Isovaleric Acidaemia

Isovaleric acidaemia is an autosomal recessive disorder of leucine breakdown caused by deficiency of isovaleryl-CoA dehydrogenase, leading to accumulation of isovaleric acid and its derivatives.

Incidence is about 1 in 100 000 live births. Many cases are found by newborn screening. Some mild forms are diagnosed only after screening and need less intensive care.

Clinical forms are acute neonatal (severe), chronic intermittent (episodes triggered by infection or high protein intake) and asymptomatic (detected by screening, including a common variant in some populations).

Pathophysiology.

Isovaleryl-CoA accumulates and is converted to isovaleric acid, 3-hydroxyisovaleric acid and isovalerylglycine. Isovaleric acid is neurotoxic and gives the characteristic odour.

Organic acid accumulation causes ketoacidosis, hyperammonaemia and bone marrow suppression, with toxic effects on the brain.

• Neonatal: poor feeding, vomiting, lethargy, hypotonia, seizures and coma, with a characteristic odour of sweaty feet.
• Ketoacidosis, hyperammonaemia, hypoglycaemia in some, neutropenia, thrombocytopenia and pancytopenia.
• Later episodes with infection, fasting or high protein intake, with growth and development preserved in treated infants.

Red flags.

• High anion gap acidosis with sweaty feet odour.
• Pancytopenia with encephalopathy.
• Coma in a neonate with hyperammonaemia.

• Blood gas, anion gap, glucose, lactate, ammonia (before treatment), ketones, full blood count and electrolytes.
• Plasma acylcarnitines: raised C5 (isovalerylcarnitine). Urine organic acids: raised 3-hydroxyisovaleric acid and isovalerylglycine.
• Enzyme assay and molecular testing of IVD.

Differential diagnosis. Propionic acidaemia, methylmalonic acidaemia, glutaric acidaemia type 2, 2-methylbutyryl-CoA dehydrogenase deficiency (also raised C5 on screening), pivalate exposure, urea cycle disorders and sepsis.

Acute crisis.

• Stop protein for 24 to 48 hours. Give IV glucose 10% with electrolytes at 8 to 10 mg/kg/min, using insulin 0.01 to 0.1 units/kg/h to maintain glucose under 10 mmol/L.
• Glycine 250 to 600 mg/kg/day orally or by tube in divided doses, and L-carnitine 100 to 200 mg/kg/day IV in 3 or 4 divided doses. Both conjugate isovaleric acid for urinary excretion.
• 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. Avoid sodium benzoate with severe unconjugated hyperbilirubinaemia.
• Haemodialysis for ammonia over 400 micromol/L or poor response.

Long term.

• Leucine restricted diet with natural protein limited to a safe level for growth, with a leucine free amino acid supplement if needed, and avoidance of fasting.
• Glycine 150 to 250 mg/kg/day in divided doses and L-carnitine 50 to 100 mg/kg/day in divided doses.
• Emergency regimen for intercurrent illness.

Monitoring. Growth, development, amino acids, isovalerylglycine in urine, carnitine levels and full blood count. Ammonia and blood gases in illness.

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