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Maple Syrup Urine Disease Clinical Presentation

  • Author: Olaf A Bodamer, MD, PhD, FAAP, FACMG; Chief Editor: Luis O Rohena, MD  more...
 
Updated: Nov 04, 2014
 

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.

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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.[6]

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.[6, 9, 13, 14]

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.[5]

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.[6]

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Causes

See Pathophysiology.

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Contributor Information and Disclosures
Author

Olaf A Bodamer, MD, PhD, FAAP, FACMG Park Gerald Chair in Genetics and Genomics, Associate Chief, Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Harvard Medical School

Olaf A Bodamer, MD, PhD, FAAP, FACMG is a member of the following medical societies: American Medical Association, American Society of Human Genetics

Disclosure: Nothing to disclose.

Coauthor(s)

Brendan Lee, MD, PhD Professor, Robert and Janice McNair Endowed Chair in Molecular and Human Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine

Brendan Lee, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, Society for Pediatric Research

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Biomarin; Retrophin;.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Christian J Renner, MD Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany

Disclosure: Nothing to disclose.

References
  1. Menkes JH, Hurst PL, Craig JM. A new syndrome: progressive familial infantile cerebral dysfunction associated with an unusual urinary substance. Pediatrics. 1954 Nov. 14(5):462-7. [Medline].

  2. Chuang DT. Maple syrup urine disease: it has come a long way. J Pediatr. 1998 Mar. 132(3 Pt 2):S17-23. [Medline].

  3. Dancis J, Levits M, Westall RG. Maple syrup urine disease: branched-chain keto-aciduria. Pediatrics. 1960 Jan. 25:72-9. [Medline].

  4. Snyderman SE, Norton PM, Roitman E, Holt LE Jr. Maple syrup urine disease, with particular reference to dietotherapy. Pediatrics. 1964 Oct. 34:454-72. [Medline].

  5. Scriver CR, Mackenzie S, Clow CL, Delvin E. Thiamine-responsive maple-syrup-urine disease. Lancet. 1971 Feb 13. 1(7694):310-2. [Medline].

  6. Chuang DT, Shih VE. Maple syrup urine disease. Scriver CR, Beaudet AL, Valle DL, Sly WS, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill Co; 2000.

  7. 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].

  8. Park HD, Lee DH, Hong YH, Kang DH, Lee YK, Song J, et al. Three Korean patients with maple syrup urine disease: four novel mutations in the BCKDHA gene. Ann Clin Lab Sci. 2011 Spring. 41(2):167-73. [Medline].

  9. 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].

  10. Fernstrom JD. Branched-chain amino acids and brain function. J Nutr. 2005 Jun. 135(6 Suppl):1539S-46S. [Medline].

  11. 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].

  12. Quental S, Macedo-Ribeiro S, Matos R, Vilarinho L, Martins E, Teles EL, et al. Molecular and structural analyses of maple syrup urine disease and identification of a founder mutation in a Portuguese Gypsy community. Mol Genet Metab. 2008 Jun. 94(2):148-56. [Medline].

  13. 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].

  14. 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].

  15. 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].

  16. 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].

  17. Mazariegos GV, Morton DH, Sindhi R, Soltys K, Nayyar N, Bond G, et al. Liver Transplantation for Classical Maple Syrup Urine Disease: Long-Term Follow-Up in 37 Patients and Comparative United Network for Organ Sharing Experience. J Pediatr. 2012. 160:116-121. [Medline].

  18. 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].

  19. 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].

  20. 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].

  21. 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].

 
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