Although MSUD does have intermittent-onset and late-onset forms, clinical manifestations of the classic form typically begin within 1 to 4 weeks of birth. Poor feeding, vomiting, and tachypnea commonly are noted, but the hallmark of the disease is profound depression of the central nervous system, associated with alternating hypotonia and hypertonia (extensor spasms), opisthotonos, and seizures. The urine has the odor of maple syrup.
Laboratory manifestations of MSUD include hypoglycemia and a variable presence of metabolic acidosis, with elevation of the undetermined anions; the acidosis is caused, in part, by plasma branched chain organic acids and, inpart, by the usual ketone bodies, β-hydroxybutyrate and acetoacetate. Branched-chain ketoacids in urine (but notβ-hydroxybutyrate or acetoacetate) react immediately with2,4-dinitrophenylhydrazine to form a copious, white precipitate.
The definitive diagnosis of MSUD generally is made by showing large increases in plasma leucine, isoleucine, and valine concentrations and identification of alloisoleucine in the plasma in excess. The urinary organic acid profile is usually abnormal and shows the ketoacid derivatives of the branched chain amino acids.
Provision of adequate calories and protein, with restriction of leucine, is crucial for acute and chronic management. Hemodialysis, hemofiltration, or peritoneal dialysis can be lifesaving during acidotic crises in addition to close monitoring and therapy for cerebral edema. Ordinary catabolic stresses, such as moderate infections or labor and delivery in a pregnant mother with MSUD, can precipitate clinical crises. Liver transplantation effectively treats MSUD.
Inherited enzymatic deficiencies have been described for each of the steps of urea synthesis (Fig. 53-4). Neonatal screening does not currently detect all of the disorders in the urea cycle.
Figure 53-3 Metabolism of the branched chain amino acids. (1) Aminotransferases, (2) α-ketoacid dehydrogenase complex.
Figure 53-4 The urea cycle. Site of enzymatic defects: (1) N-acetylglutamate synthase (NAG), (2) carbamoyl phosphate synthetase, (3) ornithine carbamoyltransferase, (4) argininosuccinate acid synthetase, (5) argininosuccinate acid lyase, (6) arginase. Transporters (star). (7) citrin, (8) ornithine translocator (star). AKG, Alpha ketoglutarate.
Clinically the two most frequent disorders in the United States are ornithine carbamoyltransferase (OTC) deficiency and argininosuccinate lyase (ASL) deficiency.
Ornithine carbamoyltransferase (OTC) deficiency is X-linked. Gene mutations include both deletions and point mutations. If the enzyme is nonfunctional, there is no OTC activity in affected males, who are likely to die in the neonatal period. Affected females are heterozygous and, because of lyonization, may have a significant degree of enzyme deficiency and may be clinically affected at any time in life. Clinical manifestations range from lethal disease in the male (coma, encephalopathy) to clinical normalcy in a high percentage of females. Late-onset forms in males also occur. Manifestations in clinically affected females include recurrent emesis, lethargy, seizures, developmental delay, mental retardation, or episodic confusion. Affected females may spontaneously limit their protein intake.