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Paul M. Fernhoff, MD, FAAP, FACMG
Medical Director, Emory Medical Genetics

During the past several years, new treatments for some metabolic disorders have become available that eventually might be used to treat MSUD. This is a brief overview of two of these new treatments. One is called "Enzyme Replacement Therapy" [ERT] which is now used to treat several lysosomal storage disorders [LSDs]. LSDs include disorders such as Gaucher and Fabry Syndromes. Another technology called "Chemical Chaperone Therapy" [CCT] is in the early stages of trial for use in LSDs and other metabolic disorders.

Would either ERT or CCT work in MSUD? First a very brief reminder of what happens when someone has MSUD. You have heard many times that a person with MSUD lacks an enzyme called branched chain alpha-ketoacid dehydrogenase [BCKAD]. This enzyme is found in large amounts in the cells of our liver and kidneys. BCKAD helps our bodies break down leucine, isoleucine and valine, amino acids found in nearly all natural sources of protein.

What is an enzyme? An enzyme is a large protein made up of many different amino acids. The amino acids are carefully assembled in a certain order to make an enzyme.

This assembly occurs in a part of our cells called the endoplasmic reticulum [ER]. Think of the ER as an assembly room where enzymes and other proteins are made. Thousands of different enzymes are assembled in the ER. It’s a very busy part of the cell. After assembly, BCKAD leaves the ER, and goes into other compartments of the cell called the mitochondria, the power plants of the cell. Once inside, and in its proper place in the mitochondria, BCKAD breaks down leucine, isoleucine and valine to other chemicals and to energy that is needed by our body.

The main current treatment of MSUD is to limit the amount of leucine, isoleucine and valine in the diet of an MSUD affected individual. This prevents the build up of these amino acids and their toxic byproducts. It’s a treatment, but not a cure. Why can’t we just give someone with MSUD the missing BCKAD enzyme? Several problems. First you need to make large amounts of purified BCKAD. That’s difficult, but not impossible. Second how would you give it? If given by mouth, most of the BCKAD protein would break down in the acid of the stomach. Any BCKAD not broken down, still would not be absorbed intact from the intestines into the body.

What about injecting BCKAD directly into the blood stream? This is how ERT works to treat those individuals LSDs. The critical difference is that the enzymes that are used to treat people with LSDs are modified to be taken up directly by the certain cells and organs of their body that are most affected in the LSDs. If ERT is to work in MSUD, the BCKAD would need to first be modified so it could be taken up by cells in the liver and kidney, and also modified so that the BCKAD goes into the mitochondria, the cell’s power plants. It’s possible, but probably years away.

Of course liver transplantation has been successful in a number of patients with MSUD. A new liver, with normal BCKAD activity, effectively "cures" MSUD, although genetically they still have the disease. However given the risks of liver transplantation and the need for long-term immunosuppressant drugs, it is still being debated as to which MSUD patients are the best candidates for a liver transplant.

What about "CCT? This works differently. Many individuals who are affected with an LSDs or with MSUD do not actually lack the enzyme. They make an imperfect, but still workable enzyme, that is trapped inside the ER, the cell’s assembly room. Taken by mouth a drug, called a chemical chaperon, combines with the trapped enzyme and allows the trapped enzyme to escape the ER and get to another part of the cell where it can work. Would CCT work in MSUD? We know in some patients with MSUD, taking large doses of thiamine [Vitamin B1], helps to increase the activity of their imperfect BCKAD. This is a similar concept to CCT and it just might work in MSUD. Currently chemical chaperons are being studied in laboratories and animal models to determine their safety and how well they will work in different genetic/metabolic disorders. Once proven safe and effective, hopefully we may have another way to treat some patients with MSUD. Stay tuned!

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