Overview Maple syrup urine disease (MSUD) is a rare, inherited metabolic disorder. The disease prevents your body from breaking down certain amino acids. Amino acids are what remain after your body digests protein from the food you eat. Special enzymes process 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 your body. As the levels of these substances increase, it can result in: neurological damage

coma

life-threatening conditions In MSUD, the body lacks an enzyme called BCKDC (branched-chain alpha-keto acid dehydrogenase complex). The BCKDC enzyme processes three important amino acids: leucine, isoleucine, and valine, also called BCAAs (branched-chain amino acids). BCAAs are found in foods rich in protein, such as meat, eggs, and milk. When untreated, MSUD can cause significant physical and neurological problems. MSUD can be controlled with dietary restrictions. The success of this method can be monitored with blood tests. Early diagnosis and intervention improve the chance of long-term success.

Types of MSUD MSUD is also known as: BCKDC deficiency

branched-chain alpha-keto acid dehydrogenase deficiency

branched-chain ketoaciduria

branched-chain ketonuria I There are four subtypes of MSUD. All are inherited genetic disorders. They differ by their degree of enzyme activity, severity, and the age when the disease appears. Classic MSUD This is the most common and severe form of the condition. A person with this form has little, if any, enzyme activity — about 2 percent or less of normal activity. Symptoms are present in newborns within a few days of birth. Onset is usually triggered when the infant’s body begins to process protein from feedings. Intermediate MSUD This is a rare version of MSUD. Symptoms and age of onset vary greatly. People with this type of MSUD have a higher level of enzyme activity than classic MSUD — about 3 to 8 percent of normal activity. Intermittent MSUD This form doesn’t interfere with normal physical and intellectual growth and development. Symptoms usually don’t appear until a child is between 1 and 2 years of age. It’s a milder form of classic MSUD. Individuals have significant enzyme activity — about 8 to 15 percent of normal activity. The initial reaction of the disease often occurs when the child experiences stress, illness, or an unusual increase in protein. Thiamine-responsive MSUD This rare form of the condition often improves with large doses of thiamine, or vitamin B-1. Symptoms usually occur after infancy. Even though thiamine can be beneficial, dietary restrictions also are necessary.

Symptoms of MSUD Some 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 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

Risk factors for MSUD The National Organization for Rare Disorders (NORD) reports that MSUD occurs at the same rate in males and females (about 1 in 185,000 people). Your risk for having any form of MSUD depends on whether your parents are carriers of the disease. If both parents are carriers, their child has a: 25 percent chance of receiving two mutated genes and having MSUD

50 percent chance for receiving only one defective gene and being a carrier

25 percent chance of receiving one normal gene from each parent If you have two normal genes for BCKDC, you can’t pass the disease to your children. When two parents carry the recessive gene for BCKDC, it’s possible for one of their children to have the disease and other children to not have it. However, these children have a 50 percent chance of being carriers. They also may carry a risk later in life of having a child with MSUD.

Causes of MSUD MSUD is a recessive genetic disorder. All forms of the disease inherited from your parents. The four varieties of MSUD are caused by mutations, or changes, in the genes that are related to the BCKDC enzymes. When those genes are defective, the BCKDC enzymes aren’t produced or don’t work properly. These gene mutations are inherited on the chromosomes you receive from your parents. Typically, parents of children with MSUD don’t have the disease and they possess one mutated gene and one normal gene for MSUD. Though they carry the defective recessive gene, they aren’t affected by it. Having MSUD means that you inherited one flawed gene for BCKDC from each parent.

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, which is 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 show up after the newborn period, diagnosis of MSUD can be made by a urine analysis or blood test. A urine analysis can detect a high concentration of keto acids, and a blood test can detect a high level of amino acids. The diagnosis of MSUD also can be confirmed with an 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 diagnose your baby.

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, 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

intellectual disability

blindness

spasticity, or uncontrolled muscle tightness Eventually, life-threatening complications can develop and lead to death, especially if they go untreated.

Treatment of MSUD If your infant is diagnosed with MSUD, prompt medical treatment can avoid serious medical problems and intellectual disability. Initial treatment involves reducing the levels of BCAAs in your baby’s blood. Typically, this involves intravenous (IV) administration of amino acids that don’t contain BCAAs, combined with glucose for extra calories. The treatment will promote the utilization of existing leucine, isoleucine, and valine in the body. At the same time it will reduce the BCAA level and provide necessary protein. Your 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 their blood.

How to prevent MSUD Since MSUD is an inherited disease, there is no method 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.