AUTHOR INFORMATION

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Authored by Olaf A Bodamer, MD, PhD, FACMG, Professor, Department of Pediatrics, University of Vienna Children's Hospital, Vienna, Austria

Coauthored by Brendan Lee, MD, PhD, Associate Professor, Department of Molecular and Human Genetics, Baylor College of Medicine

Olaf A Bodamer, MD, PhD, FACMG, is a member of the following medical societies: American Society of Human Genetics, and British Biochemical Society

Edited by Christian J Renner, MD, Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Olaf A Bodamer, MD, PhD, FACMG
Editor's Email:	Christian J Renner, MD

eMedicine Journal, March 29 2006, VOLUME 7, Number 3

INTRODUCTION

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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 the infant who is not treated for MSUD. 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 who lost 4 infants 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). 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. 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. Snyderman et al initiated the first successful dietary treatment of MSUD by restricting intake of branched-chain amino acids, and in 1971, Scriver et al reported the first case of thiamine-responsive MSUD. The branched-chain alpha-keto acid dehydrogenase (BCKD) complex was purified and characterized in 1978.

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 exists, 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 transported rapidly across the blood-brain barrier and is metabolized to yield presumably glutamate and glutamine.

Frequency:

• In the US: MSUD occurs in about 1 per 180,000 newborns in the United States but may be as frequent as 1 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.

• Internationally: 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 show significant developmental delay early on and die within the first months of life. Children or juveniles with later-onset (ie, intermediate, intermittent) forms of MSUD may show 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 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 vary considerably.

Sex: No sex predilection exists.

CLINICAL

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History: Classic MSUD is the most common form of MSUD, 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 (see below) onset may be later and symptoms may be variable.

Physical: The clinical presentation of a child with MSUD shows considerable variation 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.

• With classic MSUD, neurological signs (eg, alternating muscular hypotonia and hypertonia, dystonia, seizures, encephalopathy) develop rapidly. Signs of pseudotumor cerebri may be observed. Acute transient ataxia has been reported in well-controlled patients with classic MSUD. Pancreatitis has been reported occasionally. Ketosis and the characteristic odor of maple syrup in the urine usually are present when the first symptoms develop. However, reports of otherwise healthy infants with the odor characteristic for MSUD exist. 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 are characterized by neurological impairment and developmental delay of varying degree and/or seizures. Patients may present at any age depending on residual BCKD activity, which ranges anywhere from 3-30% of the reference range for that activity. Episodes of acute metabolic decompensation are the exception.



• Intermittent MSUD is the second most common form of MSUD. Patients with intermittent MSUD 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. 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.

DIFFERENTIALS

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Other Problems to be Considered:

Aminoacidopathies and organoacidopathies presenting during the first week of life

WORKUP

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Lab Studies:

• Plasma amino acids (elevation of branched-chain amino acids, detection of alloisoleucine): The detection of alloisoleucine is diagnostic for MSUD. Alloisoleucine may not appear until the sixth day of life, even when leucine levels are elevated. Transient elevations of branched-chain amino acids (without the presence of alloisoleucine) may develop in patients with ketotic hypoglycemia and in those in the postabsorptive state.



• Measure urine organic acids by gas chromatography-mass spectrometry (GC-MS) for the detection of alpha-hydroxyisovalerate, lactate, pyruvate, and alpha-ketoglutarate.



• Newborn screening for MSUD is performed with tandem mass spectrometry by using concentrations of leucine and isoleucine and the Fisher Ratio (branch-chain amino acids/phenylalanine and tyrosine) as diagnostic measures. Immediate treatment should follow the identification of affected newborn infants.



• Enzyme activity can be measured in lymphocytes, cultured fibroblasts, or both, although this test is not necessary for diagnosis.



• Prenatal diagnosis can be performed by measuring enzyme activity in cultured amniocytes or chorion villus cells, mutation analysis, or by measuring branch-chain amino acid concentrations in amniotic fluid.

TREATMENT

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Medical Care: The 2 main aspects to the treatment of MSUD are long-term management and the treatment of episodes of acute metabolic decompensation. The mainstay in the treatment of MSUD is dietary restriction of branched-chain amino acids.

