Introduction

Maple Syrup Urine Disease song :O

link:http://www.youtube.com/watch?v=FSu_IHJ9Q0w

So...What is Maple Syrup Urine Disease?

Maple Syrup Urine Disease (MSUD) is a metabolic disease affecting branched chain amino acids. The 3 amino acids - valine, isoleucine and leucine (branched chain amino acids) is used to build proteins.




For people without MSUD, the 3 amino acids will be broken down and be used as energy when they are not used to build proteins. The 3 amino acids are normally broken down by 6 subunits that form a complex called Branched-chain alpha-ketoacid dehydrogenase (BCKD). 




People with MSUD have a mutation which causes a deficiency for one of the 6 subunits that forms BCKD. Therefore, the BCKD complex will not be formed and is unable to break down leucine, isoleucine and valine. This causes dangerously high levels of amino acids in the blood, destroying brain cells and can even lead to death if left untreated. 




Also, this disease is autosomal recessive. This means that both the parents must have the MSUD gene and the child must inherit the defective recessive gene from both parents to get the disease. 








How MSUD got its name - the accumulation of the 3 amino acids in the urine causes it to smell like maple syrup <-------- DELICIOUS!!




References

Genetic Science Learning Center (1969, December 31) Maple Syrup Urine Disease (MSUD). Learn.Genetics. Retrieved June 18, 2012, from http://learn.genetics.utah.edu/content/disorders/whataregd/msud/
Iobbi, L. P. (2012, June 8). Maple syrup urine disease (MSUD) . flipper e nuvola. Retrieved June 18, 2012, from http://flipper.diff.org/app/items/info/4499

Cause of MSUD

MSUD is caused by a mutation that results in a deficiency for one or more of the 6 subunits that make up BCKD complex (branched-chain alpha-keto-acid dehydrogenase). This creates a dysfunctional BCKD complex which is ineffective in breaking down the branched-chain amino acids in our body. (Leucine, Isoleucine and Valine).

WHAT IS THE BCKD complex? 

Branched-chain keto acid dehydrogenase (BCKD) is a multienzyme complex found in the inner membrane of mitochondria and is crucial in the metabolism of Leucine, isoleucine and valine amino acids. 




The complex consists of 6 subunits: branched-chain alpha-keto acid decarboxylase (E1) which is made up of 2 alpha subunits and 2 beta subunits, Dihydrolipoamide branched-chain transacylase (E2) and dihydrolipoamide dehydrogenase (E3).

The phosphorylation status of the E1a subunit affects the regulation of enzyme activity. BCKDC kinase (BDK) inactivates BCKDC and mitochondrial matrix resident type 2C phosphatase (PP2Cm) activates it.

Mutations

The most common mutations occur in the E1 complex.  




One example of a common mutation in the E1 complex is the mutation in the BCKDHA gene which encodes for the Alpha subunit of the complex.

The E1 complex is made up of 2 alpha subunits (from the gene BCKDHA) and 2 beta subunits. (from BCKDHB).

We will first cover the mutation of the BCKDHA gene, then the mutation of the BCKDHB gene.

BCKDHA:  The official name of the BCKDHA gene is the Branched chain keto acid dehydrogenase E1, alpha polypeptide.

BCKDHA gene is located from base pair 41,903,693 to base pair 41,930,909 on chromosome 19.




Most BCKDHA mutations change the single amino acids in the alpha subunit of the E1 complex.

The MOST COMMON amino acid mutation replaces the Tyrosine with Asparagine at position 438.

*note: The gene name is BCKDHA

This mutation disrupts the functionality of the BCKD complex and prevents it from breaking down the branched chain A.A. Deficiency of the alpha subunit of the BCKD complex causes Maple Syrup Urine Disease Type 1A, which is the MOST COMMON CAUSE OF MSUD.

BCKDHB: The official name of the BCKDHB gene is Branched chain keto acid dehydrogenase E1, beta polypeptide. BCKDHB gene mutation is similar to the BCKDHA mutation

The BCKDHB gene is located from base pair 80,816,343 to base pair 81,055,986 on chromosome 6. 

Most BCKDHB mutations insert or delete DNA in the gene. 

A special mutation is most common in people of Ashkenazi (eastern and central Europe) which consists of Jewish descent. This special mutation replaces the Arginine with Proline at position 183. 

