What is Maple Syrup Urine Disease?

An inability to metabolize three common amino acids

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Maple syrup urine disease gets its name because the urine of affected infants has a distinctive sweet odor. Affected people are unable to metabolize certain amino acids (the basic building blocks of proteins) and these build up to toxic levels causing organ and tissue damage.

What are the Symptoms of Maple Syrup Urine Disease?

Maple syrup urine disease (MSUD) can be categorized into different forms based on the age of onset and the severity of symptoms. The classic form of MSUD is the most common and is associated with the most severe symptoms and an onset soon after birth. Other forms, such as intermediate MSUD, do not cause any symptoms until later in infancy or childhood, and generally only cause mild symptoms.

The symptoms of the classic form include sweet-smelling ear wax, urine and sweat due to the presence of sotolon – a compound that is spontaneously produced in affected individuals. Affected infants are poor feeders, irritable, lethargic, have irregular sleep patterns and a high-pitched cry. They can suffer from spasms, where the head, neck and spine arch backwards, involuntary muscle contractions and an abnormal posture. Affected children may show developmental delays and, if MSUD is left untreated, altered levels of consciousness (obtundation) can quickly escalate and permanent brain damage, seizures, coma and death can occur.

What Causes Maple Syrup Urine Disease?

MSUD is caused by defects in the BCKAD (branched-chain alpha-ketoacid dehydrogenase) complex. This enzyme is necessary for the degradation of three branched-chain amino acids – leucine, isoleucine, and valine. Genetic defects can occur in different components of the BCKAD complex, leading to different types of MSUD. Mutations in the BCKDHA gene (encodes the (E1) alpha subunit) result in MSUD type 1A. Mutations in the BCKDHB gene (encodes the (E1) beta subunit gene) cause MSUD type 1B. Mutations in the DBT gene (encodes the dihydrolipoyl transacylase (E2) subunit) cause MSUD type 2. Types 1A, 1B and 2 cause the same phenotype and are indistinguishable biochemically. The fourth component of the BCKAD complex is lipoamide dehydrogenase (E3), encoded by the DLD gene. Mutations in DLD result in a disorder with a different phenotype, known as Lipoamide Dehydrogenase Deficiency (E3) or Dihydrolipoamide Dehydrogenase Deficiency.

In the general population, MSUD has a disease frequency of approximately 1:185,000, and 45% of these cases are attributed to MSUD type 1A, 35% attributed to MSUD type 1B and the remaining 20% attributed to MSUD type 2. However, in people of Ashkenazi Jewish heritage, the disease frequency is significantly higher (1 in 38,000-50,000) and MSUD type 1B is the most common cause.

More than 40 mutations in BCKDHA and BCKDHB have been linked to MSUD types 1A and 1B, but only a select few have been identified in people of Ashkenazi Jewish heritage. This Jewish disease panel identifies the genetic mutations that have been most commonly detected in Jewish patients suffering from MSUD. These mutations are Y438N (c.1312T>A) in BCKDHA, and R183P (c.548G>C), G278S (c.832G>A) and E372X (c.1114G>T) in BCKDHB.

How is Maple Syrup Urine Disease Diagnosed?

An early diagnosis of MSUD is essential to prevent long-term damage or death. If MSUD is diagnosed at birth, affected people can live relatively normal lives by following strict dietary requirements. However, if a diagnosis is delayed, permanent brain damage, coma and death can quickly occur. MSUD is diagnosed by clinical, biochemical and genetic analyses.

Clinical features include sweet-smelling urine (detectable at 12 hours after birth), irritability and poor feeding (by 2-3 days), and lethargy, intermittent apnea and arching of the spine and neck (by 4-5 days). However, by the time some of these clinical symptoms are present, permanent brain damage has already occurred.

Biochemical analyses to diagnose MSUD include tandem mass spectrometry of a dried blood sample taken at 12-24 hours of age to identify elevated branched-chain amino acid levels and allo-isoleucine. Gas chromatography-mass spectrometry is used to detect elevated branched-chain hydroxyacids and keto acids in the urine at 48-72 hours of age. Enzyme activity of the BCKAD protein can also be evaluated from a variety of cells including lymphoblasts. Enzyme activity is usually less than 3% of the normal level in a person with classic MSUD and ranges from 3% to 40% in an individual with intermediate MSUD.

