With the most-severe neonatal type, the infant appears normal at birth, but toward the end of the first week, poor feeding, intermittent hypertonicity, opisthotonos, and respiratory irregularities appear. These are followed by diminished neonatal automatisms, convulsions, severe ketoacidosis, and often coma and death toward the end of the second to fourth week. This disease is one of the causes of the malignant epileptic syndrome of early infancy (Brett). Four milder forms of the disease have been described. In these more chronic cases, feeding difficulties begin somewhat later in the early infantile period. They are manifest as recurrent infections, episodic acidosis, coma, and retarded growth and psychomotor development. Some of these patients, toward the end of the first year, may become quadriparetic or ataxic; or there may be only a nonspecific mental retardation. The disease derives its name from the maple syrup odor of the child’s urine, imparted by the chemical sotolon, that tests positively for 2,4-dinitrophenylhydrazine.
Other important laboratory findings in addition to increased plasma and urine concentrations of leucine, isoleucine, valine, and keto acids are secondary accumulation of a derivative of a-hydroxybutyric acid. The neuropathologic findings are uncertain. In the first acute case described, only interstitial edema of the brain was observed; but in more chronic cases, pallor and loss of myelin and gliosis of parts of the cerebral white matter that myelinate after birth may be found. This can be visualized on CT and MRI.
Treatment by severe restriction of foods containing branched-chain amino acids (leucine, isoleucine, and valine) allows reasonably normal mental development, but only if such restriction is begun in the neonatal period and maintained lifelong. A thiamine-responsive variant with a slightly different pattern of keto acids described by Prensky and Moser responds variably to 30 to 300 mg of thiamine. The acute episodes, which threaten life, may require peritoneal dialysis to remove the putative toxic metabolites; the episodes respond to the administration of glucose-amino acid mixtures that are free of branched-chain keto acids. Liver transplantation has the potential to be curative and obviate lifetime severe dietary restrictions.
In addition to maple syrup urine disease, there are a number of other metabolic disturbances, some of them of mitochondrial origin, that appear in the neonatal period or later and are marked by an organic acidemia. If they are severe, the infant develops a metabolic (lactic) acidosis soon after birth, with lethargy, feeding problems, rapid respirations, and vomiting. Or there may be irritability, jerky limb movements, and hypertonia. Later presentations take the form of feeding difficulties, repeated vomiting, hypotonia, and failure to thrive. With the passage of time, psychomotor retardation and drug-resistant seizures become evident. Metabolic stress—for example, intercurrent infection or surgical procedures—may precipitate an episode of lactic or ketoacidosis. The care of these patients during an acute illness is of extreme importance. See Lyon and colleagues for a more complete description. Rare cases, especially of biotidinase deficiency, can appear in early adulthood.