Methylmalonic Acidaemia

Methylmalonic acidaemia is a group of autosomal recessive organic acid disorders caused by deficiency of methylmalonyl-CoA mutase (complete mut0 or partial mut-) or defects in adenosylcobalamin synthesis (cblA, cblB, cblD variant 2) that impair conversion of methylmalonyl-CoA to succinyl-CoA.

Incidence is about 1 in 50 000 to 100 000 live births. Combined methylmalonic acidaemia with homocystinuria (cblC) is the most common cobalamin disorder.

Subtypes are mutase deficiency (usually vitamin B12 unresponsive), cblA and cblB (often B12 responsive), and cblC with homocystinuria and a neurological and ophthalmological phenotype.

Pathophysiology.

The block causes accumulation of methylmalonic acid, propionic acid, 3-hydroxypropionate, 2-methylcitrate and propionylcarnitine. Propionyl-CoA inhibits the urea cycle through depletion of N-acetylglutamate, causing hyperammonaemia.

Organic acid accumulation causes high anion gap metabolic acidosis, bone marrow suppression and mitochondrial dysfunction. Chronic toxic effects cause renal tubular damage, chronic kidney disease, basal ganglia injury and pancreatitis.

• Neonatal onset: poor feeding, vomiting, lethargy, hypotonia, tachypnoea, seizures and coma in the first week.
• Neutropenia, thrombocytopenia and pancytopenia during crises, with hypoglycaemia in some.
• Later: developmental delay, growth failure, feeding difficulties, recurrent ketoacidosis with infection or fasting.
• Complications: chronic kidney disease, metabolic stroke of the basal ganglia, pancreatitis, optic neuropathy and cardiomyopathy.

Red flags.

• High anion gap acidosis with ketonuria in a neonate.
• Hyperammonaemia with neutropenia.
• Encephalopathy during intercurrent illness.

• Blood gas, anion gap, glucose, lactate, ammonia (before any treatment), ketones, full blood count and renal function.
• Plasma acylcarnitines: raised propionylcarnitine (C3). Urine organic acids: raised methylmalonic acid, 3-hydroxypropionate and methylcitrate. Plasma amino acids: raised glycine.
• Total plasma homocysteine (raised in cblC) and serum vitamin B12.
• Enzyme and molecular testing for subtype. Newborn screening by C3 can lead to diagnosis.

Differential diagnosis. Propionic acidaemia, isovaleric acidaemia, urea cycle disorders, sepsis, maternal or infant vitamin B12 deficiency, maple syrup urine disease 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, using insulin 0.01 to 0.1 units/kg/h to maintain glucose under 10 mmol/L.
• Hydroxocobalamin 1 mg IM or IV daily during crises while the subtype is unknown.
• L-carnitine 100 to 200 mg/kg/day IV in 3 or 4 divided doses.
• Sodium bicarbonate for severe acidosis, giving 1 to 2 mmol/kg IV slowly when pH is 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, or severe acidosis.
• Treat infection and avoid catabolism.

Long term.

• Natural protein restriction with precursor free amino acid formula, high energy intake and avoidance of fasting.
• L-carnitine 100 mg/kg/day, hydroxocobalamin 1 mg IM daily to weekly in responsive forms, and metronidazole 10 to 20 mg/kg/day orally in intermittent courses to reduce gut propionate production.
• Liver, kidney or combined transplant in selected patients.

Monitoring. Ammonia and blood gases in illness, amino acids, methylmalonic acid, renal function (eGFR) and cystatin C, full blood count, growth, development, vision and brain MRI. Adjust medicines in chronic kidney disease.

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

Special groups. Pregnancy in affected women needs metabolic and renal specialist care.