Maple syrup urine disease (MSUD) is a rare genetic disorder characterized by deficiency of certain enzymes (branched-chain alpha-keto acid dehydrogenase complex) required to breakdown (metabolize) specific amino acids in the body. Because these amino acids are not metabolized, they, along with their various byproducts, abnormally accumulate in the cells and fluids of the body. Such accumulation can cause a variety of symptoms including lethargy, irritability, poor feeding, abnormal movements and a characteristic odor of maple syrup in the earwax (cerumen), sweat and urine of affected individuals. In addition, if untreated various neurological complications including seizures, coma and brain damage may occur. Failure to promptly detect and treat MSUD can lead to life-threatening complications. However, the disorder can be successfully managed through a specialized diet. Even with treatment affected individuals remain at risk for developing episodes of acute illness (metabolic crisis) often triggered by infection, injury, failure to eat (fasting) or psychological stress. During these episodes there is a rapid, sudden spike in amino acid levels necessitating immediate medical intervention.
At least four subtypes of MSUD have been identified in the medical literature. Some researchers include a fifth subtype, although other researchers consider this a separate distinct disorder. The various subtypes of MSUD have different levels of residual enzyme activity, different severity, and different ages of onset. All forms are inherited as autosomal recessive traits.
The onset, symptoms and severity of MSUD varies greatly from case to case. Four distinct clinical forms of the disorder have been identified: classical, intermediate, intermittent, and thiamine-responsive. Some researchers include dihydrolipoyl dehydrogenase (E3)-deficient MSUD as a fifth subtype. The severity of MSUD relates to the amount of residual enzyme activity in the body.
Classic maple syrup urine disease is the most common and most severe form of MSUD. There is little to no enzyme activity present. Most infants with classic MSUD will show symptoms within the first few days of life. Breastfeeding may delay symptoms into the second week of life. Such symptoms may include lethargy, irritability, failure to thrive, poor sucking response, and little interest in feeding. The distinctive odor of maple syrup may be detected in earwax (cerumen), sweat and urine. Additional symptoms may develop including weight loss, irregular sleep patterns (intermittent apnea), and episodes of abnormal muscle rigidity (hypertonia) alternating with periods of extreme floppiness (hypotonia). Eventually, affected infants experience seizures, coma and, if left untreated, neurological damage including mental retardation and life-threatening complications such as central respiratory failure.
Although with proper treatment, affected infants can experience normal growth and development, there is a risk of symptomatic episodes known as metabolic crisis or metabolic decompensation. These episodes are characterized by a sudden and often rapid increase in branched-chain amino acids in the blood and cells of the body. Episodes may be triggered by infection, psychological stress, injury or failure to eat (fasting). In infants, associated symptoms may include altered consciousness, a group of movement disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (dystonia) and an inability to coordinate voluntary movements (ataxia). Severe episodes can result in coma, swelling of the brain because of fluid accumulation (edema) around the brain, brain damage due to lack of blood flow (ischemia) to the brain, mental retardation, and other life-threatening complications such as central respiratory failure.
Individuals with classic MSUD may develop are a variety of behavioral issues including attention deficient hyperactivity disorder (ADHD), impulsivity, anxiety or depression.
Additional complications have occurred in some individuals with classic MSUD including generalized loss of bone mass that may predispose individuals to fractures (osteoporosis), other amino acid deficiencies, and inflammation of the pancreas (pancreatitis), which is a small organ located in the back of the stomach that makes enzymes that aid in digestion and hormones such as insulin. Some individuals may develop a condition known as pseudotumor cerebri, in which increased blood pressure in the skull causes painful headaches that are sometimes associated with nausea and vomiting.
Intermediate MSUD is extremely rare. Approximately 20 cases have been reported in the medical literature. Affected infants have more residual enzyme activity than infants with classic MSUD. The onset and symptoms of intermediate MSUD vary greatly. Affected infants may experience seizures and neurological impairment and developmental delays of varying degrees. Some affected infants experience feeding problems, poor growth and the characteristic odor of maple syrup in their earwax, sweat and urine shortly after birth. Other affected infants may remain asymptomatic until later in life.
