NORD gratefully acknowledges Neil R. M. Buist, MD, Professor Emeritus, Pediatrics and Medical Genetics, Oregon Health & Science University, Madeline Zupan, Editorial Intern from the University of Notre Dame, and the MSUD Family Support Group for assistance in the preparation of this report.
Maple syrup urine disease (MSUD) is a rare genetic disorder characterized by deficiency of an enzyme complex (branched-chain alpha-keto acid dehydrogenase) that is required to break down (metabolize) the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine, in the body. The result of this metabolic failure is that all three BCAAs, along with a number of their toxic byproducts, (specifically their respective organic acids), all accumulate abnormally. In the classic, severe form of MSUD, plasma concentrations of the BCAAs begin to rise within a few hours of birth. If untreated, symptoms begin to emerge, often within the first 24-48 hours of life.
The presentation starts with non-specific symptoms of increasing neurological dysfunction and include lethargy, irritability and poor feeding, soon followed by focal neurological signs such as abnormal movements, increasing spasticity, and shortly thereafter, by seizures and deepening coma. If untreated, progressive brain damage is inevitable and death occurs usually within weeks or months. The only specific finding that is unique to MSUD is the development of a characteristic odor, reminiscent of maple syrup that can most readily be detected in the urine and earwax and may be smelled within a day or two of birth. The toxicity is the result of damaging effects of leucine on the brain accompanied by severe ketoacidosis caused by accumulation of the three branched-chain ketoacids (BCKAs).
The disorder can be successfully managed through a specialized diet in which the three BCAAs are rigorously controlled. However, even with treatment, patients of any age with MSUD remain at high risk for developing acute metabolic decompensation (metabolic crises) often triggered by infection, injury, failure to eat (fasting) or even by psychological stress. During these episodes there is a rapid, sudden rise in amino acid levels necessitating immediate medical intervention.
There are three or possibly four types of MSUD: the classic type; intermediate type, intermittent type, and possibly a thiamine-responsive type. Each of the various subtypes of MSUD have different levels of residual enzyme activity which account for the variable severity and age of onset. All forms are inherited in an autosomal recessive pattern.
Newborn screening for MSUD is performed throughout the US and in many other countries so that most such infants are detected through these programs. Where such screening is not available, infants with MSUD usually present with advancing neurological signs. Early diagnosis and treatment stabilizes the infants and, if well and consistently performed, can largely mitigate against serious long-term complications.
The symptoms and severity of MSUD varies greatly from patient to patient and largely depends upon the amount of residual enzyme activity.
Classic maple syrup urine disease is the most common and most severe form of MSUD characterized by little to no enzyme activity. Most infants with classic MSUD show subtle emerging non-specific symptoms within 2-3 days; these include poor feeding at bottle or breast and increasing lethargy and irritability. As the decline continues, the infant further disengages and then starts to show increasing focal neurologic signs including abnormal movements together with increasing hypertonia and spasticity progressing to seizures and coma. There may be temporary episodes of extreme hypotonia. In the end, central neurologic function fails with respiratory failure and death. By the time that the early symptoms have emerged, a distinctive odor of maple syrup may be detected in cerumen, sweat, and urine. This is derived from one of the BCKA organic acids derived from its respective BCAA that accumulate as the disorder spirals out of control. The odor cannot usually be detected during periods of metabolic stability.
Once the disorder has been treated and stabilized, there remains a life-long threat of sudden or gradual recurrent metabolic decompensation that results in a return of all the symptoms typical of untreated cases. Dietary intake of the BCAAs must be strictly controlled and monitored. But even without any change in dietary intake, metabolic crises can occur caused by an imbalance between the inherent residual activity of the enzyme and increased BCAAs release of protein from the tissues due to increased breakdown (catabolism). An increasing catabolic rate can occur insidiously or may develop rapidly during any metabolic stress, including infection, even if very mild, psychological or physical stress, trauma or fasting. These episodes are characterized by emergence of the symptoms that are typical in an untreated case and are due to elevated BCAAs, especially leucine and the three associated BCKAs. Every episode can turn into a metabolic crisis and must be treated as vigorously as any episode in a newborn. Individuals with classic MSUD may show a degree of intellectual limitation and may develop a variety of behavioral issues including attention deficient hyperactivity disorder (ADHD), impulsivity, anxiety and/or depression and seizures.
Additional complications with classic MSUD include generalized loss of bone mass (osteoporosis) that may predispose to fractures, and inflammation of the pancreas (pancreatitis). Some individuals may develop increased pressure in the skull (intracranial hypertension), which causes painful headaches that are sometimes associated with nausea and vomiting.
Intermediate MSUD is characterized by greater levels of residual enzyme activity than is seen with classic MSUD. The onset and symptoms of intermediate MSUD may be neonatal, but the majority of children are diagnosed between the ages of five months and seven years. Symptoms, when they occur, are similar to those of the classical form and may include lethargy, feeding problems, poor growth, ataxia, and acute metabolic crises that result in seizures, coma, brain damage, and, in rare cases, life-threatening neurological complications. It should be noted that Intermediate MSUD patients are susceptible to the same degree of neurologic complications and extreme acidosis as those with classic MSUD. The characteristic odor of maple syrup in the earwax, sweat and urine, is present. Some affected children may remain asymptomatic until later in life. Disease management principles are the same for both.
