Types of MSUD

MSUD is a autosomal recessive metabolic disorder. As it is recessive, it is a very rare disease to be inherited through generations. What it means by recessive is that the parent of the child with MSUD can be a carrier or infected, carrying 1 normal gene and 1 mutated gene. The mutated gene is recessive and is usually dominated by the normal gene. Only when both mutated genes from the mother and the father will the mutated gene not be dominated and thus cause MSUD.

There are 4 subtypes of MSUD genetic disorders :

1. Classic MSUD
2. Intermediate MSUD
3. Intermittent MSUD
4. Thiamine-responsive MSUD

These 4 generally differ by the degree of enzyme activity(BCKDH), severity and age for MSUD to occur. 

Classic MSUD : Most common type of the 4 and has little to none enzyme activity occuring. Having little enzyme activity places classic MSUD as the most severe form. It is present in infants a few days after birth. 

Intermediate MSUD : It is an uncommon type of variant from the class MSUD. It has higher enzyme activity occuring hence have more tolerance towards BCAA. It is present ranging from infants to adults. 

Intermittent MSUD : A milder version of classic MSUD by having more enzyme activity occuring. It occurs much later in the childhood stage of about 1-2 years. 

Thiamine-responsive MSUD : Another uncommon type of MSUD that increases enzyme acitivity with response from thiamine doses. Thiamine can thus lower the severity of MSUD in the patient with the help of diatery restrictions too. It usually occurs after infancy.

Even though generally it is these 4 types, there are rare exceptions like dihydrolipoamide dehydrogenase(E3) deficiency and others.

Reference : 

Healthline, 2014. Maple Syrup Urine Disease (MSUD) [Online]
Available at : <http://www.healthline.com/health/maple-syrup-urine-disease>

UIC, 2014. Biochemical Background [Online]
Available at : <https://www.uic.edu/classes/phar/phar332/Clinical_Cases/aa%20metab%20cases/MSUD/MSUD%20biochem%20background.htm>

MSUD Family Support Group, 2010. MSUD Classifications [Online]
Available at : <http://www.msud-support.org/index.php/overview/msud-classifications>

Biochemistry of MSUD

MSUD is the deficiency in branched-chain alpha-keto acid dehydrogenase(BCKDH). BCKDH is involved in catabolism of 3 specific amino acids - Valine, Leucine, Isoleucine.
 


These 3 amino acids are branched-chain amino acids(BCAA) and for their metabolic pathways, the last step where FAD is used to become FADH2. The initial few steps proceed as normal - formation of alpha-keto acids to branched-chain carboxylic acids.

Therefore, the resultant products are the accumulation of these BCAA and their corresponding alpha-keto compounds that they form.


References :

The Medical Biochemistry Page, 2014. Introduction to Maple Syrup Urine Disease : MSUD [Online]
Available at : <http://themedicalbiochemistrypage.org/msud.php>

UIC, 2014. Biochemical Background [Online]
Available at : <https://www.uic.edu/classes/phar/phar332/Clinical_Cases/aa%20metab%20cases/MSUD/MSUD%20biochem%20background.htm>

UT South Western, 2014. Maple Syrup Urine Disease (Branched-Chain Ketoaciduria) [Online]
Available at : <http://www4.utsouthwestern.edu/chuang_lab/MSUD.html>

Cures and Treatment for MSUD

The treatments and cures are form under the basis of lowering the concentration of the three amino acids, leucine, isoleucine and valine, which are at a dangerously high concentration level due the deficient BCKDH enzyme that is unable to break down the amino acids. These treatment and cures involve diets and surgery.

Dietary Therapy

Special Formula Powder for babies

This therapy involves dietary restriction of the amino acids leucine, isoleucine and valine. Dietary therapy must begin as early as possible to prevent brain damage and is lifelong. Babies or toddlers with MSUD should eat a specially formulated powder that does not contain any of the three amino acid. As the person grows up, the person does not need to eat the formulated powder and can eat more normal sustenance that everybody eats. However, the person still has to pay special attention to his or her diet, avoiding high protein containing foods such as meat,eggs and nuts. The amount of leucine intake is calculated on a individual basis by the following the measurement of the three plasma amino acids. If levels of the three amino acids are too high, an intravenous solution is adminsitered that helps to use up excess lecuine, isoleucine and valine in the body. People with a rare form of MSUD called'' thiamine-responisve MSUD'' may need to take thiamine supplements.

Liver Transplant surgery

This is an optional treatment for people with MSUD. It has shown to very effective if the surgery is successful, being able to cure patients of the MSUD symptoms. This is due the BCKDH enzyme being located in the liver is replaced by a donor's liver with the normal BCKDH enzyme. However, the liver transplant would not be able reverse the brain damage already caused but only stop it. Furthermore, the patient must now take medication for the rest of their lives to prevent their body form rejecting the donor. The risks of surgery should also be considered.