Molecular genetic testing for MSUD offers several advantages over diagnoses based on clinical and biochemical tests. Genetic testing is useful for the identification of carriers – unaffected individuals who have one defective copy and one normal copy of one of the genes in the BCKAD complex. Although carriers themselves will not suffer from any symptoms, they have a 50% chance of passing the defective gene to the next generation. If two carriers have a child, there is a 25% chance that the child will inherit two defective genes and suffer from MSUD. Genetic testing can be conducted during pregnancy, on samples obtained by chorionic villus sampling (CVS) or amniocentesis to determine a diagnosis for the baby before birth. This prenatal diagnosis allows for the best possible outcome, as dietary modifications can be made immediately after birth. Or alternatively, genetic testing can be conducted immediately at birth, before any of the biochemical or clinical features have occurred, once again allowing for immediate diet changes before organ damage occurs.

This Jewish disease panel identifies four mutations that occur in the majority of MSUD cases in Ashkenazi Jewish people. These mutations are Y438N in BCKDHA (this mutation accounts for all known Ashkenazi Jewish patients with MSUD type 1A), and R183P, G278S and E372X in BCKDHB.

How is Maple Syrup Urine Disease Treated?

Aside from a full liver transplant, there is no cure for MSUD. However, most patients can live relatively normal lives, if dietary modifications are made at a very young age and are strictly adhered to throughout their lifetime. Without any dietary modifications, MSUD is lethal at a young age.

Dietary restriction of the branched-chain amino acids (leucine, isoleucine and valine) is important as affected individuals are unable to metabolize these protein components. Babies are usually on special formula that doesn’t contain these amino acids (called BCAA-free powder) and as the child grows the diet should be adjusted to avoid high protein foods, such as dairy, meat, fish, nuts and eggs. Regular flour and dried beans also have branched-chain amino acids and must be avoided or strictly limited. If these dietary restrictions are not followed, severe metabolic crises and organ damage can quickly occur.

Regular blood tests to monitor the levels of branched-chain amino acids in the plasma are important to manage this disorder. Weekly monitoring is essential in infants, and ideally should continue at weekly interval throughout childhood and adolescence too. Dinitrophenylhydrazine (DNPH) is a useful reagent to allow patients to monitor their own urine amino acid levels at home and with timely detection, this home therapy is very effective in the management of MSUD (particularly the less severe intermediate form). A rare form of MSUD is known as thiamine-responsive MSUD and these patients can be treated with thiamine supplements, in conjunction with dietary restrictions.

Sickness due to a bacterial or viral infection or surgery can quickly trigger a metabolic crisis, and immediate medical care is required if there are any signs of an illness or metabolic crisis (including poor appetite, vomiting, lethargy or a fever).

Neurocognitive testing is recommended in children, adolescents and adults, especially if indicated by performance or behavioural problems. Further medical care and monitoring is often also required, including psychiatric support for individuals that show signs of ADHD, anxiety or depression.

Complete liver transplants are an effective therapy for classic MSUD and offer metabolic protection. The defective BCKAD enzyme that causes MSUD is produced in the liver, hence liver replacement provides a functional BCKAD enzyme and allows for the complete metabolism of the branched-chain amino acids. However, as with any organ transplant, there are significant risks associated with this procedure, primarily organ rejection, and patients most take medication for the rest of their life. Liver transplants do not reverse any brain or other organ damage or associated cognitive disabilities, but they do prevent the progression of neurocognitive impairment and prevent life threatening brain bleeds (cerebral edemas) associated with metabolic crises.

Recommended Links:
Edelmann L, Wasserstein MP, Kornreich R, Sansaricq C, Snyderman SE, Diaz GA. (2001) Maple Syrup Urine Disease: Identification and Carrier-Frequency Determination of a Novel Founder Mutation in the Ashkenazi Jewish Population. Am J Hum Genet. 69(4): 863-868.

Ferreira JC, Schreiber-Agus N, Carter SM, Klugman S, Gregg AR, Gross SJ. (2014) Carrier testing for Ashkenazi Jewish disorders in the prenatal setting: navigating the genetic maze. Am J Obstet Gynecol. 211(3): 197-204.

Strauss KA, Puffenberger EG, Morton DH. (2006) [Updated 2013 May 9]. Maple Syrup Urine Disease. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.