eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Maple Syrup Urine Disease

Author: Olaf A Bodamer, MD, PhD, FACMG, Professor, Department of Pediatrics, Biochemical Genetics and Neonatal Screening Laboratories, University of Vienna Children's Hospital, Austria
Coauthor(s): Brendan Lee, MD, PhD, Associate Professor, Department of Molecular and Human Genetics, Baylor College of Medicine
Contributor Information and Disclosures

Updated: Jul 7, 2008

Introduction

Background

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

Pathophysiology

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.

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. Mutations in the regulatory enzymes have not been reported.

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.

Frequency

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 (eg, the Mennonites in Pennsylvania). As an autosomal recessive disorder, MSUD is more prevalent in populations with a high frequency of consanguinity.

International

In Austria, one case of MSUD has been detected among 250,000 newborn infants who have been through the Austrian Screening Program.

Mortality/Morbidity

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.

Race

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

Sex

No sex predilection is noted.

Clinical

History

Classic maple syrup urine disease (MSUD) is the most common form, with symptoms developing in neonates aged 4-7 days, depending on feeding regimen. Breastfeeding may delay onset of symptoms to the second week of life. The initial symptoms typically include poor feeding, vomiting, poor weight gain, and increasing lethargy. In cases of non-classic MSUD, onset may be later and symptoms may vary.

Physical

The clinical presentation of a child with MSUD widely varies between patients. However, 5 distinct clinical phenotypes can be distinguished based on age of onset, severity of clinical symptoms, and response to thiamine treatment as part of a clinical spectrum. These clinical phenotypes are the classic, intermediate, intermittent, thiamine-responsive, and E3-deficient forms of MSUD.

• In classic MSUD, neurological signs (eg, alternating muscular hypotonia and hypertonia, dystonia, seizures, encephalopathy) rapidly develop. Signs of pseudotumor cerebri may be observed. Acute transient ataxia has been reported in well-controlled patients with classic MSUD. Pancreatitis has been occasionally reported. Ketosis and the characteristic odor of maple syrup in the urine are usually present when the first symptoms develop. However, otherwise healthy infants with the characteristic odor of MSUD have been reported. The reason for this observation is not known.
• Intermediate MSUD is much more rare than classic MSUD; approximately 20 patients have been reported with this phenotype. Clinical signs in these patients include neurological impairment, developmental delay of varying degree, and seizures. Patients may present at any age, depending on residual BCKD activity, which ranges anywhere from 3-30% of the reference range. Episodes of acute metabolic decompensation are the exception.
• Intermittent MSUD is the second most common form of MSUD. These patients develop with normal growth and intelligence. Patients with intermittent MSUD present during episodes of catabolic stress, including intercurrent illnesses (eg, otitis media). During these episodes, ataxia, lethargy, seizures, and coma may ensue. Patients with intermittent MSUD have died during these episodes when not appropriately treated.
• Thiamine-responsive MSUD is a rare form of MSUD. Only the initial patient reported by Scriver et al has been shown to be unambiguously responsive to thiamine.⁵ Since that patient's experience, other patients have been reported to show some improvement of metabolic control to thiamine in addition to dietary restriction of branched-chain amino acids.
• E3-deficient MSUD is a very rare form of MSUD, with fewer than 10 patients reported in the medical literature. The clinical presentation is almost indistinguishable from intermediate MSUD with the exception of accompanying lactic acidosis. These patients have combined deficiencies of BCKD, pyruvate, and alpha-ketoglutarate dehydrogenase complexes.

Causes

See Pathophysiology.

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• Pediatrics, Inborn Errors of Metabolism (Emergency Medicine)
• Ataxia with Identified Genetic and Biochemical Defects (Neurology)