Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) is an autosomal recessive disorder of branched chain amino acid metabolism. It is caused by deficiency of the branched chain alpha keto acid dehydrogenase complex (BCKDHA, BCKDHB, DBT, and DLD genes).

Leucine, isoleucine, valine and their keto acids accumulate. Alpha ketoisocaproic acid is neurotoxic and causes cerebral oedema.

Incidence is about 1 in 185,000 worldwide, with a high frequency in Old Order Mennonites (1 in 380). Phenotypes: classic (neonatal; under 2% residual enzyme activity), intermediate, intermittent, and thiamine responsive forms.

• Classic: healthy at birth, with poor feeding, vomiting, lethargy and irritability at 2 to 4 days; sweet maple syrup odour of urine, cerumen and sweat (caused by sotolone), hypertonia alternating with hypotonia (opisthotonus, fencing movements, bicycling), seizures, cerebral oedema, coma and death if untreated
• Intermediate and intermittent: episodic decompensation triggered by fever, infection, fasting, surgery, trauma or postpartum catabolism, causing ataxia, lethargy, and encephalopathy
• Long term: neurodevelopmental impairment, ADHD, anxiety, and depression, even with good control
• Metabolic features: ketoacidosis (anion gap), hypoglycaemia in some, elevated leucine (neurotoxic; levels above 1000 micromol/L with symptoms), and elevated alloisoleucine

1. Newborn screening by tandem mass spectrometry (elevated leucine and isoleucine with valine; confirm by plasma amino acids).
2. Plasma amino acids (elevated leucine, isoleucine, valine and presence of alloisoleucine, which is pathognomonic), and urine organic acids (branched chain 2-hydroxy- and 2-keto acids).
3. Enzyme activity in fibroblasts or leucocytes, and genotyping (BCKDHA, BCKDHB, DBT, DLD).
4. Evaluate in acute illness: blood gas, glucose, ammonia, electrolytes, ketones, and brain imaging showing oedema.

• Acute decompensation (an emergency). Aim to reverse catabolism and rapidly lower leucine below 380 micromol/L.
  1. Stop protein intake and give an energy rich intravenous infusion: glucose 10 to 12.5% at 8 to 10 mg/kg/min in infants, with insulin infusion (0.05 to 0.1 units/kg/hour) to maintain glycaemia and anabolism.
  2. Branched chain amino acid free parenteral or enteral formula; supplement isoleucine (20 to 120 mg/kg/day) and valine (20 to 120 mg/kg/day) to prevent deficiency, guided by plasma levels, once leucine decreases.
  3. Haemodialysis or haemofiltration for severe encephalopathy, leucine above 1500 micromol/L, or failure of medical therapy.
  4. Treat precipitants (infection), avoid hypotonic fluids, monitor sodium (keep 138 to 145 mmol/L), neurological status, and cerebral oedema (mannitol or hypertonic saline if needed); avoid hyponatraemia.
• Long term.
  • Strict lifelong dietary leucine restriction using a BCAA-free medical formula with leucine from natural protein. Typical leucine intake is 40 to 100 mg/kg/day in infants and 400 to 1200 mg/day in older children and adults, adjusted to plasma levels.
  • Provide adequate energy. Monitor plasma amino acids at regular intervals (weekly in infancy, then monthly) with target leucine 150 to 380 micromol/L.
  • A sick day plan with emergency protocols and early intervention in infection is mandatory.
  • Thiamine 10 to 300 mg/day trial for thiamine responsive forms.
  • Liver transplantation (provides about 10 to 15% of normal enzyme activity, permitting a normal diet) is indicated for refractory disease.
  • Neuropsychological follow up and support.
• Genetic counselling: 25% recurrence risk; prenatal diagnosis.