Maple Syrup Urine Disease (MSUD)

Overview

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 with 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 4 subunits, E1alpha, E1beta, E2, and E3. The E3 subunit is shared by 2 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.

Other Names & Coding

Branched-chain ketoacid dehydrogenase (BCKD) deficiency
Branched-chain ketoaciduria
ICD-10 coding

E71.0, Maple syrup urine disease

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

Prevalence

A German study indicates a prevalence of 1:250,000 for MSUD. [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 early treatment, lifetime adherence to the diet, and prompt management of illnesses, the prognosis is good and normal development and IQ can be achieved. 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.

Practice Guidelines

Nutrition management guidelines for MSUD were published in 2014. These guidelines detail acute dietary treatment, thiamin supplementation, pregnancy and postnatal period, and liver transplantation. They do not include recommendations for the diagnosis, assessment, or medical management of MSUD.

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

Roles of the Medical Home

The primary care clinician will need to closely monitor the development and growth in children with MSUD for optimal outcomes. Problems in these areas may respond to better metabolic control. Individuals with MSUD need early access to care for illnesses. See 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) (PDF Document 176 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.

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. Some laboratories can perform second-tier testing on the blood spot to identify allo-isoleucine, an amino acid specific for MSUD. Children who present with possible symptoms of the disease before newborn screening results should have quantitative plasma amino acid analysis immediately.

Ongoing assessment of an individual with MSUD is complex. Infants should be followed by both their pediatrician and a metabolic geneticist every 2-8 weeks. In addition, growth and a full amino acid profile should be measured weekly. Children will need life-long follow-up with metabolic genetics. Provide an emergency protocol to the family. Medical genetics should be consulted if the individual is acutely ill, in an emergency department, or needing surgery.

Pearls & Alerts for Assessment

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 (no longer than 24-48 hours) with provision of calories from fat and sugars only, and quantitative amino acid analysis should be performed.

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.

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 psycho-stimulant and antidepressant medications. Patients should be screened for these conditions and treated appropriately. For screening tools and information, see:

Presentations

Classic form of MSUD
Presentation begins early in life, although children may not become symptomatic while leucine accumulates in the brain. Initial symptoms begin with protein ingestion and progress as follows:
  • Detection of maple syrup odor in the cerumen as early as 12-24 hours after birth and in the urine by 24-72 hours after birth
  • Elevated concentrations of the BCAA, including allo-isoleucine (Allo-ILE) by 12-24 hours
  • Elevated BCKA, ketonuria, irritability, and poor feeding by 24-72 hours
  • Encephalopathy, characterized by lethargy, intermittent apnea, opisthotonos, repetitive ”fencing” or “bicycling” movements by 4-5 days
  • Coma and central respiratory failure by 7-10 days
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 program identifies MSUD through elevated level of leucine/isoleucine. Hydroxyproline (elevated in benign hydroxyprolinemia) is not differentiated from these 2 branched-chain amino acids by standard tandem mass spectrometry having the same mass with common derivatization procedures. Hydroxyproline can be differentiated by second-tier testing (available only in a few screening labs) or by plasma amino acids. 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 or chromatographic separation before MS/MS. 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, positive ketones 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.

History & Examination

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 that has not been well controlled may have a decrease in IQ and mental health problems.

Family History

A history of MSUD in the extended family, consanguinity, or 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.

Developmental & Educational Progress

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

Physical Exam

General

Untreated infants will present with metabolic crisis, respiratory distress, and coma. Bicycling can be seen in these children and reflects neurological damage. Infants and older children who are physically stressed may present with encephalopathy and respiratory failure.

Growth Parameters

In the treated infant, growth parameters are usually normal. Ht | Wt | OFC may all be affected if adherence to diet is poor or if there are nutritional deficiencies.

HEENT/Oral

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

Common laboratory tests (CMP, CBC) can be completely normal. Urine analysis might show excess ketones. Initially, plasma amino acids need to be checked very frequently until stabilized. It is important to maintain the leucine concentration below 300 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. Urine organic acids reveal abnormal branched-chain hydroxy- and ketoacids.

