Introduction to Maple Syrup Urine Deficiency

Maple Syrup Urine Disease gets its name from the distinctive sweet odor of affected infants’ urine. This condition is characterized by poor feeding, vomiting, lethargy and development delay during early infancy. If it is left untreated, MSUD can lead to seizures, coma and even death.

To go in depth, it is an inherited autosomal recessive disorder in which it is caused by the mutation in four specific genes, known as Branched Chain Keto-Acid Dehydrogenase E1 Alpha Polypeptide (BCKDHA), Branched Chain Keto Acid Dehydrogenase E1 beta polypeptide (BCKDHB), Dihydrolipoamide Branched Chain Transacylase E2 (DBT) and Dihydrolipoamide Dehydrogenase (DLD). These four genes encodes the components of the branched-chain alpha-keto acid dehydrogenase (BCKAD) complex, which catalyzes the catabolism of the branched-chain amino acids (BCAAs), known as Leucine, Isoleucine and Valine.

The mutations in these 4 genes will reduce or eradicates the functionality of BCKAD complex and thus preventing the catabolism of the 3 proteins. As a result, accumulation of these three amino acids and their corresponding keto acids will lead to encephalopathy (degenerative brain damage), causing mental retardation, neurological difficulties in walking and speech, seizures, or death.


Reference : 

http://ghr.nlm.nih.gov/condition/maple-syrup-urine-disease
http://learn.genetics.utah.edu/content/disorders/whataregd/msud/

http://www.health.state.mn.us/divs/fh/mcshn/ncfu/cond/msud.htm

Types of MSUD

Classic MSUD is the most common type of MSUD. In classic MSUD, there’s little or no enzymatic activity taking place, usually having 2% of the enzyme activity present only. Infants with classic MSUD will show symptoms within the first several days of life. Generally, they will have poor tolerance for BCAAs, so protein should be strictly restricted in their diet.

Intermediate MSUD is a variation of the classic MSUD. Those with intermediate MSUD have a higher level of enzyme activity which approximately 3-8% from normal people. They can usually tolerate a greater amount of leucine. However, when ill or fasting, the child with intermediate MSUD reacts just like a child with classic MSUD. Management is similar for the intermediate and classic types of MSUD.

Intermittent MSUD is a milder form of the disease because there is much more enzyme activity compared to the previous types of MSUD (approximately 8-15% of normal). Often the child does not have symptoms until 12 to 24 months of age, usually in response to an illness or surge in protein intake. During episodes of illness or fasting, the BCAA levels elevate, the characteristic maple syrup (or burnt sugar) odor becomes evident, and the child can go into a metabolic crisis.

Thiamine-responsive MSUD is basically just what the name implies. Giving large doses of thiamine to the thiamine-responsive child will increase the enzyme activity which breaks down leucine, isoleucine and valine. In most cases only moderate protein restriction is needed for this more rare type of MSUD.

References:

http://www.msud-support.org/index.php?option=com_content&view=article&id=307&Itemid=88

Metabolic Pathway of MSUD

This is a more detailed pathway compared to the previous picture.

For MSUD patients, Leucine, Isoleucine and Valine will be catabolized by Branched-chain amino acid transaminases (BCAT) to alpha-ketoisocaproic acid, alpha-keto-beta-methylvaleric acid and alpha-ketoisovaleric acid respectively. However, for the second step of this pathway, it requires the Mitochondrial BCKAD complex (Branched Complex Keto Acid Dehydrogenase) to catabolize the three keto acid to Isovaleryl-CoA, alpha-methylbutyryl-CoA and Isobutyryl-CoA. These will cause the 2 components (amino acid and keto acid) to accumulate, causing health problems.

These CoAs are actually supposed to be included in this following pathway, producing important compounds such as Acetyl CoA and Succinyl CoA (intermediates in Krebs Cycle).

References:

http://flipper.diff.org/app/items/info/4499

http://www.sciencedirect.com/science/article/pii/S000991200600049X
http://www.socialstyrelsen.se/rarediseases/maplesyrupurinedisease

Symptoms of MSUD

The severity of these symptoms increases from Thiamine-responsive MSUD to Classic MSUD.

