Maple Syrup Urine Disease (MSUD)

Description

Other Names

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

Diagnosis Coding

ICD-10

E71.0, Maple syrup urine disease

ICD-10 for Maple Syrup Urine Disease (icd10data.com) provides further coding details.

Description

Maple syrup urine disease (MSUD) causes an accumulation of branched-chain amino acids (leucine, isoleucine, and valine) and related ketoacids. Accumulation of these compounds (especially leucine) disturbs brain cell volume regulation and results in brain edema and secondary impairment of neuron growth, myelin synthesis, and cerebral neurotransmitter production leading to physical and intellectual disability and, if untreated, death. The presence of branched-chain ketoacids (keto-methylvaleric, keto-isocaproic, keto-isovaleric) causes the characteristic maple syrup odor of the urine.

MSUD is caused by impaired activity of branched-chain ketoacid dehydrogenase (BCKD), a complex enzyme requiring thiamine pyrophosphate as a cofactor, involved in the metabolism of the essential branched-chain amino acids leucine, isoleucine, and valine. The BCKD complex is composed of four subunits, E1alpha E1beta, E2, and E3. The E3 subunit is shared by two other dehydrogenases, pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. A defect of any component of the complex causes MSUD, but deficiency of E3 causes a more complex phenotype that differs from MSUD.

In addition to the classic form of MSUD, there are intermediate, intermittent, and thiamine responsive forms. These may have milder and later onset of symptoms and present with anorexia, poor growth, irritability, seizures, or developmental delay in late infancy or childhood. Symptoms and episodes of metabolic crisis may be precipitated by illnesses or excess protein intake.

Prevalence

A German study indicates a prevalence of 1:250,000 for LCHADD. [Schulze: 2003] The incidence of MSUD in the United States is approximately 1:198,000, but 1:150 in the Old Order Mennonite population. [Therrell: 2014] [Carleton: 2010]

Genetics

MSUD is an autosomal recessive disorder. Mutations in the genes that code for 3 of the 4 subunits of the branched-chain ketoacid dehydrogenase enzyme complex (BCKDHA, MCKDHB, and DBT) cause MSUD.

Prognosis

With treatment before any crises occur, a lifetime adherence to the diet, and prompt management of illnesses, the prognosis is good and normal development and IQ are expected. Females with MSUD are capable of having healthy children if they adhere strictly to the diet and are monitored carefully, particularly postpartum, by a metabolic geneticist. Without treatment, one can expect intellectual disability and neurologic disturbances. Brain edema can lead to cerebellar herniation, compression of the brain stem, and death, especially in older individuals.

Roles Of The Medical Home

The primary care clinician will need to track children with MSUD for achievement of developmental milestones and growth. Problems in these areas may respond to better metabolic control. Individuals with MSUD need early access to care for illnesses. See the Maple Syrup Urine Disease for information about the primary care role when a child is identified by newborn screening. The Guidelines for MSUD (University of Utah) (Word Document 140 KB), from the Division of Metabolic Genetics, University of Utah Health Science Center, provide a brief summary of clinical considerations for diagnosis, assessment, and management of the child with MSUD.

Practice Guidelines

There are no published practice guidelines for the diagnosis, assessment, or management of MSUD.

Helpful Articles

PubMed search for maple syrup urine disease in children, last 3 years

Frazier DM, Allgeier C, Homer C, Marriage BJ, Ogata B, Rohr F, Splett PL, Stembridge A, Singh RH.
Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach.
Mol Genet Metab. 2014;112(3):210-7. PubMed abstract / Full Text

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

Clinical Assessment

Overview

Most children with MSUD in the U.S. are diagnosed by newborn screening programs. Testing is performed by a mass spectrometry quantifying the ratio of leucine + isoleucine compared to alanine + phenylalanine. Children who present with possible symptoms of the disease before newborn screening results should have quantitative plasma amino acid analysis immediately.

Ongoing assessment of individuals with MSUD is complex. Infants should be followed by both their pediatrician and metabolic geneticist monthly and have a full amino acid profile measured once a week. Children will need continued follow-up with metabolic genetics. Metabolic geneticists should be consulted if the individual is acutely ill, seen in an emergency department for any reason, and before surgeries.

