Maple Syrup Urine Disease

Updated: Nov 04, 2014
  • Author: Olaf A Bodamer, MD, PhD, FAAP, FACMG; Chief Editor: Luis O Rohena, MD, FAAP, FACMG  more...
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Maple syrup urine disease (MSUD) is an aminoacidopathy secondary 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 keto acids leads to encephalopathy and progressive neurodegeneration in untreated infants. Early diagnosis and dietary intervention prevent complications and may allow for normal intellectual development. Consequently, MSUD has been added to many newborn screening programs, and preliminary results indicate that asymptomatic newborns with MSUD have a better outcome compared with infants who are diagnosed after they become symptomatic.

In 1954, Menkes et al reported a family in which 4 infants died within the first 3 months of their lives because of a neurodegenerative disorder. The urine of these infants had an odor resembling maple syrup (burned sugar). [1] 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. [2] In 1960, Dancis et al demonstrated that the enzymatic defect in MSUD was at the level of the decarboxylation of the branched-chain amino acids. [3] Snyderman et al initiated the first successful dietary treatment of MSUD by restricting intake of branched-chain amino acids. [4] In 1971, Scriver et al reported the first case of thiamine-responsive MSUD. [5] The branched-chain alpha-keto acid dehydrogenase (BCKD) complex was purified and characterized in 1978. [2]



MSUD is caused by a deficiency of the BCKD 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. [6, 7]

The BCKD 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 MSUD. No good genotype-phenotype correlation between molecular and clinical phenotypes is known, with the exemption of mutations in E2, which cause thiamine-responsive MSUD. Mutations in E3 cause additional deficiencies of pyruvate and alpha-ketoglutarate dehydrogenases. [8] Mutations in the regulatory enzymes have not been reported. [9]

Accumulation of leucine in particular causes neurological symptoms, whereas elevation of plasma isoleucine is associated with the maple syrup odor. Leucine is rapidly transported across the blood-brain barrier and is metabolized to presumably yield glutamate and glutamine. [10, 11]




United States

MSUD occurs in about 1 case per 180,000 newborns in the United States but may be as common as 1 case per 176 newborns in selected inbred populations (ie, the Mennonites in Pennsylvania). As an autosomal recessive disorder, MSUD is more prevalent in populations with a high frequency of consanguinity. [6]


Quental et al identified a homozygous 1-bp deletion (117delC) in the BCKDHA gene in Portuguese Gypsies and estimated the carrier frequency for this deletion to be as high as 1.4%. [12]


Infants with untreated early onset (ie, classic) MSUD have significant developmental delay and die within the first months of life. Children or juveniles with late-onset (ie, intermediate, intermittent) forms of MSUD may have some form of developmental delay, depending on the residual 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 d), with appropriate treatment at presentation and during episodes of potential metabolic decompensation.


MSUD has been reported to occur in all ethnic groups, although the incidence and prevalence may widely vary. [6]


No sex predilection is noted.