Reference:

STAR-G, 2014. Newborn Screening [Online] 
Available at: <http://www.newbornscreening.info/Parents/aminoaciddisorders/MSUD.html>
Learn.Genetics, 2014. Maple Syrup Urine Disease [Online]
Available at: <http://learn.genetics.utah.edu/content/disorders/singlegene/msud/>
Medscape, 2014. Maple Syrup Urine Disease Treatment & Managment [Online]
Available at: <http://emedicine.medscape.com/article/946234-treatment#a1130>

Living with MSUD

This is a personal look on how it is like living with Maple Syrup Urine Disease written by Nicholas Lorvin.

As a child, I thought that maple syrup urine disease meant that my urine smelled like maple syrup.I really didn't understand why it would smell that way. I have had MSUD since birth. I am one of the lucky ones healthy enough to survive under the conditions of this disease.It affects my physical ability as well as my mental ability.

Let's start with the mental aspect first. Mentally I am pretty smart when it comes to material that I am interested in, but the other stuff is hard for me to learn. It isn't that I can't learn the material, it just takes me a little bit longer to comprehend the basics; then there is no stopping me. Even if I don't do that same thing for a while, I can go back and still have the knowledge and ability to do it. I can succeed at it just like the first time.

Let's take it one more step. I wanted to be a professional basketball player when I was younger. I thought I would make it, but come to find out, I didn't have the height, and I wasn't good enough to play it for a living. So all I do now is play for fun, and I like it.

Then a few years ago, I took up drums for a hobby. For a while, I thought I wanted to do this as a profession. I soon realized, after a little talk and some guidance, that I wasn't cut out to be a drummer. It takes a lot of leg and arm power, which requires a lot of energy to perform during a long concert. I knew I was having a hard time with the drums, because I would be on count (drummer talk) for the first measure, and then I would either increase or decrease the speed making the song sound funny and wrong. It is hard for me to concentrate on one aspect so that it at least sounds right.

This mental block of mine goes back as far as I can remember, and it hurt me a lot in high school.If I didn't have MSUD, I could have pushed myself harder and gotten straight A's, but school was hard for me.I worked hard to do my best, but got mostly C's and D's and only occasionally B's and A's. I guess you could say that I am a little slower than people my own age, and I'm mad about it. All I can say is I'm going to work hard to increase my intelligence to where I can function as normal as possible.

Now about my physical ability, the amount of energy in my body is quickly used up, and I am often tired. If I don't eat or drink my milk (MSUD diet powder mixed in a blender), then I need to have something that has a lot of calories. It will make me feel okay until I get my formula. I can't eat a lot of foods that other people eat, but some of the foods they eat look totally disgusting. If I don't eat right, I could have to go to the hospital where they do a lot of tests and give me shots and an IV. Being stuck with this disorder, for what might be my whole life, I have to work hard to keep myself at my full potential and keep my health in top shape. I have had my slip-ups in the past and have paid dearly for them.

I am upset a lot because I see people, like musicians, doing so much more than me and having fun doing what they do. I wish I could do that, but I have limitations and have to accept them and enjoy the hobbies I like and can do.

I mentioned the drums earlier. I still play them, but I am not as serious about them anymore. I took up singing, which brought childhood memories of when I was ten years of age. I got four of my friends together to form a group that performed for our day camp.We imitated "The New Kids On The Block," because they were what everyone my age listened to. I had fun performing on stage then, and to this day I want to be on stage as a musician more than ever.

I have a lot of obstacles in my way, but I'm willing to overcome them with all my might. MSUD is one of the obstacles, but instead of overcoming it, I will work with it and hope to increase my mental and physical abilities.

Part of the MSUD phenomenon that I have to work with is that I tire quickly. Driving is hard on me.When driving from work to where I live, which is only twenty to thirty minutes each way, I get tired and have to pull over for a nap or just relax a bit. It's just that after a hard day, my body needs to relax, and that is the only way I can make it home. I work in the shoe department of a store part time and attend school two days a week.

School is hard now (it never was easy), but classes are getting harder as I proceed with college.I'm taking two classes at this time, English 80 and Speech 212. English is hard and very boring. Speech, on the other hand, is a blast. The teacher, who is a bit on the weird side, is trying to make us learn more about our inner-self; it is called Interpersonal Communications.

I have another class that starts soon and I'm really anxious for it. It is Golf. I love the sport. When I was younger, and my dad was alive, we would play it. I remember when he would be doing something in the garage, and I got his putter out and started to putt little rocks on the concrete; he got so mad at me. The memory makes me laugh.

MSUD will affect almost anything I do in life, and I have to work around my disorder and make it work for me and not against me. Thanks for reading this little piece I have written.

