Diagnosis and treatment of maple syrup disease: a study of 36 patients.

OBJECTIVE: To evaluate an approach to the diagnosis and treatment of maple syrup disease (MSD).
METHODS: Family histories and molecular testing for the Y393N mutation of the E1alpha subunit of the branched-chain alpha-ketoacid dehydrogenase allow us to identify infants who were at high risk for MSD. Amino acid concentrations were measured in blood specimens from these at-risk infants between 12 and 24 hours of age. An additional 18 infants with MSD were diagnosed between 4 and 16 days of age because of metabolic illness. A treatment protocol for MSD was designed to 1) inhibit endogenous protein catabolism, 2) sustain protein synthesis, 3) prevent deficiencies of essential amino acids, and 4) maintain normal serum osmolarity. Our protocol emphasizes the enhancement of protein anabolism and dietary correction of imbalances in plasma amino acids rather than removal of leucine by dialysis or hemofiltration. During acute illnesses, the rate of decrease of the plasma leucine level was monitored as an index of net protein synthesis. The treatment protocol for acute illnesses included the use of mannitol, furosemide, and hypertonic saline to maintain or reestablish normal serum sodium and extracellular osmolarity and thereby prevent or reverse life-threatening cerebral edema. Similar principles were followed for both sick and well outpatient management, especially during the first year, when careful matching of branched-chain amino acid intake with rapidly changing growth rates was necessary. Branched-chain ketoacid excretion was monitored frequently at home and branched-chain amino acid levels were measured within the time of a routine clinic visit, allowing immediate diagnosis and treatment of metabolic derangements.
RESULTS: 1) Eighteen neonates with MSD were identified in the high-risk group (n = 39) between 12 and 24 hours of age using amino acid analysis of plasma or whole blood collected on filter paper. The molar ratio of leucine to alanine in plasma ranged from 1.3 to 12.4, compared with a control range of 0.12 to 0.53. None of the infants identified before 3 days of age and managed by our treatment protocol became ill during the neonatal period, and 16 of the 18 were managed without hospitalization. 2) Using our treatment protocol, 18 additional infants who were biochemically intoxicated at the time of diagnosis recovered rapidly. In all infants, plasma leucine levels decreased to <400 micromol/L between 2 to 4 days after diagnosis. Rates of decrease of the plasma leucine level using a combination of enteral and parenteral nutrition were consistently higher than those reported for dialysis or hemoperfusion. Prevention of acute isoleucine, valine, and other plasma amino acid deficiencies by appropriate supplements allowed a sustained decrease of plasma leucine levels to the therapeutic range of 100 to 300 micromol/L, at which point dietary leucine was introduced. 3) Follow-up of the 36 infants over >219 patient years showed that, although common infections frequently cause loss of metabolic control, the overall rate of hospitalization after the neonatal period was only 0.56 days per patient per year of follow-up, and developmental outcomes were uniformly good. Four patients developed life-threatening cerebral edema as a consequence of metabolic intoxication induced by infection, but all recovered. These 4 patients each showed evidence that acutely decreased serum sodium concentration and decreased serum osmolarity were associated with rapid progression of cerebral edema during their acute illnesses.
CONCLUSIONS: Classical MSD can be managed to allow a benign neonatal course, normal growth and development, and low hospitalization rates. However, neurologic function may deteriorate rapidly at any age because of metabolic intoxication provoked by common infections and injuries. Effective management of the complex pathophysiology of this biochemical disorder requires integrated management of general medical care and nutrition, as well as control of several variables that influence endogenous protein anabolism and catabolism, plasma amino acid concentrations, and serum osmolarity.