Intermittent MSUD is characterized by normal growth and intellectual development and affected individuals often can tolerate normal levels of amino acids in their diet. Symptoms usually do not occur in this form until an affected infant experiences stress, does not eat (fasts), or develops an infection. Symptoms may include lethargy, the characteristic odor of maple syrup in the earwax, sweat and urine, and the inability to coordinate voluntary movements (ataxia). Affected infants can develop metabolic crises that result in seizures, coma, brain damage, and, in rare cases, life-threatening neurological complications.
Thiamine-response MSUD is a form of the disorder that responds to treatment with thiamine, also known as vitamin B1. Thiamine helps the body convert carbohydrates into energy. The symptoms and clinical course of thiamine-responsive MSUD resembles intermediate MSUD. Symptoms are rarely present in the newborn (neonatal) period. Affected infants respond to large doses of thiamine, which boosts residual enzyme activity. No individuals with thiamine-responsive MSUD have been treated solely with thiamine- most follow a partially-restricted diet.
Some researchers consider dihydrolipoyl dehydrogenase (E3)-deficiency the fifth subtype of MSUD; other researchers believe it is a separate, distinct disorder. Fewer than 20 cases of this disorder have been reported in the medical literature and the symptoms are similar to intermediate MSUD.
Several families with multiple affected members (kindreds) have been identified who do not fit the criteria for any of the above subtypes (unclassified MSUD).
Classic, intermediate, intermittent and thiamine-response MSUD may occur due to changes or disruptions (mutations) of any one of three different genes. Dihydrolipoyl dehydrogenase (E3)-deficient MSUD is only caused by mutations of a different gene. These mutations are inherited as autosomal recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Investigators have determined that some cases of MSUD are caused by mutations of the BCKA decarboxylase (E1) alpha subunit gene (BCKDHA) on the long arm (q) of chromosome 19 (19q13.1-q13.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 19q13.1-q13.2” refers to bands 13.1-13.2 on the long arm of chromosome 19. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Two other genes, the BCKA decarboxylase (E1) beta subunit gene (BCKDHB) located on the long arm of chromosome 6 (6q14) and the BCKA decarboxylase (E1) dihydrolipoyl transacylase (E2) subunit gene (DBT) located on the short arm of chromosome 1 (1p31), are also known to cause MSUD.
Investigators have determined that dihydrolipoyl dehydrogenase (E3)-deficient MSUD is caused by mutations of the dihydrolipoamide dehydrogenase (DLD) gene located on the long arm of chromosome 7 (7q31-q32).
Mutations of the four abovementioned genes result in absence, deficiency or inactivity of enzymes in the branched-chain alpha-keto acid dehydrogenase complex. These enzymes are required to breakdown (metabolize) three of the essential amino acids (i.e., leucine, isoleucine and valine) in the body. Essential amino acids are used by the body to build proteins. The body must obtain 11 different essential amino acids as part of the daily diet because it cannot produce (synthesize) them itself. Leucine, isoleucine and valine are three of these and because all three share common characteristics and chemical structure they are known as the branched-chain amino acids (BCAAs). Failure to breakdown these amino acids results in the accumulation of leucine, isoleucine, valine and their metabolic byproducts known as ketoacids, in the blood and cells of the body. Leucine, isoleucine and valine are found in all protein-rich foods including meat and milk.
Some clinicians and geneticists prefer to classify MSUD based upon the specific gene affected: maple syrup urine disease type IA (due to mutation of E1 alpha subunit gene); maple syrup urine disease type IB (due to mutation of the E1 beta subunit gene); maple syrup urine disease type II (due to mutation of the E2 subunit gene); and maple syrup urine disease type III (due to mutation of the E3 subunit gene).
