Also known as: Brached-Chain ketoaciduria; Branched-Chain alpha-keto acid dehydrogenase deficiency; BCKD deficiency; Keto Acid Decarboxylase Deficiency; MSUD Classical; MSUD Thiamine-responsive; MSUD Intermediate; MSUD Intermittent

OMIM#248600 https://omim.org/entry/248600


  • MSUD type 1A – gene BCKDHA
  • MSUD type 1B – gene BCKDHB
  • MSUD type 2 – gene DBT

1. The disease

Maple syrup urine disease (MSUD) is categorized as classic (severe), intermediate, or intermittent. Classic maple syrup urine disease (classic MSUD) is the most severe and probably common form of MSUD, characterized by a maple syrup odor in the body fluids at birth, poor feeding, lethargy and focal dystonia, followed by progressive encephalopathy and central respiratory failure if untreated.

2. The Symptoms

Neonates with classic MSUD are born asymptomatic but without treatment follow a predictable course (see below). Lack of early signs or symptoms does not exclude the diagnosis.

  • 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 start mildly;
  • 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;
  • 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;
  • 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 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 compliance.

3. Actions to take in case of early diagnosis

  • Babies with a positive genetic test (having 2 pathogenic variants or 2 copies of a single pathogenic variant in one of the 3 genes cited above) should continue breastfeeding, high-protein avoid baby formulas.
  • Early treatment is essential in preventing chronic symptoms.
  • Biochemical correlation is essential for confirming diagnosis with biochemical NBS with tandem mass spectrometry for MSUD is primarily based on quantification of the ratios of (leucine + isoleucine) to alanine and phenylalanine concentrations on dried blood spots. Followed by plasma amino acid analysis typically demonstrates elevated concentrations of BCAAs and alloisoleucine.
  • MSUD is a lifelong disease that requires lifetime management and regular follow-up with a metabolic physician and dietician, a part from a multidisciplinary approach to care. Treatment consists of dietary leucine restriction, BCAA-free medical foods, judicious supplementation with isoleucine and valine, and frequent clinical and biochemical monitoring.
  • 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.
  • Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.

 4. For more information

Orphanet: https://www.orpha.net/consor4.01/www/cgi-bin/Disease_Search.php?lng=EN&data_id=20168&Disease_Disease_Search_diseaseGroup=MSUD&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Classic-maple-syrup-urine-disease&title=Classic%20maple%20syrup%20urine%20disease&search=Disease_Search_Simple

Biblio: https://www.ncbi.nlm.nih.gov/books/NBK1319/