Maple Syrup Urine Disease

Other Names

Branched-chain ketoacid dehydrogenase (BCKD) deficiency

Branched-chain ketoaciduria

Diagnosis Coding

E71.0, Maple-syrup-urine disease

Disorder Category

An amino acidemia

Screening

Finding

Elevated leucine, isoleucine, alloisoleucine, and valine along with an elevated (leucine+isoleucine)/alanine ratio

Tested By

Tandem mass spectrometry (MS/MS); sensitivity=94.2%; specificity=99.9%; milder or variant forms of the disease can be missed by newborn screening. [Schulze: 2003] [Puckett: 2010]

Overview

Maple syrup urine disease (MSUD) is caused by a defect in branched-chain ketoacid dehydrogenase (BCKD), which is a multi-enzyme complex with 4 components. The BCKD complex is responsible for the decarboxylation of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine). Accumulation of leucine and its corresponding branched-chain keto acid (BCKA), alpha-ketoisocaproic acid, disturbs brain cell volume regulation resulting in cerebral edema and secondary impaired neuron growth, myelin synthesis, and cerebral neurotransmitter production. Without timely treatment, the classical type of MSUD will progress to severe neurological deterioration and death. [Strauss: 2020] More mild forms of the condition exist and may not present with symptoms until later in life.

Incidence

The incidence of MSUD in the USA is approximately 1:198,000. [Therrell: 2014]

Inheritance

Autosomal recessive

Prenatal Testing

DNA testing or enzyme analysis by amniocentesis or chorionic villous sampling.

Clinical Characteristics

Without treatment, profound mental retardation and neurologic disturbances can be expected. Brain edema with increased intracranial pressure typically leads to cerebellar herniation, compression of the brain stem, coma, and death. In Classical MSUD, symptoms typically occur in the first few days of life following a short symptom-free interval after birth. Intermediate and Intermittent MSUD can have a much more variable presentation, including later onset of symptoms with typically less severe neurological impairment.

With treatment, normal IQ and development can occur if treatment is initiated before permanent damage is incurred from the initial and subsequent metabolic crises. However, proper metabolic control is difficult to achieve. Patients with MSUD remain at high risk for metabolic crises that can result in cognitive impairment, executive dysfunction, emotional strain, and social dependence. [Strauss: 2020] Treatment should be initiated by a metabolic specialist and in the acute setting consist of rapid reduction of plasma leucine by reversal of catabolism and, in some cases, dialysis. Long-term management may consist of a protein/BCAA restricted diet, supplementation of deficient amino acids, and a general avoidance of metabolic stress.

Initial Symptoms
  • 12-24 hours: Elevated concentrations of branched-chain amino acids (BCAA: leucine, isoleucine, alloisoleucine, valine) and abnormal amino acid ratios are present in the blood. Maple syrup urine smell may be present in cerumen.
  • 2-3 days: Early and nonspecific signs of metabolic intoxication (i.e., irritability, hypersomnolence, anorexia) are accompanied by the presence of branched-chain alpha-ketoacids, acetoacetate, and beta-hydroxybutyrate in urine.
  • 4-6 days: Worsening encephalopathy manifests as lethargy, apnea, opisthotonos, and reflexive "fencing" or "bicycling" movements as the sweet maple syrup odor becomes apparent in urine.
  • 7-10 days: Severe intoxication culminates in critical cerebral edema, coma, and central respiratory failure. [Strauss: 2006]
Because of the rapidity of onset, severe symptoms may be present before screening results are reported or treatment begins.
Variant forms of the disease may have milder and later onset of symptoms and present with anorexia, poor growth, irritability, or developmental delay in late infancy or childhood. Symptoms and metabolic crisis episodes may be precipitated by illnesses. Urine may also have a maple syrup odor, especially during metabolic crises. One variant may be responsive to thiamine. [Strauss: 2006]

Follow-up Testing after Positive Screen

Plasma amino acids (elevated leucine, isoleucine, alloleucine, valine) and urine organic acid analysis (abnormal branched-chain ketoacids). Hydroxyprolinemia, a benign condition, can cause abnormal newborn screening for MSUD since hydroxyproline has the same mass/charge ratio of leucine/isoleucine. [Strauss: 2006]

Molecular genetic testing can confirm the diagnosis by identifying the causative gene variant but should not delay treatment in symptomatic patients. Associated genes include BCKDHA, BCKDHB, and DBT.

