The packet contains no certified causative-gene claim and no certified inheritance pattern for this condition, so genetic causes and inheritance are unknown in this packet. The packet definition links the subtypes to the affected subunit of the pyruvate dehydrogenase complex. GeneReviews, for dihydrolipoamide dehydrogenase deficiency, states that dihydrolipoamide dehydrogenase functions as the E3 subunit of three mitochondrial enzyme complexes: the branched-chain alpha-ketoacid dehydrogenase complex, the alpha-ketoglutarate dehydrogenase complex and the pyruvate dehydrogenase complex. GeneReviews states that phenotypic severity is difficult to predict from genotype and residual enzyme function, and reports that normal intellectual functioning has been seen in individuals with certain genotypes.

GeneReviews states that no formal clinical diagnostic criteria have been established for dihydrolipoamide dehydrogenase deficiency. It describes suggestive clinical findings by presentation: early-onset hypotonia, lethargy and emesis that progress to deepening encephalopathy in untreated infants; recurrent liver injury or failure; and muscle cramps, weakness and elevated creatine kinase. Supportive laboratory findings differ by presentation. For the neurologic presentation they include metabolic acidosis and hypoglycemia; for the hepatic presentation, elevated lactate and elevated transaminases ranging from isolated elevation to fulminant hepatic failure; and for the myopathic presentation, normal to elevated creatine kinase, with occasionally elevated transaminases and lactate.

On newborn screening, GeneReviews notes that citrulline is elevated on the dried blood spot, but that screening has failed to identify asymptomatic individuals when citrulline or leucine is used as the primary analyte, that leucine is an unreliable marker, and that the condition is not currently reported on most newborn-screening panels. The packet certifies no other newborn-screening information for pyruvate dehydrogenase deficiency.

The packet certifies no FDA-approved treatments, so approved-treatment coverage is unknown in this packet. The following draws on the GeneReviews chapter for dihydrolipoamide dehydrogenase deficiency. GeneReviews states that consensus management guidance does not currently exist for that form, that theoretic difficulties arise from the several metabolic pathways affected, and that management involves a multidisciplinary approach with multiple subspecialists, with oversight and expertise from a specialized metabolic center.

For the early-onset neurologic presentation, GeneReviews states that the multiple strategies attempted do not appear to significantly alter the natural history of the disease. Its table of routine daily treatment describes protein and branched-chain amino acid intake adjusted according to whether elevated leucine is present, with limited and mixed evidence for protein restriction; a ketogenic or high-fat diet, with five of seven treated persons showing no clinical benefit and two improving clinically; and inhibition of pyruvate dehydrogenase kinase activity, with transient reductions in lactic acid in four of five treated persons and polyneuropathy reported with chronic use. It also lists feeding therapy, with gastrostomy tube placement possible for persistent feeding problems, standard care by developmental, cardiac and eye specialists, and several vitamin and cofactor supplements used with limited success.

GeneReviews' surveillance table lists growth and nutritional status, plasma amino acid levels, a metabolic specialist visit at least monthly in infancy, developmental milestones, liver size and liver tests, peripheral neuropathy examination, mobility assessment, echocardiography at least annually or based on clinical status, and eye evaluation as clinically indicated. Investigational approaches are described under research.

No natural-history field is certified in this packet. The packet definition describes manifestations from often fatal, severe neonatal lactic acidosis to later-onset neurological disorders. GeneReviews, for the early-onset neurologic presentation of dihydrolipoamide dehydrogenase deficiency, states that affected infants frequently do not survive the initial metabolic decompensation or die within the first one to two years of life during a recurrent decompensation, and that children who survive frequently show growth deficiencies and residual neurologic deficits. For the hepatic presentation, GeneReviews describes typically normal intellect between acute metabolic episodes. These descriptions apply to that one form and are not certified for the other subtypes.

The packet lists several active clinical studies for pyruvate dehydrogenase deficiency. They include a natural history and genetic study of pyruvate dehydrogenase complex deficiencies, a study in children of a metabolic agent, a rare disease patient registry and natural history study, and a late-phase trial of an investigational agent that is no longer recruiting. The packet's trial summary lists drug therapy, other interventions and gene therapy among the intervention types. Active clinical trials for this condition are listed on ClinicalTrials.gov.