Screening

For Complications

Adolescents and adults with MSUD are at increased risk for ADHD, depression, and anxiety disorders and can be treated successfully with standard psychostimulant and antidepressant medications. Patients should be screened for these conditions and treated appropriately. Screening tools and information can be found in the diagnosis modules:

Presentations

Classic form of MSUD
Presentation is in the neonatal period, although children usually do not become symptomatic in the first few days of life while leucine accumulates in the brain. Because of the rapidity of onset, severe symptoms may be present before screening results are reported (7 days of age) or treatment starts. Initial symptoms begin with protein ingestion and may include:
  • A maple syrup odor of cerumen, detectable usually by 3 days of age
  • Elevated branched-chain amino acids, leucine, isoleucine, valine, and allo-isoleucine, which are detectable shortly after birth, but can be missed by the newborn screening if the sample is obtained too early (<12h after birth) or in milder forms of the disease
  • Ketonuria that becomes evident after branched-chain amino acids become elevated
By 4-10 days, symptoms of classic MSUD include:
  • Maple syrup odor in the urine at 5-7 days of age (not always easy to appreciate)
  • Irritability, poor feeding, and vomiting
  • Intermittent apnea
  • Arching
  • Repetitive "fencing" or "bicycling" movements
  • Lethargy progressing to coma and central respiratory failure
Intermediate form of MSUD
The Intermediate form typically presents subtly and may not be diagnosed until early childhood. The diagnosis may be missed by newborn screening because some enzyme activity is present and metabolites might not be sufficiently elevated. The Intermittent form typically presents with normal early growth and development, but acute decompensation occurs with illnesses. Individuals may have developmental delays, irritability, seizures, and poor growth.

Thiamine responsive MSUD
Individuals with the thiamine responsive form can have classic or intermediate MSUD and may show symptom improvement with thiamine therapy.

Diagnostic Criteria

The newborn screening can identify elevated level of leucine/isoleucine. Hydroxyproline is not differentiated from these 2 branched-chain amino acids by standard tandem mass spectrometry. Leucine, isoleucine, and allo-isoleucine cannot be distinguished by standard mass spectrometry since they have the same mass-to-charge ratio. Chromatographic methods to separate them are used in centers that perform second-tier testing for this condition. For this reason, diagnosis needs to be confirmed by quantitative plasma amino acids using ion-exchange chromatography. In the untreated patient, leucine is usually the highest amino acid and allo-isoleucine is detected. Urine organic acids identify elevated levels of keto acids (the deamination products of branched-chain amino acids) and excess 2-OH-isovaleric acid while the child is not metabolically stable.

Differential Diagnosis

Hydroxyprolinemia
Hydroxyprolinemia is a benign condition that can cause an elevation of the leucine/isoleucine peak on newborn screening. This is easily differentiated from MSUD by plasma amino acid.

Hypoxia-ischemic encephalopathy, severe infection, and other metabolic defects
Infants with MSUD may present similarly to those with hypoxia-ischemic encephalopathy, severe infection, and other metabolic defects. Usually, the infants have a normal interval after birth of 5-10 days during which the levels of leucine and other branched-chain amino acids accumulate in brain cells. The brain cells then retain water, resulting in brain edema. Infants with MSUD usually have the maple syrup odor in their cerumen and urine, a positive DNPH test on urinalysis, and a distinctive pattern on quantitative plasma amino acid analysis. The maple syrup smell is not always easy to appreciate. CT scan of the brain can usually see brain edema at the time of acute attacks.

Pearls & Alerts

Newborns with symptoms but a negative newborn screen

Newborns with MSUD may have a negative newborn screen if performed within the first 12 hours after birth or if they have milder forms of the disease. Symptoms of MSUD should prompt immediate cessation of protein ingestion and quantitative amino acid analysis should be performed whenever the diagnosis is suspected.

Anxiety, depression, and panic attacks

Screen for anxiety, depression, and panic attacks, which are fairly common in older children and may respond to enhanced metabolic control.

