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As noted in Sandy Bulcher’s review of research supported by our group, we provided funding to Dr. Gerald Downes at the University of Massachusetts, Amherst for his work exploring the neurological consequences of BCAA toxicity in zebrafish.

In MSUD, a mutation in any one of the four genes that encode the Branched-Chain alpha-Ketoacid Dehydrogenase (BCKD) complex, the key enzyme in the metabolism of the branched-chain amino acids, leads to a buildup of these amino acids with profound neurological consequences including seizures, coma, cerebral edema (swelling of the brain), and death. How this occurs is not well understood, and we look to animal models to understand these processes.

Dr. Downes and his team developed a zebrafish model of MSUD, particularly useful because the embryos are transparent and are ready for study after only 4 days of incubation. They expected to observe an abnormal swimming pattern in those zebrafish embryos in which the BCKD gene was disrupted. They did not find this, a result which they attributed to an inadequate dosage of the chemical used to disrupt the gene.

Dr. Downes reports that new and very exciting geneediting technology has now emerged which sidesteps the dosage problem inherent in their previous experiments. It is now very possible to quickly and cheaply mutate target zebrafish genes to perform experiments. They are moving ahead, using this gene-editing strategy to investigate how branchedchain amino metabolism effects nervous system development and function. He also plans to expose the zebrafish to thousands of different chemical compounds and evaluate the impact they have on brain function, in the hopes of identifying substances which may be useful in preventing the neurological damage which occurs with elevated levels of BCAAs. Once they complete their initial experiments, they plan to submit a grant proposal to the National Institutes of Health.

We will continue to follow Dr. Downes’ research with interest.



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The MSUD Family Support Group is currently funding several research projects and we are proactively looking for researchers interested in developing new treatments or finding a cure for MSUD. Significant funding is necessary if we are to accomplish this goal.
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