Maple Syrup Urine Disease (MSUD) - Description

Other Names

Branched-chain ketoaciduria
Branched-chain ketoacid dehydrogenase (BCKD) deficiency


270.3, disorder of branched-chain amino-acid metabolism


Maple Syrup Urine Disease derives its name from the characteristic odor of the urine of these patients due to the presence of branched-chain ketoacids (keto-methylvaleric, keto-isocaproic, keto-isovaleric). The disease is caused by impaired activity of branched-chain ketoacid dehydrogenase (BCKD), a complex enzyme requiring thiamine pyrophosphate as a cofactor, involved in the metabolism of the essential branched-chain amino acids leucine, isoleucine, and valine. The BCKD complex is composed of four subunits, E1alpha E1beta, E2, and E3. The E3 subunit is shared by two other dehydrogenases, pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. A defect of any component of the complex causes maple syrup urine disease (MSUD), but deficiency of E3 causes a more complex phenotype that differs from MSUD.

MSUD causes an accumulation of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine, and related ketoacids. Accumulation of these compounds (especially leucine) disturbs brain cell volume regulation and results in brain edema and secondary impairment of neuron growth, myelin synthesis, and cerebral neurotransmitter production leading to physical and intellectual disability and, if untreated, death.

In addition to the classic form, there are variant forms of the disease – intermediate, intermittent, and thiamine responsive – which may have milder and later onset of symptoms, presenting with anorexia, poor growth, irritability, seizures, or developmental delay in late infancy or childhood. Symptoms and metabolic crisis episodes may be precipitated by illnesses or excess protein intake.


MSUD is an autosomal recessive disorder. Mutations in three genes cause MSUD – BCKDHA, MCKDHB, and DBT – and can be tested for on a clinical basis. They code for three of the four subunits of the branched-chain ketoacid dehydrogenase enzyme complex. Maple Syrup Urine Disease (GeneReviews). Prenatal testing is available measuring enzyme activity in amniocytes or by DNA testing if the familial mutations are known


With treatment before any crises occur, lifetime adherence to the diet, and prompt treatment of illnesses, prognosis is good, and normal development and IQ are expected. Females with MSUD are capable of having normal children, but need to adhere strictly to the diet and be monitored carefully, particularly postpartum, by metabolic geneticists. Without treatment, one can expect intellectual disability and neurologic disturbances. Brain edema can lead to cerebellar herniation, compression of the brain stem, and death, especially in older individuals. See Maple Syrup Urine Disease (GeneReviews).


Frequency is estimated at 1/225,000 births [Carleton: 2010]; incidence in the Old Order Mennonite population is about 1/150 live births. [Carleton: 2010]

Helpful Articles

PubMed search for maple syrup urine disease in children, last 3 years

Sotero de Menezes MA, Connolly M, Bolanos A, Madsen J, Black PM, Riviello JJ Jr.
Temporal lobectomy in early childhood: the need for long-term follow-up.
J Child Neurol. 2001;16(8):585-90. PubMed abstract

Puckett RL, Lorey F, Rinaldo P, Lipson MH, Matern D, Sowa ME, Levine S, Chang R, Wang RY, Abdenur JE.
Maple syrup urine disease: further evidence that newborn screening may fail to identify variant forms.
Mol Genet Metab. 2010;100(2):136-42. PubMed abstract

Maple Syrup Urine Disease (MSUD) Module Authors

Author: Nicola Longo, MD, Ph.D. - 2/2012
Compiled and edited by: Lynne M Kerr, MD, Ph.D. - 2/2012
Content Last Updated: 4/2012

The authors listed above are responsible for the overall Maple Syrup Urine Disease (MSUD) Module. Authors contributing to individual pages in the module are listed on those pages.

Page Bibliography

Carleton SM, Peck DS, Grasela J, Dietiker KL, Phillips CL.
DNA carrier testing and newborn screening for maple syrup urine disease in old order mennonite communities.
Genet Test Mol Biomarkers. 2010;14(2):205-8. PubMed abstract