Why does MSUD affect growth of the brain?
So, after reading the research article, why does MSUD affect the brain? First of all, in MSUD, since branched-chain alpha-ketoacid dehydrogenase is deficient, isoleucine, valine and mainly leucine cannot be broken down. Leucine will then accumulate in the brain and blood. Accumulation of branched-chain amino acid especially leucine, was found to inhibit the transport of other essential amino acids such as threonine, trytophan and tyrosine since they share the same transporter for brain access. Hence, the brain will lack these essential amino acids and paired with improper protein synthesis due to the disease, brain growth will be affected. Another proposed problem is that the accumulation of branched-chain ketoacid will inhibit the Krebs cycle and decrease energy production. ATP depletion will then lead to Na+/K+ ATPase failure and cell swelling.
A solution to leucine, MAYBE!
From the research article, it seems that scientists may have found an alternative to leucine, which is its isomer, norleucine. Apparently, this isomer competes with leucine for access to the brain. A diet with norleucine can actually increase the survival rate of the tested mice. In addition, norleucine might also inhibit branched-chain transaminase. In MSUD, there is a hypothesis that branched-chain ketoacid accumulation in neurons may induce formation of leucine and alpha-ketoglutamate over glutamate. A high alpha-ketoglutamate/glutamate ratio can disrupt mitochondrial glutamate, aspartate, malate and αKG transport resulting in Krebs cycle failure. Krebs cycle failure will then affect the growth of the brain as stated above. All in all, norleucine might be a solution to prevent leucine deficiency in the patient's diet!
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668944/
http://www.molbiolcell.org/content/11/5/1919.full
Are there any cures?
1. Liver transplant (based on the research article)
Domino liver transplant: a transplantation in which a multiorgan from donor A is being transplanted in patient B and B transplants an organ to patient C.
Patients who received liver transplants were found to have increased levels of branched-chain alpha-keto acid dehydrogenase to at least similar to those patients with mild MSUD. However, if the patient was already intellectually impaired, this liver transplant has no effect on it. Patients no longer require protein restricted diets and no longer had metabolic decompensation.
In the research article, scientists were testing for the effect of domino liver transplantation. Patient 1 had MSUD and patient 2 had hepatitis-C-induced cirrhosis and a hepatocellular carcinoma in the right lobe of the liver.
Donor for patient 1 was an unrelated woman who suffered brain death. So patient 1 received the liver from her and his liver is transplanted to patient 2 using the "piggy-back" method, where as much of the hepatic veins, portal vein and hepatic artery was conserved as much as possible, to be joined to recipient's veins.
After transplantation for both, concentration of amino acids were tested for both patients. For patient 1, his plasma concentration of BCAA decreased to near normal levels. There was no hint of metabolic , but is still at normal levels. He did not develop MSUD.
Conclusion: both patients are cured :D
Research article: http://onlinelibrary.wiley.com/doi/10.1002/lt.20744/pdf
2. Gene therapy
It is still being tested in labs and is not done on humans yet.They cultured cells from an MSUD patient. They are skin fibroblasts with a mutation in the E2 subunit of BCKDH. They expressed less than 2% of BCKDH activity as compared to normal cells. They used a retroviral vector to deliver normal E2 genes into the mutant cells. After the gene delivery, the level of BCKDH increased to 93% of normal cells.
After that, they decided to develop a MSUD mouse model to use for researching gene therapy. They mutated the E2 subunit of BCKDH by inactivating it. The mouse pups were normal at birth, but within hours they became sick and died. This is because there is a total loss of enzyme activity because the E2 gene is completely inactivated.
they solved this problem by creating a new transgenic line of mice, where the E2 gene is under control of tetracycline, so gene expression can be controlled by adding/removing tetracycline from drinking water. Since gene expression can be controlled to how MSUD is like in humnas (low enzyme activity, not total loss of activity), the mice do not die. So they can be kept alive for several months to test gene therapy on them.
They would still have to do a lot more tests on animals before gene therapy can be done on humans. But there is a possibility of gene therapy for humans with MSUD to happen someday.
Reference: http://www.msud-support.org/index.php?option=com_content&view=article&id=258%3Agene-therapy-for-msud-takes-a-big-step&Itemid=120
So, you must be wondering, what's the treatment for this disease?
First of all, a treatment is not a cure. So it's not permanent.
1. Acute decompensation of MSUD is usually treated by enteral feeding.
Acute means of short duration but severe.
Decompensation is the failure of the body to compensate for functional overload due to disease.
MSUD leads to the patient having episodes of illness or metabolic crisis, where the patient has an overload of BCAA (branched chain amino acids: leucine, isoleucine and valine) in their blood. Thus treatment must be administered quickly to reduce the amount of toxins in the blood. It is usually treated by feeding patients with amino acid mixtures free of BCAA through enteral feeding, where a nasogastric tube is used to deliver nutrients straight into the patient's body. The mixture is administered with carbohydrate polymers and lipids, and it promotes protein synthesis to reduce BCAA concentrations in blood. BCAA-free amino-acid mixtures are essential to facilitate the incorporation of excess BCAA into new proteins, thereby reducing its amount in the blood and avoiding its toxic effects.
