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By Dr. William Zinnanti
SUNY Downstate Children’s Hospital, Department of Pediatrics

Dietary control of branched-chain amino acid (BCAA) intake is critical for protection of the brain in maple syrup urine disease (MSUD). Usually this is accomplished with life-long adherence to special diets. However, simple colds and flu-like illnesses can stimulate large accumulations of BCAA that can be difficult to manage. Recent work with MSUD mice has provided clues about future alternatives to enhance brain protection during illness and potentially loosen restrictions on dietary adherence.

Classic MSUD mice do not survive for more than three days after being born. We are very fortunate that Drs. Greg Homanics, Kristin Skvorak and Harry Paul, of the University of Pittsburgh, developed an intermediate MSUD mouse model as well a classic MSUD mouse and have allowed us to use them in our experiments. The intermediate MSUD mouse was developed with a small amount of enzyme activity allowing some to survive to adulthood. This allowed us to introduce a low BCAA diet for these mice that allows them to live a normal life span. Using both models we have been able to watch events that cause brain injury quickly in classic MSUD mice and more slowly in the intermediate mouse model. Giving intermediate MSUD mice a high protein diet results in the development of brain injury within a few days, similar to the human disease.

We found that brain injury occurs in both models when the amino acid leucine accumulates in the brain rapidly and is converted to an acid, known as alpha-keto-isokaproate (aKIC). This finding gave us an idea about how we might be able to stop the brain injury from occurring. Leucine travels into the brain via a specific transporter known as the large neutral amino acid transporter. An atypical amino acid, norleucine, can also occupy this transporter because it has the same structure as leucine only slightly longer. This amino acid is 'atypical' because it is not normally found in our bodies, it does not have a natural degradation pathway, and it is not used to make proteins. Therefore, a low quantity of norleucine may competewith leucine for access to the brain. If the amount of leucine going into the brain can be controlled, then perhaps the effect of too much leucine in the brain can be controlled as well.

In MSUD mice, norleucine works to prevent or delay brain injury. Intermediate MSUD mice placed on a high protein diet became encephalopathic and died within 2-3 days. When 5% norleucine was added to the high protein diet, most of the mice survived 5-8 days with a delay in onset of encephalopathy of at least 2 days. Lower amounts of leucine and aKIC were found in the brains of these mice. Surprisingly, only 1% norleucine given to the mothers of classic MSUD mouse pups provided a substantial increase in survival for these mice. Norleucine limited the amount of leucine found in the mother’s breast milk, resulting in a low-BCAA meal for the dependent pups. Additionally, norleucine transferred to the lassic MSUD pups reduced brain leucine levels as well.

Although these initial results are exciting and promising, norleucine has not been tested or approved for human use. An immediate goal is to begin clinical trials of norleucine, so it can eventually be provided as an additional tool for brain protection in human MSUD.

How might norleucine be used in human MSUD? The first goal for use of norleucine would be for children in acute encephalopathy or to prevent encephalopathy during flu-like illness when amino acids are known to accumulate. If norleucine works similarly in humans as in mice, we hope that administration of norleucine can delay encephalopathy as efforts are undertaken to control blood levels of BCAA. Additional goals for norleucine include a loosening of dietary restrictions as norleucine may be given as a supplement to prevent brain accumulation of BCAA. Norleucine may also potentially be used by mothers of MSUD infants to allow breastfeeding. Breastfeeding provides infants with their initial immunity from the mother in addition to nutrition. Unfortunately, breastfeeding is currently contraindicated in MSUD because of the inability to control BCAA content of the breast milk.

I am grateful for the collaboration with Dr. Homanics group and the MSUD family support group. Without the awareness and support this work would not be possible. Thank you.

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