Intermittent MSUD is usually characterized by normal growth and intellectual development and affected individuals often can tolerate normal levels of protein in their diet. Symptoms are provoked by the same stressors as in classical MSUD. Thiamine-response MSUD responds to treatment with thiamine (vitamin B1). Thiamine plays a role in the BCAA enzyme complex. The symptoms and clinical course of thiamine-responsive MSUD resembles intermediate MSUD and rarely presents in the newborn 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 combination of thiamine with a partially-restricted protein diet.
While the majority of patients fall into the categories above, several families with multiple affected members have been identified who do not fit the criteria for any of the above subtypes. These unique patients are deemed unclassified MSUD.
It should be emphasized that in the presence of such apparently non-specific neurologic findings, the diagnosis of MSUD cannot be excluded by the absence of the maple syrup smell.
MSUD is caused by changes (mutations) in one of three different genes: BCKDHA, BCKDHB and DBT. Mutations in these genes result in absent or decreased activity of human branched-chain alpha-ketoacid dehydrogenase complex (BCKAD) enzymes. These enzymes are responsible for breaking down the branched chain amino acids leucine, isoleucine, and valine that are in all proteins. Accumulation of these amino acids and their toxic byproducts (ketoacids) results in the serious health problems associated with MSUD. The toxicity of these amino acids is restricted to leucine; indeed, extra valine and isoleucine are often given during treatment. Accumulation of their respective ketoacids results in the metabolic acidosis.
MSUD follows autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working 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 non-working 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 working genes from both parents is 25%. The risk is the same for males and females.
The estimated incidence in a general population is 1 in 185,000 live births. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Due to this “founder effect”, the disorder occurs with greater frequency among individuals in the Mennonite populations in the United States, where the incidence is estimated to be as high as in 1 in 380. MSUD occurs in the Ashkenazi Jewish population with an incidence estimated at 1:26,000 live births.
Many infants with MSUD are identified through newborn screening programs. Tandem mass spectrometry, an advanced newborn screening test that screens for more than 40 different disorders through one blood sample, has aided in the diagnosis of MSUD. As with all inborn errors, Infants with mild or intermittent forms of the disorder may have totally normal blood metabolites after birth and thus can be missed by newborn screening.
For patients who present later, the diagnosis usually comes at a time of metabolic decompensation when plasma amino acids and urine organic acids are normally tested at which time they are wildly abnormal. The presence of the maple syrup odor is so characteristic that this, together with appropriate symptoms, can be diagnostic enough to initiate therapy until the patient is transferred to an ICU. Initial confirmation is done by examination of plasma BCAAs and urine organic acids. The activity of the BCAA complex activity can be performed in white blood cells or cultured skin fibroblasts.
Prenatal detection cannot, at present, be done on maternal blood (looking for the fetal DNA). It is done either through chorionic villus biopsy or by amniocentesis. These analyses must be performed in a laboratory that is experienced in the relevant techniques. Molecular genetic testing for mutations in the BCKDHA, BCKDHB and DBT genes is also available to confirm the diagnosis and is necessary for purposes of carrier testing for at-risk relatives and prenatal diagnosis for at-risk pregnancies.
The treatment of classic, intermediate, intermittent, and thiamine-responsive MSUD has three chief components: 1. Lifelong therapy to maintain an acceptable diet; 2. Life-long maintenance of normal metabolic conditions including the levels of the BCAAs in the body; 3. immediate medical intervention for metabolic crises.
Individuals with MSUD must remain on a protein-restricted diet that limits the amount of branched-chain amino acids they can eat. 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 necessary for proper growth and development, but lack leucine, isoleucine and valine. Diet management is a constant balancing act between giving enough food, protein and BCAAs to provide for normal growth and development on the one hand and trying to ensure that the patient’s condition and biochemistry remain in a therapeutic range on the other. It is particularly important to limit the amount of leucine in the diet. The three amino acids are essential nutrients. They are added to the diet separately in small amounts depending upon their plasma levels. The amount of leucine, isoleucine and valine that can be tolerated by a child depends upon residual enzyme activity. Affected children must be regularly monitored to ensure that their diet is adequate and that amino acid levels remain within acceptable normal ranges.
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 follow the specialized diet strictly, the risk of metabolic crisis always remains. Episodes of metabolic crisis require immediate medical intervention to lower the levels of branched-chain amino acids, especially leucine, in the blood. Various techniques have been used to reduce plasma leucine levels including dialysis or a process in which blood is removed from the body and passed through a filter before being returned to the body (hemofiltration).
The aim of aggressive therapy for metabolic crises is to try and reduce, and then reverse, the increased protein catabolism that is the root cause of such episodes. This means that ANY method to increase calories, to reduce protein catabolism (for energy needs) may be helpful. This includes a high glucose intake with intravenous glucose, if necessary, supplemented by a “glucose-insulin drip” since insulin is known to enhance endogenous protein synthesis. Intravenous fat is another important source of calories. In addition, it is essential to provide all the other amino acids in amounts sufficient to permit new protein synthesis. This is done by the judicious use of intra GI drips or more usually, parenteral nutrition IV using solutions that lack leucine. 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, amino acids and other compounds are synthesized to form new muscle and other proteins as well as a huge variety of other compounds.
Other treatment is symptomatic and supportive.
Genetic counseling is recommended for affected individuals and their families.
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 normal foods. The new liver supplies enough enzyme activity to breakdown the three BCAAs. However, availability of a donor liver and the high cost are hurdles to this procedure. For those that do undergo liver transplantation, success rates are very high. More research is necessary to determine the long-term effects of liver transplantation on neurological development in individuals with MSUD.
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