Introduction to Maple Syrup Urine Disease (MSUD)

Maple syrup urine disease (MSUD) is a genetic metabolism disorder in which the body is unable to break down certain protein building blocks (amino acids) properly. Its name is derived from the distinctive ‘maple syrup-like’, sweet smell of the affected person’s urine.

MSUD is caused by a gene defect which results in a defective enzyme, the branched-chain α-ketoacid dehydrogenase (BCKD). Since BCKD is involved in the breakdown of the branched-chain aminoacids (BCAAs), leucine, isoleucine and valine, a deficiency in it will cause the amino acids and their byproducts to accumulate in the body. High levels of these chemicals in the body are harmful to thebrain and other organs, leading to other severe medical problems associated with MSUD.

The MSUD is characterized by symptoms like avoiding food, coma, feeding difficulties, lethargy, seizures, vomiting and the aforementioned, urine that smells like maple syrup. MSUD have varying degrees of severity, some milder, some more serious. In the most severe form, MSUD can cause brain damage when subjected to physical stress, like infection, fever or not consuming for a long period of time. However, even in the mildest form, repeated periods of physical stress can also cause mental retardation and high concentrations of leucine.

Methods of detection include the Plasma Amino Acid test and Urine Amino Acid test. A positive test will show signs of ketosis and excess acid in the blood (acidosis).

References:

Genetics Home Reference, 2008. Maple syrup urine disease. [online] Available at: <http://

ghr.nlm.nih.gov/condition/maple-syrup-urine-disease>

Medline Plus, 2011. Maple syrup urine disease. [online] Available at: <http://www.nlm.nih.gov/

medlineplus/ency/article/000373.htm>

Pubmed Health, 2011. Maple syrup urine disease. [online] Available at <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001411/>

The Medical Biochemistry Page, 2012. Introduction to Maple Syrup Urine Disease: MSUD. [online] Available at: < http://themedicalbiochemistrypage.org/msud.php/>

Types of Maple Syrup Urine Disease

The Maple Syrup Urine Disease (MSUD) is classified into 5 different types, depending on the amount and type of enzyme present in the affect individual. The 5 different types of MSUD consist of:

1) Classic

The Classic MSUD is the most severe type amongst the others and defined by the neonatal onset of encephalopathy. In classic MSUD, the branched-chain α-keto acid dehydrogenase (BCKD) level is less than 2% of normal. Hence, affected individuals are found to have elevated levels of the branched-chain amino acids (BCAAs- leucine, isoleucine and valine), especially leucine, in the blood, urine and cerebrospinal fluid. The presence of alloisoleucine (accumulated amino acid due to the inability to break them down) in the fluids is the diagnostic of MSUD.

Infants with the classic MSUD appears to be normal at birth but symptoms start developing rapidly by 4 to 7 days after birth. Such infants generally have low tolerance for BCAAs, thus a strict diet without protein must be followed. The first characteristic symptoms are lethargy and low interest in feeding. With the progression of the disease, further signs include weight loss and progressive neurological deterioration. Neurological signs will alternate from hypo- to hypertonia, and the extension of the arms will start to resemble decerebate posturing (refer to Fig. 1). At this time, the distinctive sweet-smelling urine is apparent.

Fig. 1: Decerebate Posturing

If the infants are left untreated, they will develop seizures, lapse into a coma and die. The prognosis of such untreated infants is poor with death occurring within the first few months of birth due to complications of metabolic crisis and neurological deterioration.

2) Intermediate

The Intermediate MSUD is a variant form of the classic MSUD. The difference between the 2 types is that for intermediate MSUD patients, they do not experience the severity of classic MSUD in the neonatal period. Affected individuals have a higher level of BCKD (3% to 30% of normal) and have a higher tolerance for BCAAs. Even so, they are still troubled with elevated levels of BCAAs in body fluids, and neurological deterioration. When sick or fasting, intermediate MSUD patients will react just like a classic MSUD patient. Treatment is similar for both classic and intermediate types of MSUD.

3) Intermittent

Individuals affected with the intermittent MSUD have a BCKD level of 5% to 50% of normal. Initially, these children will be asymptomatic and thus show normal early development with normal intellectual levels. During this period of time, the BCAA levels will remain normal. However, when sick or fasting, the BCAA levels increase, the distinctive maple syrup odour becomes apparent and the child is at risk for metabolic decompensation. Symptoms of the intermittent MSUD usually start to develop between 5 months and 2 years of age, in response to an infection or sudden increase in the intake of protein.

