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Maple Syrup Urine Disease

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Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Branched-chain ketoacid dehydrogenase (BCKD) deficiency
Branched-chain ketoaciduria

ICD-10 Coding

E71.0, Maple-syrup-urine disease

Disorder Category

Amino acidemia

Screening

Abnormal 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]

Description

Maple syrup urine disease (MSUD) is caused by a defect in branched-chain ketoacid dehydrogenase (BCKD) complex. When the BCKD enzyme complex is defective, branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) and corresponding branched-chain ketoacids (BCKAs) accumulate, disturbing brain cell volume regulation. This results in cerebral edema and secondary impaired neuron growth, myelin synthesis, and cerebral neurotransmitter production. Without emergent treatment, classic MSUD will progress to severe neurological deterioration with lethargy progressing to coma and death. [Strauss: 2020] There are milder forms of MSUD that may not present with symptoms until later in life. These patients are still at risk for acute metabolic decompensation.

Clinical Characteristics

With treatment, normal IQ and development can occur if treatment is initiated before permanent damage is incurred from the initial and subsequent metabolic crises. Long-term management may consist of a protein/BCAA restricted diet, supplementation of deficient amino acids, and a general avoidance of metabolic stress. One variant may be responsive to thiamine. 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 of metabolic crises should be initiated by a metabolic specialist to rapidly reduce plasma leucine by reversal of catabolism and, in some cases, dialysis.
Without treatment, profound developmental delays and neurologic disturbances such as seizures and ataxia can be expected. In Classic MSUD, symptoms typically occur in the first few days of life after an initial symptom-free period. One of the first signs can be cerumen smelling of maple syrup, followed by irritability, excessive sleepiness, poor feeding, vomiting, and tachypnea. The characteristic maple syrup-odor urine coincides with worsening encephalopathy, and finally, brain edema with increased intracranial pressure can lead to cerebellar herniation, compression of the brainstem, coma, and death. Because of the rapid onset, severe symptoms may be present before screening results are reported or treatment begins.
Untreated Intermediate and Intermittent MSUD can have much more variable presentations, including later onset of symptoms with typically less severe neurological impairment and, in some cases, metabolic decompensation. These other forms may present with anorexia, poor growth, irritability, or developmental delay in late infancy or childhood. Urine may also have a maple syrup odor, especially during metabolic crises. Symptoms and metabolic crisis episodes may be precipitated by illnesses or other triggers, such as fasting. [Strauss: 2020]

Incidence

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

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive Screen

  • Urgently contact the family and evaluate the infant for poor feeding, lethargy, irregular breathing pattern, or other symptoms described above.
  • Provide emergency treatment and referral for lethargy, tachypnea, alternating hypertonia/hypotonia, or seizures. See ACT Sheet for Maple Syrup Urine Disease (ACMG) (PDF Document 369 KB).
  • Discontinue breast or cow milk formula feeding and substitute with a special BCAA-free MSUD formula.

Confirming the Diagnosis

  • To confirm the diagnosis, work with Newborn Screening Services (see NW providers [1]).
  • The diagnosis is confirmed by measurement of 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.

If the Diagnosis is Confirmed

Resources

Information & Support

Related Portal Content
Maple Syrup Urine Disease (MSUD)
Assessment and management information for the primary care clinician caring for the child with MSUD.
Maple Syrup Urine Disease (MSUD) (FAQ)
Answers to questions families often have about caring for their child with MSUD.
After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

Communicating Newborn Screening Results to Families (ACHDNC)
One-page guide to help clinicians effectively communicate positive newborn screening results to parents; Advisory Committee on Heritable Disorders in Newborns and Children.

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 (NECMP)
Guideline for clinicians treating the sick infant/child who has previously been diagnosed with maple syrup urine disease (MSUD); 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.

For Parents and Patients

Maple Syrup Urine Disease – Information for Families (HRSA)
General information about maple syrup urine disease, screening, and treatment; Health Resources & Services Administration.

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 Maple Syrup Urine Disease (ACMG) (PDF Document 163 KB)
A resource for clinicians to help confirm diagnosis; American College of Medical Genetics.

Services for Patients & Families Nationwide (NW)

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.

Helpful Articles

PubMed search for maple syrup urine disease and newborn screening, last 5 years.

Authors & Reviewers

Initial publication: December 2015; last update/revision: February 2022
Current Authors and Reviewers:
Author: Jose Morales Moreno, MD
Contributing Author: Nicola Longo, MD, Ph.D.
Senior Author: Brian J. Shayota, MD, MPH
Reviewer: Nancy C. Rose, MD
Authoring history
2021: update: Jose Morales Moreno, MDA; Brian J. Shayota, MD, MPHSA
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