- Nicholas Lovrin

Reference:

MSUD Support, 2013. Sharing - MSUD: Nick's Story [Online] Available at: <http://www.msud-support.org/index.php/newsletter/31-volume-18-1/194-Sharing---MSUD--Nick%5C's-story>

What is MSUD? (Continued)

Maple syrup urine disease (MSUD), also known as:

branched-chain alpha-keto acid dehydrogenase deficiency

branched-chain ketoaciduria

ketoacidemia

It is a metabolism disorder passed down through families in which the body cannot break down certain parts of proteins. Urine in persons with this condition can smell like maple syrup.

MSUD results from a difficiency in an enzyme, branched-chain α-keto acid dehydrogenase (BCKDH), that is involved in the catabolism of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. A deficiency in BCKDH leads to an accumulation of those three amino acids and their corresponding branched-chain α-keto acids (BCKAs).

These three genes, BCKDHA, BCKDHB, DBT provide instructions for making proteins that work together as a BCKDH protein complex. The protein complex is essential for breaking down the amino acids leucine, isoleucine, and valine, which are present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs.

Mutations in any of these three genes reduce or eliminate the function of the protein complex, preventing the normal breakdown of leucine, isoleucine, and valine. As a result, these amino acids and their byproducts build up in the body. Because high levels of these substances are toxic to the brain and other organs, their accumulation leads to the serious health problems associated with maple syrup urine disease.

Symptoms of MSUD include:

Avoiding food

Coma

Feeding difficulties

Lethargy

Seizures

Urine that smells like maple syrup

Vomiting

MSUD can be examined and tested through plasma amino acid test and urine amino acid test. If tested positive, there will be signs of ketosis and excess acid in blood(acidosis). 

Reference : 

MedlinePlus, 2013. Maple syrup urine disease [Online] 

Available at: <http://www.nlm.nih.gov/medlineplus/ency/article/000373.htm>

Genetics Home Reference, 2013. Maple syrup urine disease [Online] 

Available at: <http://ghr.nlm.nih.gov/condition/maple-syrup-urine-disease>

The Medical Biochemistry Page, 2014. Maple Syrup Urine Disease [Online]

Available at: <http://themedicalbiochemistrypage.org/msud.php>

What is Maple Syrup Urine Disease(MSUD)?

MSUD is an inherited and rare metabolic disorder which is caused by a mutation in genes. It can cause a potentially fatal build up of amino acids in the blood. If left untreated, it can cause brain damage, physical disabilities and even death.

Globally it affects about 1 in every 185,000 live births which is very rare.

Symptoms include maple syrup smelling urine and earwax, poor feeding, vomiting, poor weight gain, lethargy and seizures.

Reference :
Dailymail, 2013.Saved with just hours to spare, the baby who was diagnosed with a deadly disease after being picked to have a new blood test [Online] 

Available at: <http://www.dailymail.co.uk/health/article-2285982/Maple-Syrup-Urine-Disease-Saved-just-hours-spare-baby-diagnosed-deadly-disease-picked-new-blood-test.html>

Baby cheating death..

Five-month-old baby, Habul Khatoon, was one of many babies chosen to be screened for five serious conditions. The test showed that Habul has the rare metabolic condition, MSUD, which causes a potentially fatal build up of amino acids in the blood. As soon as the results came in the seriously ill baby was rushed to hospital, where they discovered she was just hours from death.

 Her mother said: ‘It was a big shock to begin with. The nurses called me on the phone and then a few minutes later they were at the door. They called an ambulance straight away to take Habul into hospital. At this point she wasn't crying, she was lethargic and already in a coma-like state.’Her mother only realised there was something wrong when her daughter did not settle like normal babies. MSUD is so rare, and symptoms are initially so broad, that any number of ailments could have been causing the symptoms.

 ‘She was trying to cry but she wasn't able to. We didn't know what to do,’ said her mother. However, the child was saved because she took part in the newborn screening just six days after she was born.Two days later, when Habul was eight-days-old, the results came back showing that she had MSUD, a genetic disorder which stops the body breaking down parts of proteins called amino acids. The test identified high levels of the amino acid leucine in Habul’s blood, a condition which can lead to coma, brain damage and death if not treated.

Her mother said: 'She was a very lucky girl. She had to be taken straight to the Intensive Care Unit.’ Habul was put on dialysis to cleanse her blood and then began special feeds given via a feeding pump. After just 48 hours she came out of the coma-like state and could cry normally.

Reference :
Dailymail, 2013.Saved with just hours to spare, the baby who was diagnosed with a deadly disease after being picked to have a new blood test [Online] 

Available at: <http://www.dailymail.co.uk/health/article-2285982/Maple-Syrup-Urine-Disease-Saved-just-hours-spare-baby-diagnosed-deadly-disease-picked-new-blood-test.html>