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>