Maple Syrup Urine Disease (MSUD)

Updated: Feb 28, 2023
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Maple syrup urine disease (MSUD), also known as branched-chain ketoaciduria, is an aminoacidopathy due to an enzyme defect in the catabolic pathway of the branched-chain amino acids leucine, isoleucine, and valine. Accumulation of these 3 amino acids and their corresponding alpha-keto acids leads to encephalopathy and progressive neurodegeneration in untreated infants. [1] Early diagnosis and dietary intervention prevent complications and may allow for normal intellectual development. Consequently, maple syrup urine disease has been added to many newborn screening programs, and preliminary results indicate that asymptomatic newborns with maple syrup urine disease have better outcomes compared with infants who are diagnosed after they become symptomatic. [2]

In 1954, Menkes et al reported a family in which 4 infants died within the first 3 months of life owing to a neurodegenerative disorder. The urine of these infants had an odor similar to that of maple syrup (burnt sugar). [3] Therefore, this disorder was called maple sugar urine disease and, later, maple syrup urine disease. In the following years, Dancis et al identified the pathogenetic compounds as branched-chain amino acids and their corresponding alpha-keto acids. [4] In 1960, Dancis et al demonstrated that the enzymatic defect in maple syrup urine disease was at the level of the decarboxylation of the branched-chain amino acids. [5] Snyderman et al initiated the first successful dietary treatment of maple syrup urine disease by restricting oral intake of branched-chain amino acids. [6] In 1971, Scriver et al reported the first case of thiamine-responsive maple syrup urine disease. [7] The branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex was purified and characterized in 1978. [4]



Maple syrup urine disease is caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex, which catalyses the decarboxylation of the alpha-keto acids of leucine, isoleucine, and valine to their respective branched-chain acyl-CoAs. These are further metabolized to yield acetyl-CoA, acetoacetate, and succinyl-CoA. [1, 8, 9]

The BCKD enzyme complex, which is associated with the inner mitochondrial membrane, has 3 different catalytic components (ie, E1, E2, E3) and 2 associated regulatory enzymes (ie, BCKD phosphatase, BCKD kinase). In addition, the E1 component consists of 2 distinct subunits (ie, E1 alpha, E1 beta) that form an alpha-2 beta-2 heterotetramer. The E3 component is associated with 2 additional alpha-ketoacid dehydrogenase complexes, namely pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. Mutations in E1, E2, or E3 cause maple syrup urine disease. No clear genotype-phenotype correlation between molecular and clinical phenotypes is known, with the exemption of mutations in E2, which cause thiamine-responsive maple syrup urine disease. Mutations in E3 cause additional deficiencies of pyruvate and alpha-ketoglutarate dehydrogenases. [10] Mutations in the regulatory enzymes have not been reported. [11]

Accumulation of plasma leucine causes neurological symptoms. Leucine is rapidly transported across the blood-brain barrier and is metabolized to presumably yield glutamate and glutamine. The accumulation of plasma isoleucine is associated with the maple syrup urine odor. [12, 13]




United States

Maple syrup urine disease occurs in about 1 case per 185,000 live births. Within the Ashkenazi Jewish population, the incidence is higher, at 1 per 26,000 live births. In select inbred populations (ie, the Mennonites in Pennsylvania), it may be as common as 1 case per 176 newborns. As an autosomal recessive disorder, maple syrup urine disease is more prevalent in populations with a high occurrence of consanguinity. [8]


Quental et al identified a homozygous 1-bp deletion (117delC) in the BCKDHA gene (this gene codes for the alpha subunit of the BCKD enzyme complex, specifically E1) in Portuguese Gypsies and estimated the carrier frequency for this deletion to be as high as 1.4% (about 1 case per 71 live births). [14]


Infants with untreated early onset (ie, classic) maple syrup urine disease have significant developmental delay and die within the first months of life. Children or juveniles with late-onset (ie, intermediate, intermittent) forms of maple syrup urine disease may have some form of developmental delay, depending on the residual enzyme activity of BCKD. All children are at increased risk for metabolic decompensation during periods of increased protein catabolism (eg, intercurrent illness, trauma, surgery). Morbidity can almost entirely be prevented with early diagnosis (in a neonate younger than 10 days), with appropriate treatment at presentation and during episodes of potential metabolic decompensation.


Maple syrup urine disease has been reported to occur in all ethnic groups, although the incidence and prevalence may widely vary. [8]


No sex predilection is noted, as the genetic case is autosomal recessive and not related to the sex chromosomes.


Patient Education

Educate patients and their caregivers about the principles of dietary treatment, how to calculate their dietary leucine requirement and overall daily nutritional needs, and how to obtain emergency care for episodes of metabolic decompensation. Supply a written emergency regimen and emergency contact card to families and caregivers.

Resources for patients, families, and caregivers include the following:

MSUD Family Support Group

March of Dimes

Organic Acidemia Association

  • 9040 Duluth Street
  • Golden Valley, MN  55427
  • Phone: 763-559-1797 
  • Website:
  • Email: