Pyruvate Dehydrogenase Complex Deficiency

Pyruvate dehydrogenase complex (PDC) deficiency is a mitochondrial disorder of pyruvate oxidation, most often X-linked due to variants in PDHA1, causing lactic acidosis, neurodevelopmental impairment and structural brain abnormalities. Other genes (PDHB, DLAT, PDHX, DLD) cause autosomal recessive disease. Symptoms range from fatal neonatal lactic acidosis to intermittent ataxia.

Pathophysiology. The pyruvate dehydrogenase complex converts pyruvate to acetyl-CoA, linking glycolysis to the citric acid cycle. Deficiency forces pyruvate to lactate, and starves the brain of acetyl-CoA, so energy failure occurs and carbohydrate loads worsen acidosis.

Females with PDHA1 variants are affected because of X inactivation mosaicism.

A ketogenic diet bypasses the block by supplying ketone bodies as an alternative fuel.

• Neonatal lactic acidosis, poor feeding and hypotonia
• Developmental delay and intellectual disability
• Seizures including infantile spasms
• Microcephaly and corpus callosum agenesis or hypoplasia
• Leigh syndrome with basal ganglia lesions
• Episodic ataxia, dystonia and peripheral neuropathy in milder forms
• Facial dysmorphism resembling foetal alcohol syndrome in some
• Respiratory problems and apnoea
• Episodic lactic acidosis with illness, carbohydrate loads or febrile infection
• Males are usually more severely affected than females

• Blood and CSF lactate and pyruvate: raised lactate with a normal lactate/pyruvate ratio (under 20).
• Plasma alanine: often raised.
• Pyruvate dehydrogenase complex activity in fibroblasts or lymphocytes.
• PDHA1 sequencing with deletion and duplication analysis, then panel testing for PDHB, DLAT, PDHX and DLD.
• Brain MRI: corpus callosum agenesis, cystic lesions, ventriculomegaly, and Leigh like changes.
• MR spectroscopy: raised lactate peak.
• Urine organic acids: raised lactate, pyruvate and alanine.

Differential diagnosis.

• Respiratory chain disorders (raised lactate/pyruvate ratio over 25)
• Leigh syndrome of other genetic causes
• Pyruvate carboxylase deficiency
• Biotinidase and holocarboxylase deficiency
• Hypoxic ischaemic injury and sepsis

• Ketogenic diet: the mainstay, at a 3:1 to 4:1 ratio of fat to carbohydrate plus protein, started in a hospital setting with monitoring of ketones, glucose, bicarbonate and lipids. A strictly carbohydrate limited diet improves seizure control and neurology.
• Thiamine: 100 to 300 mg daily orally (up to 1000 mg daily in some centres) as a cofactor, since a response occurs in some patients.
• Dichloroacetate: 12.5 to 25 mg/kg orally every 12 hours, lowering lactate by activating the complex; peripheral neuropathy limits use, and a specialist must supervise.
• Acute lactic acidosis: stop intravenous glucose at high rates, correct acidosis with sodium bicarbonate 1 to 2 mmol/kg intravenously for pH under 7.1, and use haemodialysis in severe cases. Avoid dextrose infusions above 4 mg/kg/min unless needed for hypoglycaemia.
• Drug avoidance: valproate, which inhibits the complex, and propofol infusions.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, with other agents by seizure type. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Feeding and respiratory care: gastrostomy for unsafe swallow, omeprazole 0.7 to 1 mg/kg daily for reflux, and vaccination.
• Development and education: early intervention, physiotherapy, and special education.
• Genetic counselling: for PDHA1, a carrier mother has a 50% chance of transmitting the variant to each child, and many variants arise de novo; autosomal recessive genes carry a 25% recurrence risk.

Special groups.

• Females with PDHA1 variants: assess for mild to moderate disease and treat with diet when symptomatic.

Monitoring. Lactate, ketones and acid base balance during diet initiation and every 3 months afterwards. Growth, lipids and kidney stones on the diet, and neurological review every 3 to 6 months.

Referral and escalation. Refer to clinical genetics, metabolic medicine and neurology. Emergency for severe lactic acidosis, apnoea or status epilepticus.