Imaging

Brain edema can be seen with MRI or CT during acute attacks

Genetic Testing

Diagnosis can be confirmed DNA testing of all by enzyme assay in cultured fibroblasts. Enzyme assay can be performed if DNA testing identifies variant of unknown significance. Genetic testing of the 3 causative genes will identify the responsible gene mutation.

Other Testing

Prenatal testing is available by DNA testing if the familial mutations are known.

Specialty Collaborations & Other Services

Pediatric Metabolics (see ID providers [1])

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

Nutrition, Metabolic (see ID providers [1])

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

Developmental - Behavioral Pediatrics (see ID providers [3])

Consider referral 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 BCAA restriction. Thiamine should be tested in all patients for its capacity to increase BCAA tolerance. Treatment needs to be continued for life in classic and all variant forms of MSUD. 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) (PDF Document 176 KB), from the Division of Metabolic Genetics, University of Utah Health Science Center, provide a summary of clinical considerations for diagnosis, assessment, and management of the child with MSUD.

Pearls & Alerts for Treatment & Management

Protocol for illness

Adherence to protocol during times of illness may prevent admission to the hospital or shorten the stay if admission is required. BCAA content in the diet should never be reduced for more than 24-48 hours; consider a hospital admission if this does occur. Regardless of its cause, fever should be reduced aggressively 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 metabolic stress.

Liver transplantation

Domino liver transplantation is increasingly common in MSUD. The liver is responsible for 9-13% of BCKDH enzyme production; a liver transplant can restore adequate enzyme function and prevent long-term complications. While a liver transplant is not curative in MSUD, it should allow for nearly complete normalization of the diet. After transplantation, the patient should continue to have close follow-up with their metabolic center.

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

Growth or Weight Gain

Growth should be monitored closely in all patients with MSUD; inadequate calorie intake or weight loss can lead to catabolism and may result in metabolic decompensation from elevated leucine levels.

Development (cognitive, Motor, Language, Social-Emotional)

Monitor development periodically and provide supportive services if there are delays in motor or speech.

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 by the metabolic clinic, 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 is not eating well, needs IV fluids specially designed for individuals with MSUD, or requires close monitoring of amino-acid levels. See Emergency Metabolic Protocol for MSUD (University of Utah) (PDF Document 184 KB).

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.

Specialty Collaborations & Other Services

Nutrition, Metabolic (see ID providers [1])

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 for evaluation and management. Management information can be found in the:

Specialty Collaborations & Other Services

Early Intervention for Children with Disabilities/Delays (see ID providers [153])

Children with MSUD should be referred to early intervention.

Early Childhood Education/Preschool (see ID providers [14])

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

Developmental - Behavioral Pediatrics (see ID providers [3])

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

Pediatric Physical Medicine & Rehabilitation (see ID providers [1])

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

Psychiatry/Medication Management (see ID providers [20])

Consider for evaluation and management of children with MSUD who are experiencing mental health and behavior issues.

Issues Related to Maple Syrup Urine Disease (MSUD)

Funding & Access to Care

Appealing Funding Denials

Ask the Specialist

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 the content of branched-chain amino acids in breast milk significantly.

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.

Resources for Clinicians

On the Web

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)
Contains health supervision guidelines and other useful resources for the care of children with genetic disorders; American Academy of Pediatrics.

Helpful Articles

PubMed search for articles published in the last 3 years about maple syrup urine disease in children and adolescents

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, & Self-Care Plans

Guidelines for MSUD (University of Utah) (PDF Document 176 KB)
An example of 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 Metabolic Protocol for MSUD (University of Utah) (PDF Document 184 KB)
An example of 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) (PDF Document 61 KB)
A blank EIF (Emergency Information Form) PDF 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.

Resources for Patients & Families

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.

National & Local 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.

Services for Patients & Families in Idaho (ID)

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: February 2012; last update/revision: August 2019
Current Authors and Reviewers:
Authors: Nicola Longo, MD, Ph.D.
Chelsea Norman, BS, RDN, CD
Authoring history
2012: first version: Nicola Longo, MD, Ph.D.A
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