Primary Care Management

Upon Notification of the + Screen

If the Diagnosis is Confirmed

  • Educate the family about signs, symptoms, and the need for urgent care if the infant becomes ill. See Maple Syrup Urine Disease - Information for Parents (STAR-G).
  • Support initiation and maintenance of dietary restriction of BCAAs (found in animal and vegetable food sources) and use of medical formulas. Provide protein as essential, and non-essential amino acids and supplementation with isoleucine or valine as needed.
  • Consider thiamine for children with the thiamine-responsive variant.
  • See patients readily when illness occurs since that is the primary cause of decompensation. Facilitate monitoring of urinary BCKA excretion with DNPH reagent strips at home. Measure amino acid levels through blood tests when indicated.
  • Admit to the hospital and seek expert assistance for management for any decompensation that does not promptly respond to outpatient treatment.
  • Assist in management of irreversible consequences as necessary, particularly with developmental and educational interventions.
  • See the Portal’s Maple Syrup Urine Disease (MSUD).

Specialty Care Collaboration

Provide initial consultation and ongoing collaboration, particularly for dietary management and prompt management of illnesses resulting in metabolic stress (i.e., fever, vomiting, poor PO intake). Liver transplantation can be effective therapy that allows unrestricted diet and possibly prevents further neurologic deterioration. Facilitate genetic counseling for the family.

Resources

Information & Support

For Professionals

Maple Syrup Urine Disease (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Maple Syrup Urine Disease (MSUD) (NECMP)
Guideline for clinicians treating the sick infant/child who has previously been diagnosed with maple syrup urine disease (MSDU); developed under the direction of Dr. Harvey Levy, Senior Associate in Medicine/Genetics at Children’s Hospital Boston, and Professor of Pediatrics at Harvard Medical School, for the New England Consortium of Metabolic Programs. Click PDF to view the complete protocol.

For Parents and Patients

Support

Maple Syrup Urine Disease Family Support Group
A non-profit organization that provides information, newsletters and articles, family stories, support services, recipes and formulas, and dietary resources.

General

Maple Syrup Urine Disease - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of a newborn disorder; Screening, Technology and Research in Genetics.

Maple Syrup Urine Disease (MedlinePlus)
Information for families includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Tools

ACT Sheet for Maple Syrup Urine Disease (ACMG) (PDF Document 369 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Confirmatory Algorithm for MSUD (ACMG)
A resource for clinicians to help confirm diagnosis; American College of Medical Genetics.

Services for Patients & Families in Rhode Island (RI)

Genetics clinic services throughout the US can be found through the Genetics Clinic Services Search Engine (ACMG).

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: March 2007; last update/revision: October 2021
Current Authors and Reviewers:
Author: Jose Morales Moreno, MD
Senior Author: Brian J. Shayota, MD, MPH
Authoring history
2015: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Puckett RL, Lorey F, Rinaldo P, Lipson MH, Matern D, Sowa ME, Levine S, Chang R, Wang RY, Abdenur JE.
Maple syrup urine disease: further evidence that newborn screening may fail to identify variant forms.
Mol Genet Metab. 2010;100(2):136-42. PubMed abstract

Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF.
Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications.
Pediatrics. 2003;111(6 Pt 1):1399-406. PubMed abstract

Strauss KA, Carson VJ, Soltys K, Young ME, Bowser LE, Puffenberger EG, Brigatti KW, Williams KB, Robinson DL, Hendrickson C, Beiler K, Taylor CM, Haas-Givler B, Chopko S, Hailey J, Muelly ER, Shellmer DA, Radcliff Z, Rodrigues A, Loeven K, Heaps AD, Mazariegos GV, Morton DH.
Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes.
Mol Genet Metab. 2020;129(3):193-206. PubMed abstract

Strauss KA, Puffenberger EG, Carson VJ.
Maple Syrup Urine Disease.
[Updated 2020 Apr 23] ed. Seattle: University of Washington; 2006. https://www.ncbi.nlm.nih.gov/books/NBK1319/
In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet].

Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY.
Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.
Mol Genet Metab. 2014;113(1-2):14-26. PubMed abstract / Full Text