• Treat episodes of metabolic decompensation aggressively. Initiate intravenous glucose infusions (5-8 mg/kg/min for infants) as rapidly as possible. Insulin infusions may be added to promote anabolism. Stop intake of branched-chain amino acids, but resume intake as soon as plasma branched-chain amino acids normalize. Whenever possible, continue additional dietary support, including lipids and/or formulas free of branched-chain amino acid. In rare circumstances, hemodialysis or peritoneal dialysis is required to remove branched-chain amino acids and keto acids.



• Three successful liver transplants in patients with classic MSUD have been reported. However, consider the risks and potential long-term complications of liver transplantation in contrast to the beneficial low-risk dietary therapy that has equally good outcome.



• Initial studies using retroviral vectors to infect MSUD lymphocytes have shown stable correction of the enzyme deficiency. However, human gene therapy trials for MSUD remain to be performed.



• Several successful pregnancies in patients with MSUD have been reported. The most critical period seems to be the immediate postpartum period. Take particular care to counteract catabolism during this time.

Diet: Normalization of branched-chain amino acids (particularly of leucine) by restricting intake of branched-chain amino acids without impairing growth and intellectual development is the goal of dietary therapy. Dietary therapy must be lifelong. Several commercially available formulas and foods are available without branched-chain amino acids or with reduced levels of branched-chain amino acids. New products, such as MSUD Express for juveniles and adults with MSUD, have become available. The intake of leucine is calculated on an individual basis following the measurement of plasma branched-chain amino acids. Measure plasma amino acid levels on a regular basis at appropriate intervals for the first 6-12 months of life. In addition to dietary therapy, administer thiamine (10-20 mg/d) for 4 weeks to determine thiamine responsiveness.

Activity: Do not restrict activity.

MEDICATION

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Drug Category: Vitamins -- Organic substances required by the body in small amounts for various metabolic processes. Vitamins may be synthesized in small or insufficient amounts in the body or not synthesized at all, thus requiring supplementation. Administer thiamine in cases of thiamine-responsiveness.

Drug Name	Thiamine (Thiamilate) -- An essential coenzyme in carbohydrate and amino acid metabolism. Combines with adenosine triphosphate (ATP) to form thiamine pyrophosphate. PO absorption is poor, but parenteral route may be associated with severe adverse reactions.
Adult Dose	10-20 mg/d PO divided tid; not to exceed 300 mg/d
Pediatric Dose	10-20 mg/d PO divided tid for 2 wk, then 5-10 mg/d for 1 mo followed by reassessment of response; not to exceed 50 mg/d 10-25 mg/d IV/IM for limited time ( <1 wk), then change to PO
Contraindications	Documented hypersensitivity
Interactions	IV dextrose solutions increase thiamine requirement; may enhance the effects of neuromuscular blocking agents
Pregnancy	A - Safe in pregnancy
Precautions	Pregnancy category C if dose exceeds RDA; sensitivity reactions can occur (intradermal test-dose recommended in suspected sensitivity); deaths have resulted from IV use

FOLLOW-UP

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Further Outpatient Care:

• Follow up with patient at regular intervals (ie, at least once every 6-12 mo) with a biochemical geneticist familiar with the management of MSUD.

Deterrence/Prevention:

• Patients should avoid consuming branched-chain amino acids (ie, natural protein) above their daily allowance.

Complications:

• Patients with MSUD are at risk for metabolic decompensation during periods of increased catabolism. Dietary compliance is necessary to prevent developmental delay and neurological symptoms.

Patient Education:

• Educate patients and their caregivers about the principles of dietary treatment, calculation of leucine requirement, and intake and initial management of acute episodes. Supply a written emergency regimen and emergency card.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to provide adequate dietary branched-chain amino acids, natural protein, or both



• Failure to restrict branched-chain amino acids

TEST QUESTIONS

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CME Question 1: A 5-day-old newborn presents with feeding problems and increasing lethargy. An odor is noted. Which of the following is the most likely diagnosis?

A: Maple syrup urine disease (MSUD)
B: Methylmalonic aciduria
C: Phenylketonuria
D: Glycogen storage disease type I
E: Homocystinuria

The correct answer is A: Newborns with MSUD present when aged 3-7 days with feeding problems, poor weight gain, and increasing lethargy. The urine typically has a characteristic odor resembling maple syrup.

CME Question 2: Which of the following findings diagnoses maple syrup urine disease (MSUD)?

