Late‐infantile 3‐methylcrotonyl‐CoA carboxylase deficiency presenting as global developmental delay

The enzyme 3-methylcrotonyl-CoA carboxylase (3-MCC) is involved in leucine deg- radation. Fifteen cases of isolated 3-MCC de—ciency (McKusick 210200) have been described (Mourmans et al 1995; Rutledge et al 1995). The neonatal or early- infantile form presents with seizures, hypotonia, feeding difficulties and vomiting. The prognosis is poor. The late-infantile form presents as a Reye-like syndrome with seizures, hyperammonaemia and hypoglycaemia. The juvenile form is characterized by vomiting and dehydration, precipitated by increased protein intake. The latter two forms have a good prognosis (Bannwart et al 1992). Therapy is directed at protein restriction and administration of glycine and L-carnitine to avoid secondary depletion (Rutledge et al 1995). We describe two siblings with isolated 3-MCC de—- ciency. Patient 1: A female, the —rst child of nonconsanguineous parents, had a full-term normal delivery with birth weight 3.65 kg. There were no neonatal problems, but by 2 years she had a developmental age of 10 months, with marked speech delay, weight \10th centile, height (90th centile and head circumference (90th centile. There was marked urinary 3-hydroxyisovalerate and 3-methylcrotonylglycine but no excess of propionic acid metabolites. Total plasma carnitine was 9 kmol/L (normal 23¨60) and free carnitine was 3 kmol/L (normal 15¨53). 3-MCC activity in cultured —broblasts was 0.083 nmol/h per mg protein (normal 5.91 ^ 3.35); propionyl-CoA carboxylase was 28.3 nmol/h per mg protein (normal 53 ^ 26). Bio- tinidase activity was normal. Treatment was begun at diagnosis with a diet giving 77 kcal/kg per day and 1.5 g/kg per day of natural protein. Ketonuria and hypothermia (35.3¡C rectally) per- sisted on this regimen. Caloric intake was increased to 100 kcal/kg per day but ketonuria persisted until the addition of 1 g/kg per day of a leucine-free amino acid supplement, with natural protein of 0.7 g/kg per day. A fall in blood leucine concen- tration was recti—ed by increasing the natural protein to 1 g/kg per day. Patient 2: This patient was a male sibling who had a full-term normal delivery with birth weight 3.2 kg. When seen at 9 months of age he had a developmental age of 5 months with height and weight \10th centile and head circumference (90th centile. On a protein intake of 5 g/kg per day, the urine contained very large concen- 175