Maple Syrup Urine Disease (MSUD)

Written by Anna Giorgi
Medically Reviewed by George Krucik, MD

Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) is a rare, inherited metabolic disorder. With MSUD, the body cannot break down certain amino acids. Individuals who have the disease produce urine that has a distinctive maple syrup odor.

Amino acids are what remain after your body digests the protein from the food you eat. Special enzymes process the amino acids so they can be used to maintain all of your body functions.

If some of the necessary enzymes are missing or defective, the amino acids and their byproducts, called keto acids, collect in the body. As the levels of these substances increase, neurological damage, coma, and life-threatening conditions can result.

In MSUD, the body does not have enzymes from a group called the branched-chain alpha-ketoacid dehydrogenase complex (BCKAD). BCKAD enzymes process three important amino acids: leucine, isoleucine, and valine. These are branched-chain amino acids (BCAAs). BCAAs are found in foods like meat, eggs, and milk, which are rich in protein.

MSUD is also known as:

  • BCKD deficiency
  • branched-chain alpha-ketoacid dehydrogenase deficiency
  • ketoacidemia
  • branched-chain ketoaciduria
  • branched-chain ketonuria I

When untreated, MSUD can cause significant physical and neurological problems. However, MSUD can be controlled with dietary restrictions. Its success can be monitored with blood tests. Early diagnosis and intervention improves the chances of long-term success.

Types of MSUD

There are four subtypes of MSUD. All are inherited genetic disorders. They differ by their degree of enzyme activity, severity, and age when the disease appears.

Classic MSUD is the most common form of this condition. In this form, the patient has little, if any, enzyme activity (about two percent or less than normal activity). This is the most severe form of MSUD. Symptoms are present in newborns within a few days of birth.

Intermediate MSUD is a very rare form of the disease. It is a version of classic MSUD. The symptoms and age of onset of this type vary greatly. Individuals with intermediate MSUD have a higher level of enzyme activity than classic MSUD (about three to eight percent of normal activity).

Intermittent MSUD does not interfere with normal physical and intellectual growth and development. It is a milder form of classic MSUD. Individuals have more significant enzyme activity (about 8 to 15 percent of normal activity). Symptoms usually don’t appear until a child is between 1 and 2 years of age. The initial reaction often occurs when the child experiences stress, an illness, or an unusual increase in protein.

Thiamine-responsive MSUD is a rare form of the condition that often improves with large doses of thiamine, or vitamin B1. Symptoms in a child with thiamine-responsive MSUD usually occur after infancy. Even though thiamine can be beneficial, dietary restrictions also are necessary.

Causes of MSUD

The four varieties of MSUD are caused by mutations, or changes, in the genes that tell your body to make certain enzymes. Gene mutations are inherited on the chromosomes you received from your parents. When the genes related to the BCKAD enzymes are defective, the BCKAD enzymes are not produced or work inaccurately.

MSUD is a recessive genetic disorder. All forms of MSUD are received from your parents.

Typically, parents of children with MSUD do not have the disease. They possess one mutated gene and one normal gene for MSUD. Though they carry the defective gene, they are not affected by it. The defective gene is called recessive. Parents of children with MSUD are called carriers.

Having MSUD means that you inherited one flawed gene for MSUD from each parent. Both parents must carry a mutation of the gene associated with MSUD to pass the disease on to their child.

Risk Factors for MSUD

The National Organization for Rare Disorders (NORD) reports that MSUD occurs at the same rate in males and females. In the general population, MSUD appears in about one in 185,000 people. However, its incidence is much more significant among Mennonites in the United States, where MSUD occurs in one in 176. (NORD, 2007)

Your risk for having any form of MSUD depends on whether or not your parents are carriers of the disease. If both parents are carriers, each child has a 25 percent chance of receiving two mutated genes and having MSUD, a 50 percent chance for receiving only one defective gene and being a carrier, and a 25 percent chance of receiving one normal gene from each parent. If you have two normal genes for MSUD, you cannot pass the disease to your children.

When two parents carry the recessive gene for MSUD, it is possible for one child to have the disease and other children to be normal. However, children of parents who are carriers also can be carriers with one defective gene, like their parents.

If one of your children is diagnosed with MSUD, any other children you have will have a 50 percent chance of being carriers. They also may carry a risk later in life of having a child with MSUD.

Symptoms of MSUD

Symptoms of MSUD vary according to the disease subtype. In classic MSUD, the most common type of the disease, symptoms become present in an infant within a few days after birth. The onset is usually triggered when the infant’s body begins to process protein from feedings.