MSUD affects males and females in equal numbers. The incidence is estimated to be 1 in 185,000 people in the general population. The disorder occurs with greater frequency among individuals in the Mennonite populations in the United States, where the incidence is estimated to be in 1 in 176. MSUD was first described in the medical literature by doctor John Menkes (et al.) in 1954.
Many cases of MSUD are detected through newborn screening programs. Tandem mass spectrometry, an advanced newborn screening test that allows physicians to test for more than 30 different disorders through one blood sample, has aided in the diagnosis of MSUD.
In states where testing for MSUD is unavailable or where newborn screening fails to detect MSUD, a diagnosis may be suspected based upon characteristic finding (e.g., lethargy, failure to thrive, odor of maple syrup in earwax, sweat or urine). Tests to diagnose MSUD may include urine analysis to detect high levels of ketonic acids (ketoaciduria) and blood analysis to detect abnormally high levels of amino acids.
A diagnosis may be confirmed through analysis of white blood cells (lymphocytes) or cells taken from an affected individual’s skin.
The treatment of classic, intermediate, intermittent and thiamine-responsive MSUD has two chief aspects- lifelong therapy to maintain acceptable amino acid levels in the body and immediate medical intervention for metabolic crises.
Individuals with MSUD must remain on a protein-restrictive diet that limits the amount of branched-chain amino acids they take in. Protein-restriction must start as soon as possible after birth to promote proper growth and development. Artificially-made (synthetic) formulas are available that provide all the nutrients (e.g., vitamins, minerals) necessary for proper growth and development, but lack leucine, isoleucine and valine. It is particularly important to limit the amount of leucine in the diet. The three amino acids are added to the diet separately in small amounts so that affected individuals can grow and develop normally. The amount of leucine, isoleucine and valine affected individuals can tolerate varies based upon their residual enzyme activity. Supplementation with these amino acids cannot exceed an affected individual’s personal tolerance threshold. Affected children must be regularly monitored to ensure that their amino acid levels do not climb to unsafe levels.
Some physicians recommend a trial of thiamine therapy to determine whether an affected individual is thiamine-responsive. However, no individual with MSUD has been treated solely with thiamine.
Even if affected individuals strictly follow a specialized diet, a risk of metabolic crisis still exists. Episodes of metabolic crisis require immediate medical intervention to lower the levels of branched-chain amino acids, especially leucine, in the blood plasma. Various techniques have been used to reduce plasma leucine levels including dialysis or a process in which plasma is removed from the body and passed through a filter before being returned to the body (hemofiltration).
Intravenous glucose administration is sometimes used to treat individuals during metabolic crisis. Many hospitals may use total parenteral nutrition solutions that lack branched-chain amino acid. In addition, insulin may be used to stimulate a metabolic process known as anabolism. During anabolism, various cellular components (including proteins) are combined (synthesized) to formed energy-rich compounds.
The so-called fifth subtype of MSUD (dihydrolipoamide dehydrogenase deficiency) has been treated with various drugs and dietary restrictions of fat and branched-chain amino acids. However, these therapies have generally been ineffective in treating affected individuals.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. Early intervention is important in ensuring that children with MSUD reach their highest potential.
Liver transplantation has been used to treat individuals with classic MSUD. This procedure has resulted in individuals who are symptom-free and able to eat protein-rich foods. The new liver supplies enough of the enzymes needed to breakdown the three amino acids that accumulate in MSUD. However, the procedure (as a treatment for MSUD) remains controversial because of its inherent risks including a condition called graft-versus-host disease in which the body rejects the transplanted organ. Individuals who receive a liver transplant must remain on immunosuppressive medications for the remainder of their lives to prevent rejection. Availability of a donor liver and the high cost are also hurdles to this procedure. Despite the risks, liver transplantation has been highly effective for the handful of individuals with classic MSUD who have undergone the procedure. More research is necessary to determine the long-term effects of liver transplantation on neurological development in individuals with MSUD.
Researchers are studying gene therapy as a potential treatment for individuals with MSUD.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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