Maple Syrup Urine Disease: Causes, Symptoms and Treatment

Author: Thomas C. Weiss
Published: 10 Apr 2010 - Updated: 2 Oct 2026
Publication Type: Informative

Table of Contents:
Synopsis - Definition - Overview - FAQs - Insights, Updates - Related Content

Synopsis

This information covers maple syrup urine disease (MSUD), an inherited metabolic disorder in which a deficiency of the branched-chain alpha-keto acid dehydrogenase (BCKD) complex leaves the body unable to break down the amino acids leucine, isoleucine, and valine. It outlines the causes, the classic, intermittent, thiamine-responsive, and E3-deficient forms, the symptoms that typically appear in newborns between four and seven days of age, and how a blood test showing alloisoleucine confirms the diagnosis. The material is useful because it sets out both emergency care during a metabolic episode and the lifelong diet needed to prevent nervous system damage, in terms that parents, caregivers, and adults living with the condition can follow. It also notes that the U.S. Social Security Administration lists MSUD as a Compassionate Allowance condition, which matters to families and people with disabilities seeking a faster decision on a disability claim.*

At a Glance

1 - Hemodialysis or peritoneal dialysis may be used during an episode to lower amino acid levels in the blood.
2 - MSUD was first described in 1954 by Menkes, in a family where four infants died within three months of birth.
3 - About one in 180,000 newborns in America has MSUD, but the rate may be as high as one in 176 among Mennonites in Pennsylvania.
4 - A buildup of leucine is responsible for the neurological symptoms of MSUD, while elevated plasma isoleucine is linked to the maple syrup odor of the urine.

Topic Definition

Maple Syrup Urine Disease (MSUD): Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder, passed on in an autosomal recessive pattern, in which the body lacks enough working branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex to break down the amino acids leucine, isoleucine, and valine found in protein. These amino acids and their by-products build up in the blood and urine, giving the urine a sweet odor like maple syrup and, if untreated, causing poor feeding, lethargy, seizures, brain damage, and death in infancy. The condition is managed with a lifelong diet that restricts branched-chain amino acids, along with close monitoring of blood amino acid levels.

Overview

Defining MSUD

Maple syrup urine disease (MSUD) is a metabolic disorder passed down through families. The disorder affects people in a way that their bodies are unable to break down particular portions of proteins. The urine of people affected by this disorder may have the scent of maple syrup, thus the name of the disorder.

The U.S. Social Security Administration (SSA) has included Maple Syrup Urine Disease as a Compassionate Allowance to expedite a disability claim.

The year 1954 found Menkes describing a family in which four infants died within the first three months of their lives due to a neurodegenerative disorder. The infant's urine presented an odor reminiscent of maple syrup, naming the disorder as 'Maple Sugar Urine Disease.' In the years that followed, Dancis was able to identify the pathogenetic compounds as branched-chain amino acids and corresponding alpha-keto acids. The year 1960 found Dancis demonstrating that the enzymatic defect in MSUD was at the level of the decarboxylation of the branched-chain amino acids. The first successful dietary treatment of MSUD was found by Snyderman, who restricted the intake of branched-chain amino acids. By the year 1971, Scriver reported the first person with thiamine-responsive MSUD. The year 1978 found the branched-chain alpha-keto acid dehydrogenase (BCKD) complex was purified and characterized.

Approximately one newborn out of one-hundred and eighty-thousand in America has MSUD. However, it might be as common as one newborn in every one-hundred and seventy-six in selected populations such as the Mennonites in Pennsylvania. MSUD is an autosomal recessive disorder, so it is more prevalent in populations with a higher frequency of consanguinity. Around one newborn in a quarter-million in Austria has MSUD, as reported by the Austrian Screening Program.

Causes of MSUD

MSUD is caused by a deficiency of the BCKD complex. The BCKD complex catalyzes the decarboxylation of the alpha-keto acids of isoleucine, valine, and leucine to their respective branched-chain acyl-CoAs. These are further metabolized to produce acetyl-CoA, succinyl-CoA, and acetoacetate. The BCKD complex is associated with the inner mitochondrial membrane; it has three different catalytic components - E1, E2, and E3. BCKD also has two associated regulatory enzymes, BCKD kinase, and BCKD phosphatase. The E1 component consists of two subunits, E1 alpha and beta, forming an alpha-2 beta-2 heterotetramer. The E3 component is associated with two additional alpha-ketoacid dehydrogenase complexes, alpha-ketoglutarate dehydrogenase, and pyruvate dehydrogenase. Mutations in E1, E2, or E3 cause MSUD. No good genotype-phenotype correlation between molecular and clinical phenotypes is known, with the exception of mutations in E2, which cause thiamine-responsive MSUD. Mutations in E3 cause deficiencies of alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase. There have been no reports of mutations in the regulatory enzymes.

The significant accumulation of leucine causes people affected by MSUD to experience neurological symptoms. Elevation of plasma isoleucine has been associated with the maple syrup odor of the urine of people with the disorder. Leucine is quickly transported across the blood-brain barrier of people with MSUD, where it is metabolized and yields glutamine and glutamate.

Symptoms of MSUD

There are several types of Maple Syrup Urine Disease (MSUD). The more common, or classic, form of the disorder usually produces symptoms in newborn infants between the ages of four and seven days. The symptoms of MSUD can include the following:

Coma
Vomiting
Poor feeding
Poor weight gain
Increasing lethargy
Neurological damage
Difficulties with waking the infant up
Characteristic burned sugar smell to urine
Changes in muscle tone, muscle spasms, and seizures

Infants with MSUD who remain untreated will die within the first few months of their lives. People with intermittent MSUD, the second most common disorder, will experience average development. When people with intermittent MSUD become ill, they display the classic signs of MSUD. Intermediate MSUD is a rare form of the disorder. People with this form of MSUD have three to thirty percent of the average level of BCKD enzyme, meaning the symptoms of MSUD might start at any age. People who experience thiamine-responsive MSUD, another form of the disorder, have shown improvement when taking thiamine supplements. There is a sporadic form of MSUD called 'E3-deficient MSUD.' People with this form of the disorder have additional deficient metabolic enzymes.

