Approximately 200 patients with defects involving the pyruvate dehydrogenase complex have been described. Most patients have a defect involving the E1-a subunit, and a male predominance is expected because the gene is located on the X chromosome. The neonatal presentation includes hypotonia, episodic apnea, convulsions, weak suck, dysmorphic features, lethargy, low birth weight, failure to thrive, and coma. Dysmorphic features include broad nasal bridge, up turned nose, micrognathia, low set and posteriorly rotated ears, short fingers, short arms, simian creases, hypospadias, and anteriorly placed anus. The infantile phenotype usually presents between 3 and 6 months of age psychomotor retardation with hypotonia, convulsions, episodic apnea, ataxia, pyramidal tract signs, lethargy, dysmorphic features, deceleration of head growth, ophthalmoplegia, optic atrophy, peripheral neuropathy, ptosis, dysphagia, deceleration of somatic growth, extrapyramidal signs, and cranial nerves palsies. The neuropathology in most autopsied cases with infantile phenotype were consistent with Leigh Syndrome. Male children may have a benign phenotype with fluctuating ataxia, post exercise fatigue, transient paraparesis, and thiamine responsiveness. These children may have normal mental and motor development between episodes. A high fat diet has been recommended as an alternative source of acetyl-CoA in patients with PDH deficiency. Thiamine, lipoic acid, and L-carnitine supplementation may be helpful in selected cases.