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Maple Syrup Urine Disease Gene Panel

July 06, 2018

Disease summary:

Maple syrup urine disease (MSUD) is an inherited metabolic disorder characterized by the distinctive sweet odor of the affected infants’ urine1. MSUD is caused by the deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKAD), causing abnormal accumulation of the branched-chain amino acids (leucine, isoleucine and valine) and their metabolic by-products, resulting in ketoacidosis in blood and urine. These metabolic changes  are responsible for the severe symptoms such as feeding abnormalities, encephalopathy, lethargy, coma and central respiratory failure5, 6. Pathogenic variants in the BCKDHA, BCKDHB, DBT and DLD  genes (Table 2) cause MSUD. 

Autosomal dominant

1/185,000 1, 2, 3

Major clinical symptoms for MSUD include the following 1

  • Maple syrup odor of earwax
  • Poor feeding, irritability, lethargy
  • Focal dystonia
  • Stereotypic behaviours
  • Coma and central respiratory failure

Diagnosis of maple syrup urine disease is based on the presence of characteristic findings such as:

  • Presence of allo-isoleucine in plasma is diagnostic
  • Elevated BCAAs in plasma,
  • Elevated BCKAs in urine, and/or

the presence of pathogenic variants in one of the associated genes: BCKDHA, BCKDHB, DBT, DLD

Treatment for MSUD includes specific nutrition and dietary measures1:

  • Restriction of leucine and intake of only BCAA-free foods
  • Supplementation with isoleucine and valine
  • Correction of metabolic decompensation by providing glucose, insulin, free amino acids, isoleucine, and valine for protein synthesis
  • Hemodialysis/hemofiltration to remove accumulated BCAA.
  • Liver transplantation is an effective therapy for classic MSUD
  • Thiamine supplementation
  • Urea cycle defects (NAGS deficiency, ornithine transcarbamylase deficiency, citrullinemia, arginase deficiency and others)
  • Organic acidemias (propionic academia, isovaleric academia, methylmalonic academia with homocystinuria, multiple carboxylase deficiency)
  • Beta-ketothiolase deficiency
  • Glycine encephalopathy (non-ketotic hyperglycinemia)

To confirm/establish the diagnosis, CENTOGENE offers the following tests:

  • MSUD NGS Panel which includes sequencing of the BCKDHA, BCKDHB, DBT and DLD genes
  • MSUD NGS Panel + CNV which includes sequencing and additionally detection of large deletions and duplications from the NGS data
  • Individuals with a positive family history of maple syrup urine disease
  • Individuals with most common symptoms of MSUD (regardless of family history)

Confirmation of a clinical diagnosis through genetic testing of MSUD can allow for genetic counseling and may direct medical management.

Table 1. The overview of the main subtypes of maple syrup diseases

MSUD typeOnset BCKAD activity Biochemical findings Clinical features
Classic Neonatal 0%-2% Elevated BCAAs in plasma

Elevated plasma allo-isoleucine

Elevated BCKAs in urine

Positive urine DNPH test

  • Maple syrup odor of earwax
  • Poor feeding, irritability, lethargy
  • Focal dystonia
  • Stereotypic behaviours
  • Coma and central respiratory failure
Intermediate Variable 3%-30% Similar but less severe than in classic MSUD

Maple syrup odor of earwax

Poor growth, poor feeding, irritability

Developmental delays

Intermittent Variable 5%-20%

Normal BCAAs when symptoms are absent

Similar to classic MSUD

Normal early growth and development

Episodes of (severe) decompensation 
Thiamine-responsive Variable 2%-40% Improvement of leucine tolerance and biochemical profile with thiamine therapySimilar to intermediate type