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Maple Syrup Urine Disease.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
2006 Jan 30 [updated 2013 May 9].

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Clinic for Special Children, Strasburg, Pennsylvania



Maple syrup urine disease (MSUD) is classified as classic or intermediate. Twelve hours after birth, untreated neonates with classic MSUD have a maple syrup odor in cerumen; by 12-24 hours, elevated plasma concentrations of branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine) and allo-isoleucine, as well as a generalized disturbance of plasma amino acid concentration ratios; by age two to three days, ketonuria, irritability, and poor feeding; by age four to five days, deepening encephalopathy manifesting as lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling." By age seven to ten days, coma and central respiratory failure may supervene. Individuals with intermediate MSUD have partial BCKAD enzyme deficiency that only manifests intermittently or responds to dietary thiamine therapy; these individuals can experience severe metabolic intoxication and encephalopathy during sufficient catabolic stress.


MSUD is diagnosed by the presence of clinical features, elevated BCAAs and allo-isoleucine in plasma, and branched-chain hydroxyacids and ketoacids (BCKAs) in urine. Newborn screening (NBS) programs that employ tandem mass spectrometry detect MSUD by measuring the whole blood combined leucine-isoleucine concentration and its ratio to other amino acids such as alanine and phenylalanine. The three genes in which pathogenic variants are associated with MSUD are BCKDHA, encoding BCKA decarboxylase (E1) alpha subunit (MSUD type 1A); BCKDHB, encoding BCKA decarboxylase (E1) beta subunit (MSUD type 1B); and DBT, encoding dihydrolipoyl transacylase (E2) subunit (MSUD type 2).


Treatment of manifestations: Treatment consists of dietary leucine restriction, BCAA-free medical foods, judicious supplementation with isoleucine and valine, and frequent clinical and biochemical monitoring. Metabolic decompensation is corrected by treating the precipitating stress while delivering sufficient calories, insulin, free amino acids, isoleucine, and valine to achieve sustained net protein synthesis in tissues. Some centers use hemodialysis/hemofiltration to remove BCAAs from the extracellular compartment, but this alone does not establish net protein accretion. Brain edema is a common complication of metabolic decompensation and requires careful management in an intensive care setting. Adolescents and adults with MSUD are at increased risk for ADHD, depression, and anxiety disorders and can be treated successfully with standard psychostimulant and antidepressant medications. Orthotopic liver transplantation is an effective therapy for classic MSUD. Prevention of primary manifestations: Dietary management should allow age-appropriate tolerance of leucine, isoleucine, and valine, and maintain stable plasma BCAA concentrations and BCAA concentration ratios. Use of a "sick-day" formula recipe (devoid of leucine and enriched with calories, isoleucine, valine, and BCAA-free amino acids) combined with rapid and frequent amino acid monitoring allows many catabolic illnesses to be managed in the outpatient setting. Evaluation of relatives at risk: It can be determined if newborn sibs of an affected individual (who have not been tested prenatally) are affected (1) by molecular genetic testing of umbilical cord blood if the family-specific pathogenic alleles have been identified by prior testing of parents or an affected sib; or (2) by plasma amino acid analysis at approximately 24 hours of life. Early diagnosis may allow management of asymptomatic infants out of hospital by experienced providers. Pregnancy management: For women with MSUD, metabolic control should be rigorously maintained before and throughout pregnancy by frequent monitoring of plasma amino acid concentrations and dietary adjustments to avoid the likely teratogenic effects of elevated maternal leucine plasma concentration. Fetal growth should be monitored to detect any signs of essential amino acid deficiency.


MSUD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member.

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