. PDHC deficiency is one of the most common causes of primary lactic acidosis in children. The severity of the disease progression is thought to be related to the severity of the lactic acidosis as well as the level of residual enzyme activity.

PDHC deficiency can be caused by defects in the E1 alpha, E1 beta, E2, or E3 subunits. The most common cause of PDHC deficiency is a defect in the E1 alpha gene, located on the X chromosome. Both females and males with an E1 alpha gene mutation are affected with PDHC deficiency, thus it is classified as X-linked dominant. Mutations in the E1 alpha gene are typically de novo.

The most important initial diagnostic test is the measurement of blood and cerebrospinal fluid lactate and pyruvate, along with a lactate-to-pyruvate (L:P) ratio (typically normal ratio with elevated lactate and pyruvate). Additionally, plasma amino acids (AAQP / Amino Acids, Quantitative, Plasma) may detect an increase in alanine. A diagnosis of PDHC deficiency depends on the measurement of enzyme activity in cells or tissues, most commonly in skin fibroblasts.