Propionic Acidaemia

Propionic acidaemia is an autosomal recessive organic acid disorder caused by deficiency of propionyl-CoA carboxylase (PCCA or PCCB variants), which impairs conversion of propionyl-CoA to methylmalonyl-CoA.

Incidence is about 1 in 100 000 live births, higher in some populations. Presentation is usually in the first week of life.

Propionate arises from catabolism of isoleucine, valine, methionine and threonine, from odd chain fatty acids and from gut bacteria.

Pathophysiology.

Accumulation of propionyl-CoA and derivatives (propionic acid, 3-hydroxypropionate, methylcitrate, propionylcarnitine) causes metabolic acidosis, inhibition of the urea cycle (hyperammonaemia), and bone marrow suppression.

Mitochondrial toxicity affects the heart, brain and pancreas. Cardiomyopathy and QT prolongation are important late complications.

• Neonatal poor feeding, vomiting, lethargy, hypotonia, tachypnoea, seizures and coma.
• Neutropenia, thrombocytopenia and hypoglycaemia.
• Later: developmental delay, movement disorders from basal ganglia injury, pancreatitis, osteoporosis, growth failure and recurrent ketoacidosis.
• Dilated cardiomyopathy and prolonged QTc.

Red flags.

• Prolonged QTc or arrhythmia during crises.
• Cardiac failure in a child with known disease.
• Severe hyperammonaemia with neutropenia in a neonate.

• Blood gas, anion gap, glucose, lactate, ammonia (before treatment), ketones, full blood count and electrolytes.
• Plasma acylcarnitines: raised propionylcarnitine (C3). Urine organic acids: raised 3-hydroxypropionate, methylcitrate and tiglylglycine, with normal or only mildly raised methylmalonic acid. Plasma amino acids: raised glycine.
• Enzyme assay and molecular testing of PCCA and PCCB.
• ECG, echocardiography and lipase.

Differential diagnosis. Methylmalonic acidaemia, isovaleric acidaemia, urea cycle disorders, sepsis, multiple carboxylase deficiency (biotinidase and holocarboxylase deficiency) and other organic acidaemias.

Acute crisis.

• Stop protein for 24 to 48 hours. Give IV glucose 10% with electrolytes at 8 to 10 mg/kg/min, with insulin 0.01 to 0.1 units/kg/h to maintain glucose under 10 mmol/L.
• L-carnitine 100 to 200 mg/kg/day IV in 3 or 4 divided doses.
• Sodium bicarbonate 1 to 2 mmol/kg IV slowly for severe acidosis (pH under 7.1).
• Ammonia over 150 micromol/L: sodium benzoate 250 mg/kg and sodium phenylbutyrate 250 mg/kg IV in glucose 10% over 90 to 120 minutes, then 250 mg/kg of each over 24 hours. Maximum 12 g daily for each. Carglumic acid 100 to 250 mg/kg/day orally in 2 to 4 divided doses is an alternative or addition. Avoid sodium benzoate with severe unconjugated hyperbilirubinaemia.
• Haemodialysis for ammonia over 400 micromol/L, or poor response.
• Treat infection and avoid catabolism.

Long term.

• Natural protein restriction with precursor free amino acid formula and enough energy. Gastrostomy feeding may be needed.
• L-carnitine 100 mg/kg/day, and metronidazole 10 to 20 mg/kg/day orally in courses to reduce gut propionate production.
• Liver transplant in selected patients lowers decompensations but does not fully prevent neurological or cardiac complications.

Monitoring. ECG and echocardiography every 1 to 2 years from childhood, with QTc monitoring and avoidance of QT-prolonging drugs. Ammonia and gases in illness, amino acids, growth, development and bone density.

Referral and escalation. Refer to a metabolic centre. Provide an emergency regimen letter and early admission for febrile illness or vomiting. Refer to cardiology for cardiomyopathy.