Some of the initial symptoms characteristic of classic MSUD are:

  • lethargy
  • poor appetite
  • weight loss
  • weak sucking ability
  • irritability
  • a distinctive maple sugar odor in earwax, sweat, and urine
  • irregular sleep patterns
  • alternating episodes of hypertonia (muscle rigidity) and hypotonia (muscle limpness)
  • high-pitched cry

Symptoms of intermediate MSUD and the age of onset vary greatly. Infants with thiamine-response MSUD have similar symptoms and onset. Signs of intermediate and thiamine-response MSUD include:

  • seizures
  • neurological deficiencies
  • developmental delays
  • feeding problems
  • poor growth
  • a distinctive maple sugar odor in earwax, sweat, and urine

Infants with intermittent MSUD usually do not experience symptoms until they are past the newborn stage. They often can process close to normal levels of amino acids on their own. However, when an infant experiences an episode of stress, fasting, or infection, the following symptoms may appear:

  • lethargy
  • a distinctive maple sugar odor in earwax, sweat, and urine
  • ataxia (lack of voluntary coordination of muscle movement)

Complications of MSUD

Complications from undiagnosed and untreated MSUD can be severe and even fatal. Even babies in a treatment plan can experience incidents of extreme sickness. The incidents are called metabolic crises.

Metabolic crises occur when there is a sudden and intense increase of BCAAs in the system. If untreated, the situation can lead to serious physical and neurological damage. A metabolic crisis usually is indicated by:

  • extreme fatigue or lethargy
  • loss of alertness
  • irritability
  • vomiting

When MSUD is undiagnosed, or metabolic crises are untreated, the following severe complications can occur:

  • seizures
  • swelling of the brain
  • lack of blood flow to the brain
  • metabolic acidosis: a situation in which the blood contains high levels of acidic substances
  • coma

When these conditions occur, they can result in severe neurological damage, mental retardation, blindness, or spasticity (uncontrolled muscle tightness). Eventually, life-threatening complications can develop, leading to death. Untreated babies with classic MSUD eventually die within a few months of birth.

Diagnosis of MSUD

Data from the National Newborn Screening and Genetics Resource Center (NNSGRC) indicates that every state in the United States tests infants for MSUD as part of their newborn screening program. (NNSGRC, 2011) Newborn diagnosis is made through a blood test that also screens for more than 30 different disorders.

Identifying the presence of MSUD at birth is critical to preventing long-term damage. In cases when both parents are carriers and their child’s test is negative for MSUD, additional tests may be advised to confirm the findings and prevent the onset of symptoms.

When symptoms become present after the newborn period, diagnosis of MSUD can be made by urine analysis or a blood test. In a child with MSUD, urine analysis will show a high rate of keto acids; a blood test will show a high level of amino acids. The diagnosis of MSUD also can be confirmed with enzyme analysis of white blood cells or skin cells.

If you are concerned that you might be a carrier of MSUD, genetic testing can confirm if you possess one of the malformed genes that cause the disease. During pregnancy, your physician can use samples obtained by chorionic villus sampling (CVS) or amniocentesis to determine a diagnosis for your baby.

Treatment of MSUD

If your infant is diagnosed with MSUD, prompt medical treatment can avoid serious medical problems and mental retardation. The initial treatment involves reducing the levels of BCAAs in the baby’s blood.

Typically, this will involve the intravenous (IV) administration of amino acids that do not contain BCAAs, combined with glucose for extra calories. The treatment will promote the utilization of existing leucine, isoleucine, and valine in the body, simultaneously reducing the BCAA levels and providing necessary protein.

A physician will create a long-term treatment plan for your child with MSUD in conjunction with a metabolic specialist and a dietitian. The goal of the treatment plan is to provide your child with all the protein and nutrients needed for healthy growth and development. The plan will also avoid allowing too many BCAAS to collect in the blood.

A treatment plan for MSUD often includes the following components:

  • Your infant will use a MSUD medical formula. The formula provides carefully controlled amounts of BCAAs, without leucine, isoleucine, or valine. It is made to ensure that your child receives all the necessary vitamins, minerals, nutrients, and protein needed for healthy growth and development.
  • As your child begins to eat food, you will monitor his or her diet to prevent the consumption of too many BCAAs. This requires excluding foods that are high in protein, usually meat, fish, nuts, eggs, and dairy products. Your physicians and dietitian will assist you in finding the right diet for your child’s individual needs.
  • Your child will eventually learn to take charge of his or her dietary needs. The dietary restrictions necessary for MSUD last a lifetime. A metabolic crisis can result when dietary guidelines are ignored.
  • If your child has thiamine-responsive MSUD, thiamine supplements may be helpful. However, children with this form of the disease also must follow dietary restrictions.
  • Your physician will monitor your child’s amino acid levels with regular blood tests. The results will indicate if dietary changes are needed.

Long-Term Outlook for MSUD

Children with MSUD can lead active, normal lives. Regular medical monitoring and careful attention to dietary restrictions can help your child avoid potential complications. You can achieve the best results if treatment is started and maintained as early as possible.

However, even with careful monitoring, a metabolic crisis can erupt. Tell your physician if your child develops the following symptoms:

  • loss of appetite
  • extreme fatigue or lethargy
  • vomiting
  • any illness
  • any infection
  • fever
  • behavioral changes

How to Prevent MSUD

Since MSUD is an inherited disease, there is no technique for prevention. A genetic counselor can help you determine your risk for having a baby with MSUD. Genetic testing can tell you if you or your partner is a carrier of the disease. DNA testing can identify the disease in a fetus before birth.

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