Maple Syrup Urine Disease

In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
[updated ].


Clinical characteristics: Maple syrup urine disease (MSUD) is categorized as classic (severe), intermediate, or intermittent. Neonates with classic MSUD are born asymptomatic but without treatment follow a predictable course:

  1. 12–24 hours. Elevated concentrations of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) and alloisoleucine, as well as a generalized disturbance of amino acid concentration ratios, are present in blood and the maple syrup odor can be detected in cerumen;

  2. Two to three days. Early and nonspecific signs of metabolic intoxication (i.e., irritability, hypersomnolence, anorexia) are accompanied by the presence of branched-chain alpha-ketoacids, acetoacetate, and beta-hydroxybutyrate in urine;

  3. Four to six days. Worsening encephalopathy manifests as lethargy, apnea, opisthotonos, and reflexive "fencing" or "bicycling" movements as the sweet maple syrup odor becomes apparent in urine;

  4. Seven to ten days. Severe intoxication culminates in critical cerebral edema, coma, and central respiratory failure.

Individuals with intermediate MSUD have partial branched-chain alpha-ketoacid dehydrogenase deficiency that manifests only intermittently or responds to dietary thiamine therapy; these individuals can experience severe metabolic intoxication and encephalopathy in the face of sufficient catabolic stress. In the era of newborn screening (NBS), the prompt initiation of treatment of asymptomatic infants detected by NBS means that most individuals who would have developed neonatal manifestations of MSUD remain asymptomatic with continued treatment adherence.

Diagnosis/testing: Suggestive biochemical findings on NBS include whole-blood concentration ratios of (leucine + isoleucine) to alanine and phenylalanine that are above the cutoff values for the particular screening lab. Follow-up plasma amino acid analysis typically demonstrates elevated concentrations of BCAAs and alloisoleucine. The diagnosis of MSUD is confirmed by identification of biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT.

Management: 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. A BCAA-restricted diet fortified with prescription medical foods can maintain average plasma BCAA concentrations within standard reference intervals and preserves the ratios among them. 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. Acute 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 intervention does not alone establish net protein accretion. Brain edema is a common complication of metabolic encephalopathy and requires careful management in an intensive care setting. Adolescents and adults with MSUD are at increased risk for attention-deficit/hyperactivity disorder, depression, and anxiety disorders and can be treated successfully with standard psychostimulant and antidepressant medications.

Prevention of primary manifestations: Transplantation of allogeneic liver tissue affords affected individuals an unrestricted diet and protects them from metabolic crises, but does not reverse preexisting psychomotor disability or mental illness. In those who have not undergone liver transplantation, strict and consistent metabolic control can decrease the risk of developing neuropsychiatric morbidities. Consider a trial of enteral thiamine to determine if an affected individual may have thiamine-responsive disease.

Prevention of secondary complications: Any trauma care or surgical procedures should be approached in consultation with a metabolic specialist.

Surveillance: Weekly or twice-weekly assessment of amino acid profile for rapidly growing infants; weekly amino acid profile assessment in children, adolescents, and adults; routine monitoring of calcium, magnesium, zinc, folate, selenium, and omega-3 essential fatty acid levels; at least monthly visit with a metabolic specialist in infancy; assessment of developmental milestones at each visit or as needed.

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 plasma amino acid analysis at approximately 24 hours of life; or (2) by molecular genetic testing of umbilical cord blood if the family-specific pathogenic variants have been identified. Early diagnosis may allow management of asymptomatic infants out of hospital by experienced providers. Before confirmatory molecular testing is complete, at-risk neonates can be managed with an MSUD prescription diet if serial plasma amino acid profiles provide evidence of MSUD.

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. The catabolic stress of labor, involutional changes of the uterus, and internal sequestration of blood are potential sources of metabolic decompensation of the affected mother. Appropriate monitoring of the affected mother at a metabolic referral center at the time of delivery and in the postpartum period are recommended.

Genetic counseling: 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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