As soon as a MSUD baby is fed protein, the symptoms will start.
Some of the first symptoms are:
• Poor appetite
• Unable to drink from milk bottle
• Loss of weight
• High-pitched cry
• Urine smelling of maple syrup or burnt sugar

Babies with MSUD have episodes of illness called metabolic crisis. Some of the first symptoms of a metabolic crisis are:
• Extreme sleepiness
• Lacking alertness or energy
• Gets irritated easily
• Vomiting

If not treated, other symptoms can follow:

• Muscle tones between rigid and floppy
• Brain Swelling
• Seizures
• High levels of acidic substances in the blood (Metabolic Acidosis)
• Coma (sometimes leading to death)

Symptoms of a metabolic crisis often happen:
• Being in a hungry state for too long
• Illness or Infection
• Stressful events (eg. surgery)

Reference:

http://flipper.diff.org/app/items/info/4499

Treatments for MSUD

Dietary treatment

Minimise the intake of branched-chain amino acids and to avoid potential attack triggers. In mild forms of this disease, it is often sufficient to restrict protein intake. In most cases, replacing of dietary proteins with special formulas containing all important amino acids except for branched chain amino acids will be sufficient enough. These formulas can be supplemented with low protein products and small, carefully measured amounts of natural protein.

The goal of the treatment is to maintain the level of branched-chain amino acids in the body within a safe range.

Dietary management of MSUD may be quite tedious, and should be regulated and carried out with the assistance from experienced dietician from a medical centre for diagnosis and treatment of metabolic disorders.

Liver Transplant

Liver transplantation is another alternative option for treatment of MSUD. As the liver consists of new functioning enzymes, they are being used to replace those abnormal enzymes that causes MSUD and therefore a successful liver transplant will allow the patient to not have severe dietary restrictions which will in turn lessen the risk of having a recurrence of the symptoms of MSUD. Liver transplantation is a great solution to treat MSUD, however there are some risk factors to it as well.  For example, organ rejection from the patients, risk of surgery, anti-rejection medications are needed to be monitored in this liver transplant process. 

References:

http://www.msud-support.org/index.php?option=com_content&view=article&id=314%3Amedical-therapy-for-maple-syrup-urine-disease&Itemid=5

News Article: Doctors cure St. Louis boy's MSUD with liver transplant

At 7:30 a.m. on Feb. 3, 11-year-old Austin Sprock was on the operation table to receive a new liver.

It was less than 18 hours since he even knew he was on the waiting list.

The boy from High Ridge had received high priority because he had a rare condition, maple syrup urine disease, which prevented his body from properly processing protein.

MSUD is caused by the lack of an enzyme that breaks down certain types of amino acids, causing a toxic buildup in the bloodstream. The name comes from the sweet-smelling urine of infants with the disease.

Before last week, Austin could not eat meat, dairy, eggs, bread or a range of other foods. All his food was measured with a scale to make sure he did not exceed his protein limit for the day. He ate potatoes at every meal.

"I got really sick of them," Austin said.

A liver transplant is the only known cure for MSUD, but the risks scared Austin's parents from seeking the procedure until this winter, as his sicknesses grew more frequent and severe. A simple cold could touch it off.

"Over Christmas, Austin was extremely, extremely ill, almost to seizure level," mother Tina Sprock said. "We just couldn't do it anymore. We were afraid that one illness could cause permanent damage."

Austin wanted the operation. He just wanted to be able to eat normally.

His new liver gave him the enzymes to break down the branched-chain amino acids leucine, isoleucine and valine.

Upon his return home from St. Louis Children's Hospital, he ate his first ever piece of meat, a breakfast sausage.

"It tasted good," Austin said, speaking lethargically through the phone Sunday.

Tina Sprock said her son is recovering but has yet to regain his strength.

Post-surgery, he gets blood drawn twice a week from a central IV line in his chest, so doctors can check that there are no infections. Tina Sprock said Austin has gotten his blood drawn close to 700 times.

Austin is on heavy doses of immunosuppressant drugs to prevent his body from rejecting the new liver.

Tina Sprock said the 10 pills each morning and nine each evening can take him an hour to swallow. He doesn't like pills.

"It's hard," Austin said.

There won't be so many pills in coming months. After three months, most liver transplant patients are on only a couple different medicines, and by the end of a year, only one medicine, said Jeff Lowell, chief of Abdominal Organ Transplant at St. Louis Children's Hospital, who performed Austin's transplant.

Lowell said the transplant itself went perfectly, although Austin's sensitivity to the immunosuppressant drugs caused some problems with his kidney shortly after transplant. The dose was lowered, and the kidney quickly returned to normal.

"It's not uncommon that we have to fine tune things immediately afterward," Lowell said.

MU researchers have been studying MSUD in recent years.

Central Missouri's Mennonite community, which has a much higher rate of MSUD than the general population, has gained the attention of MU biochemistry professor Charlotte Phillips.

Reference:

http://www.themaneater.com/stories/2009/2/23/doctors-cure-st-louis-boys-msud-liver-transplant/