This mutation disrupts the functionality of the BCKD complex and prevents it from breaking down the branched chain A.A. Deficiency of the beta subunit of the BCKD complex causes Maple Syrup Urine Disease Type 1B.

E2 complex: Dihydrolipoamide branched chain transacylase (E2) subunits are encoded by the DBT gene. Mutations in this gene lead to Maple Syrup Urine Disease Type 2.

E3 complex: Dihydrolipoamide dehydrogenase (E3) subunits are encoded by the DLD gene. Mutations in this gene lead to E3-deficient Maple Syrup Urine Disease. 

References

Gibson, L. R. (2001). Amino Acid Biosynthesis Inhibitors. Iowa State University. Retrieved July 12, 2012, from http://www.agron.iastate.edu/courses/Agron317/AA_inhibitors.htm
Brunetti-Pierri, N., Lanpher, B., Erez, A., Ananieva, E. A., Mohammad, I., Marini, J. C., . . . Lee, B. (1994). Phenylbutyrate therapy for maple syrup urine disease. Human Molecular Genetics, 20(4), 631–640.
Genetics Home Reference (2012, June 11). BCKDHA. Retrieved June 18, 2012, from http://ghr.nlm.nih.gov/gene/BCKDHA
Genetics Home Reference (2012, June 11). BCKDHB. Retrieved June 18, 2012, from http://ghr.nlm.nih.gov/gene/BCKDHB
Genetics Home Reference (2012, June 11). DLD. Retrieved June 18, 2012, from http://ghr.nlm.nih.gov/gene/DLD
Genetics Home Reference (2012, June 11). DBT. Retrieved June 18, 2012, from http://ghr.nlm.nih.gov/gene/DBT

What happens and symptoms

How does it affect patients with the disease?


Accumulation of leucine causes people to experience neurological symptoms
Accumulation of plasma isoleucine causes the presence of the maple syrup odor in the urine.






Symptoms


First few symptoms when the patients is fed protein shortly after birth
- Poor appetite
- weak suck
- weight loss
- high pitched cry
- urine that smells like maple syrup



MSUD causes patients to get sick easily. This is called metabolic crisis.
First few symptoms include
- extreme sleepiness
- sluggishness
- irritable mood
- vomiting 


If left untreated, other symptoms will appear
- Muscle tones alternates between rigid and floppy
- brain swelling
- seizures
- metabolic acidosis (high levels of acid in the blood)
- coma
- death




How does metabolic crisis happen?
- When the patient goes too long without food
- When the patient experience an illness or infection
- When the patient undergoes stressful events like surgery






Multiple metabolic crises may lead to permanent brain damage. 






References

Weiss, T. C. (2010, October 4). Maple Syrup Urine Disease (MSUD) - Facts and Information. Disabled World. Retrieved June 18, 2012, from http://www.disabled-world.com/disability/types/msud.php
Iobbi, L. P. (2012, June 8). Maple syrup urine disease (MSUD) . flipper e nuvola. Retrieved June 18, 2012, from http://flipper.diff.org/app/items/info/4499

Biochemistry of BCKD activity

The 3 amino acids valine, leucine and isoleucine are catabolized in many steps. 

First Step

Transamination using a single BCAA aminotransferase, with  α-ketoglutarate as the amine acceptor

As a result, 3 different α-keto acids are produced.

Second Step

These α-keto acids are oxidised using a common BCKD, yielding the 3 different CoA derivatives.

Isovaleryl-CoA is produced from leucine by these two reactions, alpha-methylbutyryl-CoA from isoleucine, and isobutyryl-CoA from valine.

 These acyl-CoA’s undergo dehydrogenation, catalyzed by three different but related enzymes, and the breakdown pathways then diverge.  

Leucine is ultimately converted to acetyl-CoA and acetoacetate; 

Isoleucine to acetyl-CoA and succinyl-CoA; and 

Valine to propionyl-CoA (and subsequently succinyl-CoA)

The final products of the catabolism of the 3 amino acids are fully oxidised via the TCA cycle.

So what happens when there is no BCKD or when there is dysfunctional BCKD?

