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 certain enzymes (branched-chain alpha-keto acid dehydrogenase complex) 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 their various byproducts, accumulate abnormally throughout the body. In the classic, severe form of MSUD, the 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 “non-specific” symptoms are those of increasing neurological dysfunction and include lethargy, irritability and poor feeding, followed soon by focal neurological signs such as abnormal movements and increasing spasticity, and shortly thereafter, by convulsions and deepening coma. If untreated, progressive brain damage is inevitable and death ensues usually within weeks or months. The finding that is unique to MSUD is the emergence 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 disorder can be successfully managed through a specialized diet. However, even with treatment, both affected children and adults patients with MSUD remain at high risk for developing episodes of acute illness (metabolic crises) often triggered by infection, injury, failure to eat (fasting) or even by psychological stress. During these episodes there is a rapid, sudden spike 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. The various subtypes of MSUD have different levels of residual enzyme activity, severity, and age of onset. All forms are inherited as autosomal recessive traits.
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 the neurological signs in an advanced state. Early diagnosis and treatment stabilizes the infants and, if well performed, can largely mitigate against serious metabolic decompensations and long-term complications.
The symptoms and severity of MSUD at onset varies greatly from patient to patient and largely relate to 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 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 athetoid [so called “fencing and “cycling”] movements together with increasing hypertonia, spasticity and opisthotonus progressing to convulsions 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 symptoms have emerged, a distinctive odor of maple syrup may be detected in cerumen, sweat, and urine. This is derived from one of the organic acids that accumulate along with the BCAAs as the disorder spirals out of control.
Once the disorder has been treated and stabilized, there remains a life long threat of recurrent metabolic decompensation. Even without any change in dietary intake, these episodes occur due to increased breakdown of protein resulting from a number of metabolic stresses. Infection, psychological stress, fasting, trauma, fasting or indeed any major change in dietary habits all cause a change in the metabolism of protein resulting in more of the BCAAs requiring to be metabolized. These episodes are characterized by emergence of the symptoms that are typical in an acute untreated case and due to elevated BCAAs and metabolites. Every such episode has the potential to turn into a metabolic catastrophy 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.
Additional complications with classic MSUD include generalized loss of bone mass that may predispose individuals to fractures (osteoporosis), and inflammation of the pancreas (pancreatitis). Some individuals may develop a condition known as intracranial hypertension, in which increased blood pressure in the skull 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. Affected children may experience seizures and neurological impairment and developmental delays of varying degrees. Some experience feeding problems, poor growth and the characteristic odor of maple syrup in their earwax, sweat, and urine shortly after birth. Other affected children may remain asymptomatic until later in life. Intermediate MSUD patients are susceptible to the same neurologic conditions and extreme symptoms as those with classic MSUD. Due to the indefinite distinction between the classic and intermediate forms of MSUD, disease management principles are the same for both.
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 child experiences stress, does not eat, or develops an infection. Symptoms may include lethargy, the characteristic odor of maple syrup in the earwax, sweat and urine, and ataxia. Affected children 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 (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 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 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 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 protein-rich foods, [The BCAAs are the only amino acids that have a split main carbon chain]. 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 seems to be restricted to the leucine; indeed, extra valine and isoleucine are often given during treatment. Accumulation of their respective ketoacids results in metabolic acidosis.
MSUD is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits 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 altered gene and 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 is 25%. The risk is the same for males and females.
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.
MSUD affects males and females in equal numbers. Estimated incidence is 1 in 185,000 live births. Due to a 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 30 different disorders through one blood sample, has aided in the diagnosis of MSUD. Infants with mild or intermittent forms of the disorder may have totally normal blood amino acids after birth and thus can be missed by newborn screening.
In places where testing for MSUD is unavailable or where newborn screening fails to detect MSUD, a diagnosis may be suspected based upon symptomatic findings (lethargy, failure to thrive, neurologic signs or, during a metabolic crisis, odor of maple syrup in earwax, sweat or urine). Tests to diagnose MSUD may include urine analysis to detect high levels of keto acids (ketoaciduria) and blood analysis to detect abnormally high levels of amino acids.
An enzymatic diagnosis may be confirmed through analysis of white blood cells (lymphocytes) or cells taken from an affected individual’s skin. Early diagnosis, especially in suspected individuals, allows for management of asymptomatic infants before the onset of the usual clinical manifestations. Diagnosis through DNA testing is readily available and prenatal diagnosis is available.
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 two chief components: 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 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 that can be tolerated by a child varies based upon residual enzyme activity. Affected children must be regularly monitored to ensure that their 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 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).
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, various cellular components (including proteins) are combined (synthesized) to formed energy-rich compounds.
Other treatment is symptomatic and supportive. Early intervention is important in ensuring that children with MSUD reach their highest potential.
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 protein-rich foods. The new liver supplies enough of the enzymes needed to breakdown the three amino acids that accumulate in MSUD. However, availability of a donor liver and the high cost are hurdles to this procedure. For those that do undergo transplantation, success rates are very high. University of Pittsburgh Children’s Hospital and the Clinic for Special Children conducted a collaborative study involving 52 liver transplants between 2004 and 2013. Of these 52, 100% of the patients had disease-free survival and graft survival. More research is necessary to determine the long-term effects of liver transplantation on neurological development in individuals with MSUD.
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