History & Examination

Family History

A history of MSUD in the extended family and a Mennonite background may lead to a high suspicion of MSUD in newborns. Prenatal testing is available. Most children with MSUD are the first in their family and a negative family history does not exclude this condition.

Current & Past Medical History

Children with the intermediate form may present with irritability, growth and developmental delay, and a history of decompensation with illness.

Interim illnesses, surgeries, and other stressors are important to track since older individuals with MSUD without excellent metabolic control may have a decrease in IQ and mental health problems.

Developmental & Educational Progress

Behavior and school problems, particularly ADHD, are common in children with MSUD, even those with good adherence to treatment.

Physical Exam

General

Untreated infants will present with metabolic crisis, respiratory distress, and coma. Infants and older children who are physically stressed may present with encephalopathy and respiratory failure.

Vital Signs

Ht | Wt | OFC may all be affected if adherence to diet is poor or if there are nutritional deficiencies.

Growth Parameters

In the treated infant, growth parameters are usually normal.

HEENT

Smelling the tip of the otoscope probe might reveal the maple syrup smell.

Neurologic Exam

Untreated infants may have neurologic findings, e.g., arching, fencing or bicycling movements. Older children may have ataxia.

Testing

Laboratory Testing

Initially, plasma amino acids need to be checked very frequently until stabilized. It is important to maintain the leucine concentration below 600 micromolar and as close as possible to normal. Levels of valine and isoleucine should be carefully checked and supplementation should be given if their level falls below the normal range. Blood counts, chemical parameters, calcium, magnesium, zinc, folate, selenium, and omega-3 essential fatty acids may also be monitored by the metabolic geneticist. Weekly (by "send in") full plasma amino acid determination.

Genetic Testing

Diagnosis can be confirmed by enzyme assay in cultured fibroblasts. These can be followed by Western blot analysis to identify the causative gene. Genetic testing of the 3 causative genes will identify the responsible gene mutation.

Other Testing

Prenatal testing is available measuring enzyme activity in amniocytes or by DNA testing if the familial mutations are known.

Subspecialist Collaborations & Other Resources

Pediatric Metabolic Genetics (see Services below for relevant providers)

Children with MSUD require lifelong management for this condition and should be referred at diagnosis to a metabolic genetics clinic.

Nutrition, Metabolic (see Services below for relevant providers)

Follow-up with metabolic nutrition on an on-going basis is crucial for growth and development.

Developmental Pediatrics (see Services below for relevant providers)

A referral to developmental pediatrics may be helpful for ongoing surveillance of developmental problems, symptoms of ADHD, and behavior problems.

Treatment & Management

Overview

Infants and children with MSUD require close monitoring by their medical home and their metabolic geneticist and nutritionist. Treatment for MSUD consists of a diet low in branched-chain amino acids with, in most cases, supplements of isoleucine and valine. These are necessary because leucine is the most abundant amino acid in foods and in our muscles; its restriction leads to low levels of the other 2 branched-chain amino acids. Some patients respond to high doses of thiamine with increased protein tolerance.

Medical treatment is similar in the different types of MSUD, with milder forms requiring less protein restriction. Thiamine should be tested in all patients for its capacity to increase protein tolerance. Treatment needs to be continued for life in classic and all variant forms of MSUD. The Guidelines for MSUD (University of Utah) (Word Document 140 KB), from the Division of Metabolic Genetics, University of Utah Health Science Center, provide a brief summary of clinical considerations for diagnosis, assessment, and management of the child with MSUD.

How should common problems be managed differently in children with Maple Syrup Urine Disease (MSUD)?

Common Complaints

Common illness can lead to reduced caloric intake, cause elevations in branched-chain amino acids, and precipitate a metabolic crisis; therefore, individuals with MSUD need prompt access to their health care provider. If the illness is caught early and a sick day regimen instituted, the child may be able to avoid hospitalization.

The sick day regimen is designed by the metabolic nutritionist to include adequate calories and amino acids. Fever should be reduced aggressively using standard antipyretics. Hospitalization to avoid neurologic complications of decompensation may be necessary, particularly if the child isn't eating well, needs IV fluids specially designed for individuals with MSUD, or requires close monitoring of amino-acid levels. See Emergency Letter for a Child with MSUD (University of Utah) (Word Document 130 KB).