4) Thiamine-responsive

The symptoms of this more rare type of MSUD has a similar course of progress to that seen in the intermediate MSUD patients. The BCKD level is around 20% of normal and BCAAs levels are around 5 times of normal. The presence of alloisoleucine is also apparent in these patients. Following what the name implies, giving large doses of thiamine together with a low protein diet will increase enzyme activity, breaking down the BCAAs.

5) Dihydrolipoyl dehydrogenase (E3)- deficient

This form of MSUD is due to a deficient E3 component of the BCKD complex. The symptoms of this rare type of MSUD are similar to that seen in the intermediate MSUD patients. However, this form of MSUD is accompanied with severe lactic acidosis. Initially, for the first few months of life, the affected infants remain relatively normal. Between 2 and 6 months of age, persistent lactic acidosis starts to develop.

References:

MSUD Family Support Group, 2010. MSUD Classifications. [online]. Available at: <http://www.msud-support.org/index.php?option=com_content&view=article&id=307&Itemid=88>

The Medical Biochemistry Page, 2012. Introduction to Maple Syrup Urine Disease: MSUD. [online]. Available at:<http://themedicalbiochemistrypage.org/msud.php>

Drugs Information Online,. Diseases Reference Index «Decerebrate posture». [online] Available at: <http://drugline.org/ail/pathography/943/>

Treatments for Maple Syrup Urine Disease

The primary aims of treatment are to lower the concentration of toxic substances in the body and to prevent further accumulation.The mainstay in the treatment of MSUD is dietary restriction of branched-chain amino acids.

Acute treatment

Acute interventions are often required as soon as the diagnosis is made, or when a person already diagnosed seeks medical attention for acute neurological symptoms. They may be triggered by fasting, infections, injuries or other stressful situations, but in some cases the precipitating factor is not so obvious.

Administering glucose and minimising and regulating protein and amino acid intake helps in lowering the concentration of toxic substances in the body. Glucose stimulates insulin release, which in turn blocks protein degradation. Special amino acid solutions can also be administered intravenously. In acute situations the risk of brain oedema must be considered, as specific treatment is required. Blood sodium and glucose imbalances may occur, and there is a risk of developing pancreatitis. 

Dietary treatment 

This involves minimizing the intake of branched-chain amino acids and staying away from any potential attack triggers. In mild forms of the disease it is often sufficient to restrict protein intake. In intermittent forms, with normal levels of amino acid between attacks, dietary restrictions are sometimes not needed. However, for majority of the time, special formulas are required to compensate the nutrients lost as it contains all the essential amino acids except branched-chain amino acids. These formulas can be supplemented with low protein products and small, carefully measured amounts of natural protein. 

The aim is to maintain the level of branched-chain amino acids in the body within a safe and acceptable range. The diet of the patient should be adjusted according to the blood concentration of the amino acids.Nutrients such as vitamins, minerals and trace elements should also be supplied in sufficient amounts. It can be difficult to maintaining adequate levels of isoleucine and valine while striving to lower leucin to acceptable concentrations. Dietary suppliments may be necessary due to low valine and isoleucine levels which can cause nutritional deficiency symptoms. 

Liver transplantation

It has been shown to prevent future organ damage in MSUD, but does not reverse complications already present. The new liver can supply enough functional enzyme to regulate amino acid concentrations, even without dietary restrictions. 

All surgical procedures imply risks to individuals with MSUD and certain safety precautions should be taken, as both anaesthesia and the surgical intervention cause stress and trauma. Surgery should be carried out when the metabolic balance is as good as possible and certain safety precautions should be taken such as minimal preoperative fasting and administration of intravenous glucose administered throughout the surgery. Additionally  catabolism should be avoided before and after the surgery, blood concentration of amino acids monitored and the patient should be given special medicinal formulas as early as possible after the procedure.

References:

MSUD Family Support Group, 2009. Description and Treatment of Maple Syrup Urine Disease. [online]. Available at:< http://www.msudsupport.org/index.php?option=com_content&view=article&id=219%3Adescription-a-treatment-of-maple-syrup-urine-disease&Itemid=120> 

The New York Times, 2011. Maple Syrup Urine Disease. [online]. Available at:<http://health.nytimes.com/health/guides/disease/maple-syrup-urine-disease/overview.html>

Medscape Reference, 2012. Maple Syrup Urine Disease. [online]. Available at:<http://emedicine.medscape.com/article/946234-treatment>

Can It be Prevented?