Diagnosing MSUD

Should a doctor suspect that a person has MSUD, based upon the presentation of physical symptoms in the person - particularly the presence of that characteristic maple syrup odor associated with the person's urine, the doctor may order a blood test for amino acids. If alloisoleucine is detected in the person's blood, a diagnosis of MSUD is confirmed. All states in America screen newborns at the time of their birth for MSUD. Additional testing may include the urine amino acid test and plasma amino acid test. People with MSUD will present with signs of ketosis and excess acid in their blood, also referred to as 'acidosis.'

Treatment of MSUD

Once a person has been diagnosed with MSUD, and during episodes, treatment of the disorder involves the consumption of foods that are free of proteins. Sugars, fluids, and potential fats are administered intravenously. Hemodialysis or peritoneal dialysis may reduce the level of amino acids in the affected person. Once the person's amino acid levels have reached average levels, they are placed on a diet restricted in branched-chain amino acids. A health care provider follows the person's amino acid levels closely, adjusting the person's diet according to the person's amino acid levels.

The long-term treatment of MSUD requires a special diet that includes artificial infant formula containing low levels of amino acids such as isoleucine, leucine, and valine. People with MSUD must remain on a diet that is low in branched-chain amino acids permanently. The importance of following a low amino acid diet cannot be over-emphasized for persons with MSUD. The diet is essential for the prevention of nervous system damage. Blood testing to assess the levels of amino acids in the person's bloodstream must be pursued frequently and closely supervised by a registered dietitian and a physician. Cooperation on the part of the person's family members is equally crucial.

MSUD may be life-threatening if it goes untreated. Even if people with the disorder pursue dietary treatment, stressful situations or illnesses may still cause high levels of certain amino acids in them. Episodes caused by stress or illness may lead to the individual's death. Following strict dietary treatment, children with MSUD have grown into healthy adults.

Frequently Asked Questions

NOTE: Researched FAQs by Disabled World (DW)

What genes are linked to maple syrup urine disease?

MSUD is caused by changes in the BCKDHA, BCKDHB, or DBT genes, which provide instructions for the E1 alpha, E1 beta, and E2 parts of the BCKD enzyme complex. Changes in the DLD gene affect the E3 part and cause a related condition involving several enzyme deficiencies.

What are the chances of carrier parents having a child with MSUD?

When both parents carry one altered copy of the same MSUD gene, each pregnancy has a 25 percent chance of a child with MSUD, a 50 percent chance of a child who is a carrier without symptoms, and a 25 percent chance of a child who inherits two working copies.

How is MSUD found through newborn screening?

A few drops of blood are taken from the baby's heel in the first days of life and tested by tandem mass spectrometry for raised levels of leucine and isoleucine. An out-of-range result is followed by confirmatory plasma amino acid testing, since screening alone does not confirm the diagnosis.

Can a liver transplant treat maple syrup urine disease?

Yes. A transplanted liver supplies enough working BCKD enzyme to keep amino acid levels stable on a normal diet and to prevent metabolic crises. It does not reverse brain injury that has already happened, and it requires lifelong anti-rejection medication.

What foods are restricted on an MSUD diet?

High-protein foods such as meat, poultry, fish, eggs, milk, cheese, nuts, and legumes are strictly limited because they are rich in leucine, isoleucine, and valine. Most protein needs are met with a medical formula free of these three amino acids, with measured amounts of natural protein added under a metabolic dietitian's guidance.

Can the maple syrup odor be noticed anywhere other than urine?

Yes. The sweet odor can often be detected in earwax within 12 to 24 hours of birth, before it becomes noticeable in urine, and it may also be present in sweat. The smell comes from sotolone, a compound produced from the breakdown of isoleucine.

Can MSUD be diagnosed before birth?

Yes. When the gene changes in a family are already known, prenatal testing can be done on cells collected by chorionic villus sampling or amniocentesis. Genetic counseling is recommended for couples with a family history of MSUD who are planning a pregnancy.

Can women with MSUD have a safe pregnancy?

Successful pregnancies have been reported in women with MSUD, but they need close supervision by a metabolic team with frequent amino acid monitoring and diet adjustments. The period right after delivery carries a higher risk of metabolic crisis because the body breaks down its own protein.

Insights, Analysis, and Developments

Editorial Note: MSUD shows how much early detection and steady follow-through can change an outcome. A disorder that claimed every infant in the first family studied is now one that children can grow up with, provided the diet is kept strictly, blood amino acid levels are checked often by a physician and registered dietitian, and the family stays involved in day-to-day management. The caution worth repeating is that diet alone does not remove the risk - an ordinary illness or a stressful period can still push amino acid levels dangerously high, so any sign of an episode calls for prompt medical attention. For parents of a newly diagnosed baby, and for adults who have lived with the condition for decades, that mix of routine vigilance and fast response is what keeps a rare metabolic disorder manageable.*

Ability Lane Author Credentials: Thomas C. Weiss is a researcher and editor for Disabled World. Thomas attended college and university courses earning a Masters, Bachelors and two Associate degrees, as well as pursuing Disability Studies. As a CNA Thomas has provided care for people with all forms of disabilities. Explore Thomas' complete biography for comprehensive insights into his background, expertise, and accomplishments.

* Editorial additions by Ian C. Langtree.