Pearls & Alerts

Sick day regimen

Protocol for sick days may prevent admission to the hospital or shorten the stay if admission is required. In general, if protein content in the diet is reduced because the child is too sick to eat for more than 48 hours, hospital admission should be considered. Fever should be reduced aggressively independent of its cause to decrease energy demands and minimize catabolism.

Preventing intellectual disability

A decrease in IQ over the years may be avoidable by strict adherence to dietary restrictions and avoidance of decompensation due to stress.

Liver transplantation

Liver transplantation is sometimes performed in infants with MSUD and, if successful, obviates the need for dietary restrictions and the threat of decompensation with physical stress.

Systems

Nutrition/Growth/Bone

Metabolic dietary management varies with patient age and severity of disease. For each infant, the metabolic nutritionist will prescribe a special formula and supplements to ensure the intake of needed calories and protein, which is provided as both essential and non-essential amino acids. Full amino acid profiles are initially collected weekly and the diet is adjusted accordingly.

Older children and adults must follow a carefully controlled diet that limits protein and ensures the correct balance of leucine, isoleucine, and valine, which involves using MSUD-specific formulas that contain all amino acids except leucine, isoleucine, and valine. In most cases, dietary restriction will reduce levels of isoleucine and valine below the normal range, since the leucine content of normal foods is higher than the content of the other 2 branched-chain amino acids. For these reasons, isoleucine and valine might be supplemented (as free amino acids) in most children with MSUD. High-protein foods such as meat, eggs, and dairy are avoided. Families need to strictly adhere to specific amounts of food, usually needing to weigh them (with a gram scale) and measure all food given to the child.

Subspecialist Collaborations & Other Resources

Nutrition, Metabolic (see Services below for relevant providers)

Individuals with MSUD will require ongoing management by a metabolic nutritionist.

Mental Health/Behavior

Individuals who do not strictly adhere to the diet or who have had acute metabolic decompensation may have ataxia, anxiety and mood disorders, ADHD, and physical and intellectual disability. Pediatric physiatry, behavioral health, educational interventions, and psychiatry may be helpful in evaluating and managing such individuals. Management information can be found in the:

Subspecialist Collaborations & Other Resources

Early Intervention for Children with Disabilities/Delays (see Services below for relevant providers)

Children with MSUD should be referred to early intervention.

Early Childhood Education/Preschool (see Services below for relevant providers)

Preschool services for children with disabilities may be needed in a child who has had metabolic decompensations.

Developmental Pediatrics (see Services below for relevant providers)

A referral for evaluation and management may be helpful if a child with MSUD has had decompensations and is exhibiting delays in development or problems in school.

Developmental - Behavioral Pediatrics (see Services below for relevant providers)

If mood or anxiety disorders are suspected, a consultation may be helpful.

Pediatric Physical Medicine & Rehabilitation (see Services below for relevant providers)

If physical disabilities have occurred secondary to metabolic consultations, a consultation may be helpful.

Psychiatrist, Child-18 (MD) (see Services below for relevant providers)

Referral may be helpful for evaluation and management of children with MSUD who are experiencing mental health and behavior issues.

Frequently Asked Questions

What should I tell a mother of an infant with MSUD about breastfeeding?

Upon diagnosis, all breastfeeding is stopped to avoid a metabolic decompensation while blood testing is performed and a diet initiated. Breastfeeding can sometimes be resumed after the diet has been instituted, although with controls to limit the intake of branched-chain amino acids normally present in breast milk. Dietary changes in the mother do not modify significantly the content of branched-chain amino acids in breast milk.

What shall I tell my adolescent patient with MSUD about the risks of having children?

Most women with MSUD are able to become pregnant and have healthy babies assuming they are strictly adherent to the diet and are monitored carefully through pregnancy and postpartum. The latter is actually more of a risky time for the mother because of all the changes going on in the woman's body post-pregnancy; metabolic monitoring will need to continue for several months after birth.

