Maple syrup urine disease gene panel
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 type | Onset | 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 Ketonuria |
|
| Intermediate | Variable | 3%-30% | Similar but less severe than in classic MSUD | Maple syrup odor of earwax Poor growth, poor feeding, irritability Developmental delays Encephalopathy |
| 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 therapy | Similar to intermediate type |
Table 2. Overview of the genes in CENTOGENE´s maple syrup urine disease panel:
| Gene (OMIM) | Chr.locus | Associated/allelic disorders (OMIM) |
|---|---|---|
| BCKDHA (608348) | 19q13.2 | Maple syrup urine disease type Ia (248600) |
| BCKDHB (248611) | 6q14.1 | Maple syrup urine disease type Ib (248600) |
| DBT (248610) | 1p21.2 | Maple syrup urine disease type II (248600) |
| DLD (238331) | 7q31.1 | Maple syrup urine disease type III; Dihydrolipoamide dehydrogenase deficiency (246900) |