A: Elevated plasma lactate
B: Elevated plasma alanine
C: Elevated plasma glutamine
D: Elevated plasma alloisoleucine
E: Elevated plasma branched-chain amino acids

The correct answer is D: Elevation of plasma alloisoleucine is diagnostic for MSUD. Elevation of branched-chain amino acids also is observed in ketotic hypoglycemia and postabsorptive plasma samples.

Pearl Question 1 (T/F): The most common clinical form of maple syrup urine disease (MSUD) is the late-onset form.

The correct answer is False: The most common clinical form is the early-onset, or classic, form of MSUD.

Pearl Question 2 (T/F): Most children with maple syrup urine disease (MSUD) present during the neonatal period.

The correct answer is True: Most children with MSUD present when aged 4-7 days.

Pearl Question 3 (T/F): Children with known maple syrup urine disease (MSUD) are at risk for metabolic decompensation during episodes of increased catabolism (eg, surgery, intercurrent illness).

The correct answer is True: Children with MSUD are at risk for metabolic decompensation during any period of increased catabolism, such as intercurrent illnesses, trauma, and surgery.

Pearl Question 4 (T/F): Maple syrup urine disease (MSUD) occurs most frequently in populations with increased rates of consanguinity.

The correct answer is True: MSUD occurs most frequently in populations with a high frequency of consanguinity, such as the Mennonite population in Pennsylvania.

BIBLIOGRAPHY

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• Chuang DT, Shih VE: Maple syrup urine disease. In: Scriver CR, Beaudet AL, Valle DL, Sly WS, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. NY: McGraw-Hill Co; 2000.
• Fernstrom JD: Branched-chain amino acids and brain function. J Nutr 2005 Jun; 135(6 Suppl): 1539S-46S[Medline].
• Hallam P, Lilburn M, Lee PJ: A new protein substitute for adolescents and adults with maple syrup urine disease (MSUD). J Inherit Metab Dis 2005; 28(5): 665-72[Medline].
• Harris RA, Joshi M, Jeoung NH, Obayashi M: Overview of the molecular and biochemical basis of branched-chain amino acid catabolism. J Nutr 2005 Jun; 135(6 Suppl): 1527S-30S[Medline].
• Heldt K, Schwahn B, Marquardt I, et al: Diagnosis of MSUD by newborn screening allows early intervention without extraneous detoxification. Mol Genet Metab 2005 Apr; 84(4): 313-6[Medline].
• Henneke M, Flaschker N, Helbling C, et al: Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease. Hum Mutat 2003 Nov; 22(5): 417[Medline].
• Hoffmann B, Helbling C, Schadewaldt P, Wendel U: Impact of longitudinal plasma leucine levels on the intellectual outcome in patients with classic MSUD. Pediatr Res 2006 Jan; 59(1): 17-20[Medline].
• Hoffmann GF, von Kries R, Klose D, et al: Frequencies of inherited organic acidurias and disorders of mitochondrial fatty acid transport and oxidation in Germany. Eur J Pediatr 2004 Feb; 163(2): 76-80[Medline].
• Mitsubuchi H, Owada M, Endo F: Markers associated with inborn errors of metabolism of branched-chain amino acids and their relevance to upper levels of intake in healthy people: an implication from clinical and molecular investigations on maple syrup urine disease. J Nutr 2005 Jun; 135(6 Suppl): 1565S-70S[Medline].
• Morton DH, Strauss KA, Robinson DL, et al: Diagnosis and treatment of maple syrup disease: a study of 36 patients. Pediatrics 2002 Jun; 109(6): 999-1008[Medline].
• Righini A, Ramenghi LA, Parini R, et al: Water apparent diffusion coefficient and T2 changes in the acute stage of maple syrup urine disease: evidence of intramyelinic and vasogenic-interstitial edema. J Neuroimaging 2003 Apr; 13(2): 162-5[Medline].
• Wendel U, Saudubray JM, Bodner A, Schadewaldt P: Liver transplantation in maple syrup urine disease. Eur J Pediatr 1999 Dec; 158 Suppl 2: S60-4[Medline].
• Yudkoff M, Daikhin Y, Nissim I, et al: Brain amino acid requirements and toxicity: the example of leucine. J Nutr 2005 Jun; 135(6 Suppl): 1531S-8S[Medline].

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