Prevention

Genetic counseling is encouraged for people who want to have children and who have a family history of maple syrup urine disease.

If a screening test shows that your baby may have Maple Syrup Urine Disease (MSUD), a follow-up blood test for amino acid levels should be done right away to confirm the disease.

References: 

The New York Times, 2011. Maple Syrup Urine Disease. [online]. Available at:< http://health.nytimes.com/health/guides/disease/maple-syrup-urine-disease/overview.html>

Maple Syrup Urine Disease- It’s Not Sweet

Eight day old Anna was diagnosed with Maple Syrup Urine Disease (MSUD) also known as branched-chain ketoaciduria, a rare metabolic condition caused by her body’s inability to break down certain amino acids. From then on, Anna’s life changed drastically.

Anna has been made to follow a restrictive protein-free diet of no meats, dairy products, chocolate or soy. Every day, she has to consume a special high-calorie formula, which consists of mainly carbohydrates, to compensate for her missed nutrients.

“It is a hard life,” said Anna, a chocolate lover like any other girl.

The disease has also caused Anna to have a lower immunity than the normal people, causing her to be susceptible to diseases such as Urinary Tract Infection (UTI). When subjected to stress (e.g. infections, physical stress), it will trigger her 2,4-Dinitrophenylhydrazaine(DNPH) levels to elevate to high levels, causing her to miss classes.  

Additionally, due to brain damage caused by MSUD, she suffers from cognitive impairments. For Anna, this has led to speech, occupational and physical therapy over the years as well as placement in a special education classroom.  

Having her life dictated by numerous blood tests and the constant fear of having elevated amino acid levels that could lead to metabolic crisis has led Anna to struggle emotionally. Tears, anger and meltdowns have become more frequent.

“She’s starting to show the beginning signs of self-harm. Something seemingly insignificant will cause her to just fall apart. She is seeing a psychologist now, but so far I haven’t seen any changes. I just wish I knew what to do or say. I hate that she’s hurting inside, and it’s a hurt I don’t know how to fix.” said Paula Ruter, Anna’s mother.

Having to battle with her illness has not stopped Anna from living her life to the fullest. She competes in track and soccer through Special Olympics, also participates in the yearbook committee in her middle school and volunteers at an equine therapy ranch.

“I’m just an average normal kid, I am in a different class, I don’t care, I’m still a kid, I have a heart, bones and brains, I’m okay.” says Anna.

References: 

Central Michigan Life, 2010. Local Girl copes with rare maple syrup urine disease. [online]. Available at:< http://www.cm-life.com/2010/04/14/sweet-smell-of-courage-local-girl-copes-with-rare-maple-syrup-urine-disease/>

The Global Genes Project, 2012. Maple Syrup Urine Disease-It’s Not Sweet. [online]. Available at:< http://globalgenes.org/patient-stories-of-hope-and-inspiration-meet-anna/>

Ruter, Paula,. 2012. Our Transplant Journey. [online]. Available at:< http://www.ourtransplantjourney.net/>

Sweet Smell of Hope

At exactly 3 pm on September 22^nd 2012, Anna finally received the call of hope. At 7 pm, she was riding to the Children’s Hospital of Pittsburgh where she was taken to the transplant floor to ensure that the liver donated was a viable match.

“It was just a little panicking, a little, ‘Oh my gosh this is it—it’s really happening’ kind of moment,” Paula said. The operation finally began at about 9 a.m.

After 15 years of a non-protein diet, Anna remembers the first time she ate chicken. Similar to a brand new child, Anna has been trying new foods that she could never have eaten before the transplant. An entire world has been opened up to her.

Although Anna will always have medication and the need to watch out for rejection, she will no longer have to experience the potentially fatal effects of MSUD.

“Every morning for 15 years I mixed Anna’s medical formula. I don’t have to do that anymore, and that will take some getting used to.”

References: 

Transplant Families, 2012. The Morning Sun- Mt. Pleasant girl receives liver transplant to cure life-long disease. [online]. Available at:< http://transplantfamilies.org/blog/2012/10/01/the-morning-sun-mt-pleasant-girl-receives-liver-transplant-to-cure-life-long-disease/>

Ruter, Paula,. 2012. Our Transplant Journey. [online]. Available at:< http://www.ourtransplantjourney.net/>