Pyruvate dehydrogenase (PDH) deficiency is a highly heterogeneous disorder that is one of the major causes of severe primary lactic acidosis in the newborn period and infancy. It can also present as a more chronic neurodegenerative disease with extensive cerebral atrophy and structural anomalies in the brain, as Leigh syndrome or as episodic ataxia. Antenatally, neurodevelopmental lesions, and craniofacial dysmorphisms may be present. The majority of cases of PDH deficiency (~60% to >80%) are due to pathogenic variants in the PDHA1 gene that encodes the pyruvate dehydrogenase E1 α-subunit (see separate information sheet for details on PDHA1 gene analysis). A very rare cause of PDH deficiency is due to variants in the PDHB gene, that encodes the E1-beta subunit of pyruvate dehydrogenase. Features of PDH deficiency due to variants in the PDHB gene are similar to those seen in individuals with PDHA1 deficiency except that ataxia appears to be more frequent in PDHA1 cases. Consanguinity is more common in the families with PDHB gene variants.