The  α-keto acids will not be oxidised, causing incomplete catabolism of these amino acids. The final products acetyl-CoA and Succinyl-CoA will not be produced. This will disrupt the TCA cycle, creating less ATP and NADH for muscle.

Due to the incomplete catabolism of the animo acids, there will be a accumulation of Leucine, Isoleucine and Valine in the body.

Excessive levels of these amino acids in the body will lead to brain damage. 

References

The Alchemist Kitten (2009, November 19). The Citric Acid Cycle (aka, Krebs or TCA cycle). The Alchemist Kitten's Notebook. Retrieved June 18, 2012, from http://thealchemistkitten.wordpress.com/tag/tca-cycle/
Valine, Leucine and Isoleucine Degradation. (n.d.). Retrieved June 18, 2012, from http://pathman.smpdb.ca/pathways/SMP00032/pathway?level=2

Cure

So How do you cure MSUD?

1. DIETARY RESTRICTION OF THE BCAAs ( leucine,isoleucine and valine). This restriction must start from young to prevent potential brain damage. Babies with MSUD must eat a BCAA-free formula. As the patient grows up, he/she must carefully watch their diet and avoid HIGH PROTEIN foods such as meat or eggs. vegetarians pretty much!! :( 


2.However, if the 3 AAs' levels are still too high, patients can undergo dialysis to remove the excess BCAAs in their bodies or inject solutions into the patient's bloodstream to stimulate the usage of the excess BCAAs for muscle protein synthesis.


3. Another potential cure is GENE THERAPY. This would involve incorporating good copies of the gene into the patient, allowing the patient's cells to generate a functional BCKD protein complex and break down the excess AAs. However, it is not exactly safe because it might induce mutations elsewhere in the patient's body and cause other problems.

References

Genetic Science Learning Center (1969, December 31) Maple Syrup Urine Disease (MSUD). Learn.Genetics. Retrieved June 18, 2012, from http://learn.genetics.utah.edu/content/disorders/whataregd/msud/

Prevention

Currently, there is no prevention for this metabolic disorder..


However, genetic counseling is recommended for people who have a history of MSUD and still want to have children.


Also, all newborn babies are screened for MSUD via blood tests.
If a screen test show that the baby may have MSUD, another blood test for amino acid levels is done immediately to confirm the disease.






References
Haldeman-Englert ,MD, Wake Forest School of Medicine, Department of Pediatrics, Section on Medical Genetics, C., Salem, NC, W., & Zieve, MD, MHA, Medical Director, A.D.A.M., Inc., D. (2011, May 15). Maple syrup urine disease - Prevention. University of Maryland Medical Center. Retrieved June 18, 2012, from http://www.umm.edu/ency/article/000373prv.htm

The Different Types of MSUD

Classic: The most severe form of MSUD


Intermediate:
Severity not as bad as classic MSUD. Increased BCAA levels and neurological impairment present. 
Acute metabolic decompensation not present.<--- not as serious as classic 
BCKD activity 3% to 30% of normal

Intermittent: 
Normal early development, normal intelligence. BCAA levels normal. 
However under stress, acute metabolic decompensation might occur.
Initial symptoms of intermittent form appears between 5 months to 2 years in association with infection
BCKD activity 5% to 50% of normal

Thiamine Responsive:
Symptoms similar to intermediate form. BCAA levels are high and alloisoleucine is detectable in the plasma.
However, low protein diet and thiamine results in reduction of BCAA levels. Withdrawal of thiamine treatment cause the BCAA levels to become high again. However, thiamine treatment alone is not enough to lower levels of BCAA. Thiamine affects the BCAA levels in plasma


Maple Syrup Urine Disease Type 2: Dihydrolipoamide branched chain transacylase (E2) subunits are encoded by the DBT gene. Mutation in this gene will lead to dysfunctional E2 subunit, causing MSUD type 2.

E3-deficient Maple Syrup Urine Disease: Dihydrolipoamide dehydrogenase (E3) subunits are encoded by the DLD gene. Mutation in this gene will lead to dysfunctional E3 subunit, causing E-3-deficient MSUD.

References

King, M. W. (2012, February 1). Maple Syrup Urine Disease (MSUD). The Medical Biochemistry. Retrieved June 18, 2012, from http://themedicalbiochemistrypage.org/msud.php