Issues Related to Maple Syrup Urine Disease (MSUD)

Funding & Access to Care

Appealing Funding Denials

Resources

Information for Clinicians

Maple Syrup Urine Disease (GeneReviews)
An expert-authored, peer-reviewed, current disease description that applies genetic testing to diagnosis and management information; sponsored by the U.S. National Center for Biotechnology Information, U.S. National Library of Medicine.

Maple Syrup Urine Disease - Information for Professionals (STAR-G)
Structured list of information about the condition and links to more information; Screening, Technology, and Research in Genetics.

Maple Syrup Urine Disease Acute Illness Protocol (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.

Genetics in Primary Care Institute (AAP)
The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. It includes health supervision guidelines and other useful resources; represents a collaboration among the Health Resources & Services Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

Helpful Articles

PubMed search for maple syrup urine disease in children, last 3 years

Frazier DM, Allgeier C, Homer C, Marriage BJ, Ogata B, Rohr F, Splett PL, Stembridge A, Singh RH.
Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach.
Mol Genet Metab. 2014;112(3):210-7. PubMed abstract / Full Text

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

Clinical Tools

Care/Action Plans

Guidelines for MSUD (University of Utah) (Word Document 140 KB)
A basic approach to diagnosis, evaluation, and management of the child with MSUD; from the Division of Medical Genetics, University of Utah.

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.

Other

Emergency Letter for a Child with MSUD (University of Utah) (Word Document 130 KB)
A letter with immediate recommended treatment details for the ill child with MSUD; from the Division of Medical Genetics, University of Utah.

Emergency Information Form (EIF) for Individuals with Special Health Care Needs (ACEP)
A blank EIF (Emergency Information Form) in Word to download, print, and use in the event of an emergency. Includes diagnoses and procedures; medications; allergies; and signature/consent - from American College of Emergency Physicians.

Information & Support for Families

Family Diagnosis Page

Information on the Web

Maple Syrup Urine Disease (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; sponsored by the U.S. National Library of Medicine.

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.

Resources for Maple Syrup Urine Disease (Disease InfoSearch)
Compilation of information, articles, research, case studies, and genetics links; from Genetic Alliance.

Support National & Local

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.

Services for Patients & Families in Montana

Select services for a different state: ID, NM, NV, RI, UT

Developmental - Behavioral Pediatrics

See all Developmental - Behavioral Pediatrics services providers (4) in our database.

Developmental Pediatrics

See all Developmental Pediatrics services providers (3) in our database.

Early Childhood Education/Preschool

See all Early Childhood Education/Preschool services providers (15) in our database.

Early Intervention for Children with Disabilities/Delays

See all Early Intervention for Children with Disabilities/Delays services providers (22) in our database.

Nutrition, Metabolic

See all Nutrition, Metabolic services providers (2) in our database.

Pediatric Metabolic Genetics

See all Pediatric Metabolic Genetics services providers (1) in our database.

Pediatric Physical Medicine & Rehabilitation

See all Pediatric Physical Medicine & Rehabilitation services providers (5) in our database.

Psychiatrist, Child-18 (MD)

See all Psychiatrist, Child-18 (MD) services providers (17) in our database.

For other services related to this condition, browse our Services categories or search our database.

Authors & Reviewers

Initial Publication: January 2014; Last Update: February 2012
Current Authors and Reviewers (click on name for bio):
Author: Nicola Longo, MD, Ph.D.
Authoring history
(Limited detail is available on authoring dates before 2014.)
AAuthor; CAContributing Author; SASenior Author; RReviewer

Bibliography

Carleton SM, Peck DS, Grasela J, Dietiker KL, Phillips CL.
DNA carrier testing and newborn screening for maple syrup urine disease in old order Mennonite communities.
Genet Test Mol Biomarkers. 2010;14(2):205-8. PubMed abstract

Frazier DM, Allgeier C, Homer C, Marriage BJ, Ogata B, Rohr F, Splett PL, Stembridge A, Singh RH.
Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach.
Mol Genet Metab. 2014;112(3):210-7. PubMed abstract / Full Text

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

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