ICD-11

Pyruvate dehydrogenase deficiency (PDHD) is a rare neurometabolic disorder characterised by a wide range of clinical signs with metabolic and neurological components of varying severity. Manifestations range from often fatal, severe, neonatal to later-onset neurological disorders.

Pyruvate dehydrogenase complex deficiency is a disorder of carbohydrate metabolism characterised by variable degrees of neurological degeneration during childhood. Several hundred cases have been reported so far but the frequency of this disorder is probably underestimated as some mutations are asymptomatic, especially in females. Three clinical phenotypes have been described : 1) a severe neonatal form characterised by neurological symptoms with lactic acidosis, facial dysmorphism and prenatal cerebral anomalies (for example agenesis of the corpus callosum); 2) an infantile form with hypotonia, lethargy, onset of seizures or dystonia, psychomotor delay, Leigh syndrome (present in the majority of cases; see this term), and hyperlactataemia (less severe than in the neonatal form) and 3) an intermediate form observed only in males and characterised by episodes of ataxia with relapses associated with hyperlactataemia that worsens after intake of sugar-rich foods. Pyruvate dehydrogenase complex deficiency results in perturbation of the citric acid cycle, leading to muscular and cerebral energy deficit. Around 100 genetic anomalies have been described so far. Nearly all these mutations were localised to the PDHA1 gene (Xp22.2-p22.1) encoding the E1-alpha subunit of the enzyme and the majority of these mutations are sporadic. However, autosomal recessive mutations have also been identified in the PDHX gene (11p13) encoding the pyruvate dehydrogenase protein X component; in PDHB (3p21.1-p14.2) encoding the pyruvate dehydrogenase E1 component subunit beta; in DLAT (11q23.1) encoding the pyruvate dehydrogenase complex E2 subunit and in PPM2C (8q22.1) encoding the pyruvate dehydrogenase (acetyl-transferring)-phosphatase 1 (PDP1) enzyme. Hyperlactataemia is nearly always present and is found in association with a normal lactate:pyruvate ratio. Differential diagnosis should include other causes of congenital hyperlactataemia with an elevated lactate:pyruvate ratio. Families should be informed that the majority of the PDHA1 mutations arise de novo but germinal mosaicism may occur, and that disease caused by other mutations is inherited in an autosomal recessive manner. Prenatal diagnosis through molecular analysis is feasible. Thiamine supplements should be recommended to all patients. The defect in carbohydrate metabolism can be compensated for in part by a ketogenic diet (low in carbohydrates and rich in fat). The neonatal form is associated with a poor prognosis and early death. The prognosis for the infantile form is poor but depends on the severity of the cerebral involvement at the time of diagnosis, as progression of the cerebral manifestations can be slowed by adopting a ketogenic diet. The prognosis is good for thiamine-responsive forms of the disease.