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Maple syrup urine disease

Orpha number ORPHA511
Synonym(s) BCKD deficiency
BCKDH deficiency
Branched-chain 2-ketoacid dehydrogenase deficiency
Branched-chain ketoaciduria
MSUD
Prevalence Unknown
Inheritance
  • Autosomal recessive
Age of onset Neonatal/infancy
ICD-10
  • E71.0
OMIM
UMLS
  • C0024776
  • C0268576
MeSH
  • D008375
MedDRA
  • 10026817
SNOMED CT
  • 190700007
  • 24013007
  • 27718001

Summary

Maple syrup urine disease (MSUD) is a rare inherited disorder of branched-chain amino acid metabolism classically characterized by poor feeding, lethargy, vomiting and a maple syrup odor in the cerumen (and later in urine) noted soon after birth, followed by progressive encephalopathy and central respiratory failure if untreated. The four overlapping phenotypic subtypes are: classic, intermediate, intermittent and thiamine responsive MSUD (see these terms).

The estimated prevalence is around 1/150,000 live births.

Classic MSUD presents in the first days of life with poor feeding and drowsiness followed by a worsening encephalopathy with lethargy, intermittent apnea, stereotypic movements ("fencing" and bicycling") and opisthotonus. Coma and central respiratory failure supervene 7 to 10 days after birth. The only abnormality in biochemistry is ketosis. Intermediate MSUD clinically resembles classic MSUD but it can have a later onset and less severe symptoms. Intermittent MSUD patients are asymptomatic at birth but may suffer episodes of acute decompensation or develop neurological symptoms and developmental delay during childhood. Thiamin-responsive MSUD is clinically similar to intermediate MSUD with thiamin therapy improving dietary leucine tolerance.

MSUD is due to mutations in the genes encoding subunits E1a, E1b, and E2 of branched chain 2-ketoacid dehydrogenase (BCKAD), the second enzymatic step in the degredation of the branched chain amino acids (BCAAs): leucine, isoleucine and valine. BCKAD has four subunits: E1a, E1b, E2, and E3, which are encoded by the genes BCKDHA (19q13.1-q13.2), BCKDHB (6q14.1), DBT (1p31) and DLD (7q31-q32) respectively. Mutations in these genes lead to the accumulation of BCAAs (especially leucine) and their branched-chain alpha-ketoacids. Mutations in the E3 subunit gene (DLD) are not associated with MSUD but lead to pyruvate dehydrogenase E3 deficiency (see this term). A mutation in the PPM1K gene (4q22.1) has been reported in a single case of mild intermediate MSUD.

MSUD follows an autosomal recessive inheritance pattern and genetic counseling is possible.

Expert reviewer(s)

  • Dr Bridget WILCKEN

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Detailed information

Emergency guidelines
  • EN (2012,pdf)
Clinical genetics review
  • EN (2013)
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