2. Hemodialysis to remove BCAAs from the patient's blood
3. Dietary restriction. BCAA-free formulas
4. Metabolic decompensation may lead to brain edema, and this requires immediate attention in intensive care settings.
References
http://www.ncbi.nlm.nih.gov/books/NBK1319/
http://link.springer.com/content/pdf/10.1007%2Fs10545-012-9570-2
Here is a simple diagram that differentiates a normal person from one with MSUD.
I hope this will help u understand MSUD a little bit more!
Reference: http://nutritionfornormalpeople.com/2011/08/15/maple-syrup-urine-disease/
Okay guys! So here is a life story of Emily who has Maple Syrup Urine Disease (MSUD). (Click on the link below)
Emily's Life Story.
Sad story isn't it? Well, i'm glad that Emily had continued with her life although she was struck by such a disease. Good going! Alright, here are some points to note from her story itself.
1. MSUD gives a sweet smell to your urine and ear wax
2. Strict diet - Low protein food.
3. Metabolic rate for the three offending amino acids(Leucine, isoleucine and Valine) was only 5% the rate of normal.
4. Eating in small quantity holds MSUD at check. ( Less likely for bad reactions to occur)
5. Exercising helps patients with MSUD because it gets rid of the toxins.
6. The law protects people with disabilities including MSUD!!
Here is a picture of the MSUD formula that emily was talking about!
This diet powder is specially formulated for people with MSUD! It has no leucine, isoleucine or valine.
Has anyone been wondering how emily's brother had died from the disease?
Well, it seems that brain edema is the most dangerous complication of MSUD and is normally the cause of death of these patients during a metabolic crisis. Brain edema is also known as brain swelling. So what causes the swelling? It is actually not the amino acids that causes the swelling. Changes in the serum sodium level does. Here is the mechanics behind it. When serum sodium level decreases, the extracellular osmolarity will decrease as well. Since the intracellular omolarity is now higher, water will diffuse into the intracellular space to dilute the intracellular osmolites to the same level. Hence, intracellular water % would increase. However, the brain can only tolerate a certain % of brain swelling due to limitations by the skull. Beyond that, critical pressure develops and your life will be in danger. So that is how emily's brother died.
So there it is, the life story of Emily....
I hope all of you readers learnt something. =)
References: http://www.msud-support.org/index.php?option=com_content&view=article&id=79%3Acerebral-edema-a-maple-syrup-urine-disease&Itemid=5
http://www.cardinal.com/us/en/distributedproducts/ASP/MJ041802.asp?cat=med_surg
Hi guys!
So, what is Maple Syrup Urine Disease(MSUD)?
-Leucine, isoleucine and valine can only be broken down by 6 proteins that make up a complex called BCKD (branched-chain alpha-ketoacid dehydrogenase)
-People with MSUD have a deficiency in one of the 6 proteins, and therefore can't break down those 3 amino acids
Why is it so serious?
-dangerously high levels of the 3 amino acids will accumulate in the blood, which causes rapid brain cells degeneration and can lead to death if untreated
How do people get MSUD?
-mutation in gene
-autosomal recessive
most common defect: alpha subunit in BCKD complex
caused by mutation in gene on chromosome 19 (BCKDHA gene)
Types of MSUD:
1) Classic MSUD ( Most common) - Symptoms of this type is normally detected within 4-7 days in newborn infants
- Symptoms include
- Poor feeding
- Vomiting
- Poor weight gain
- Increasing lethargy (difficult to wake up)
- Characteristic burned sugar smell to urine
- Changes in muscle tone, muscle spasms, and seizures
2) Intermittent MSUD
- 2nd most common
- 5% to 50% Branched-chain alpha ketoacid dehydrogenase
- Exhibits classic MSUD symptoms during infections or illnesses.
- Otherwise, infants can still develop normally
3) Intermediate MSUD
- Affected individuals will still have about 3% to 30% of branched-chain alpha ketoacid dehydrogenase
- Can appear well during the neonatal stage.
- So they can live a more normal life, but symptoms can still occur at any age.
4) Thiamine-responsive MSUD
- As the name suggests, Administering thiamine to the patient and a controlled diet will improve their condition.
- It is similar to intermediate MSUD
5) E3-deficient MSUD
- Rarest.
- Patients have additional deficient metabolic enzymes.
- Symptoms similar to that of intermediate MSUD but with severe lactic acidosis
Diagnosis:
- Newborns are normally screened for MSUD in screening programs.
- It is detected based on physical symptoms, clinical features and by decreased levels of BCKAD enzyme activity causing accumulation of BCAAs, allo-isoleucine, and branched-chain ketoacids (BCKAs) in tissues and plasma.
- Blood test for amino acid levels for those with family history of MSUD.
Treatment:
- Life long low protein diet
- Thiamine for those with thiamine-responsive MSUD
Symptoms:
-loss of appetite
-fussiness
-urine that smells like maple syrup
If left untreated, condition worsen:
-seizures
-go into coma
-death
References:
http://rarediseases.about.com/od/rarediseases1/a/062004.htm
http://flipper.diff.org/app/items/info/4499
http://themedicalbiochemistrypage.org/msud.html
http://learn.genetics.utah.edu/content/disorders/whataregd/msud/
Hi everyone
We will be doing a study on maple syrup urine disease! Stay tuned for more posts! :D