Maple Syrup Urine Disorder

AaSHAE Singletary

Maple Syrup Urine Disease (MSUD), a potentially life threatening and rare disorder, affects 1 in every 180,000 babies born annually. Caused by the inability to metabolize the amino acids leucine (leu), isoleucine, and valine in protein, the disease produces a maple syrup smell in the urine of diagnosed persons; thus, earning its name. (The smell is produced due to the build up of these chemicals in the blood) First discovered in 1954, by John Menkes, this recessive trait is produced by a gene defect passed down through various families. It consists of a classic form and several less common forms each varying in its strength and features. Although they differ, all forms of the disorder can be caused by mutations in any of the 6 genes used to build the branched-chain alpha-ketoacid dehydrogenase (BCKDHA) of Chromosome 19. Babies with MSUD often appear normal at birth but within 3-4 days can display other symptoms such as food avoidance, vomiting and fussiness. If left untreated, seizures occur and the baby will naturally slip into a coma shortly ending in death. Treatment of this disorder is managed by a strict diet free of the three harmful amino acids discussed earlier and must be performed early enough to avoid brain damage. Baby formula with these restrictions are available but as the child grows into adolescence, they must always monitor their diets, especially paying attention to avoidance of high proteins such as eggs, nuts and meat. In the most acute mode, MSUD can induce mental retardation as a result of physical stress. Fever, infection or lacks of sustenance are examples of this. Only discovered less than 60 years ago, much more is to be learned about this disease. MSUD research helps to take the guessing out of medical care and proper treatment. The following three article summaries are examples of such research that are helping scientists better understand this disease.
The effects of leu neurological damage associated with MSUD are still inadequately understood as are the breakdown of these neurotoxins associated with this event. A group of scientists in South America decided to further investigate this occurrence using 30-day-old male Wistar rats. Previous background revealed that leu provokes oxidative stress in rat brain homogenates by increasing the oxidation of lipids and by reducing the brain non-enzymatic antioxidant defense system. After incubating the rat cerebral cortex homogenates for an hour, various effects were observed when Leu was introduced to the equation. Leucine increased ThioBarbituric acid reactive substance levels, inhibited antioxidant enzyme activities and thiol in protein-SH content, and had little effect on the rate of DCFH oxidation and cyclic voltammeter studied. Results concluded that antioxidants such as vitamins E and C should be considered as a potential supplemental therapy for MSUD affected patients especially in predicaments when the levels of the brain chained amino acids increase dramatically.
The second article solely focused on the populations of Portugal. As mentioned earlier, Maple syrup urine disease is a recessive disorder of branched-chain amino acids metabolism with a worldwide frequency of 1/180,000 live newborns. Previously, the frequency of MSUD mutational occurrences within Portugal hadn’t been assessed. Based on the evaluation of the cases diagnosed by mass analysis, an incidence of 1/86,800 live newborns was estimated in Portugal, significantly higher than that of the world’s average population occurrence. This particular study evaluated 30 MSUD patients while also evaluating seventeen recognized mutations having been identified previously and seven being described for the first time. Their study “piggybacked” on the notion that the most common mutation identified was a C deletion in BCKDHA gene, already reported in the Spanish population. Amazingly enough, the same mutation was found in all patients of a Gypsy community from South of the country. This discovery brought to light a founder effect possibly connecting the high incidence of the disease in this community. Structural models of MSUD mutations have been constructed to understand their pathogenic effect for clarification and often to predict the severity of a mutation clinical consequence.
Finally, the third article was based on the idea that a proper remedy requires life-long dietary restriction and monitoring of branched-chain amino acids to avoid brain injury. The reason for conducting the study was the fact that in lieu of managing a diet, children commonly suffer metabolic decompensation as a result of catabolic stress associated with various illnesses tied to MSUD. The underlying system linked with decompensation and brain injury is still severely misunderstood. The scientists assessed biochemical, behavioral and neuropathological changes that occurred during encephalopathy in a group of model mice especially formulated for this study. The study revealed that intense brain leucine accumulation displaces other essential amino acids resulting in united mechanisms of neurotransmitter depletion and disruption of normal brain growth and development involving BCAA growth restriction and energy deprivation.
In conclusion, what heightens society’s need for MSUD awareness is the idea that death is a likely result and there’s still so much that we don’t understand about this disorder. What I found most interesting were the new ideas for future studies formulated as a result and the fact that you always learn something from an experiment. Regardless of if it’s what not to do next time, the scientists still advanced in their field of study. For example, a lot of scientists suggested that classic and intermediate mice models along with norleucine were very effective in studying potential treatment and brain injury. Another fascinating thought was the fact that inbreeding is the cause for the influx of MSUD in certain populations. Norleucine, an isomer of leucine used in experimental studies of protein structure and function, was also proposed as potential treatment to prevent encephalopathy in children with MSUD during catabolic stress. I chose to study this disorder for the same reason scientists are still conducting research, little is still known about it. With a name like maple syrup urine disorder, how could you not want to figure out what the disorder entails?
References
1. Bridi, R., Latini, A., Braum, C., Zorzi, G., Wajner, M., Lisis, E.;(2005). Evaluation of the mechanisms involved in leucine-induced oxidative damage in cerebral cortex of young rats. Free radical research; Vol. 39 Issue 1, p71-79, 9p

2. Quental, S., Gusmao, A., Rodriguez-Pombo, P., Ugarte, M., Vilarhino, L.,Amorim, A.;(2010). Revisiting MSUD in Portuguese Gypsies: evidence for a founder mutation. Molecular Genetics & Metabolism, Vol. 100, Issue 4,p385 387, 3p 3. Zinnanti, W., Lazovic, J.; Griffin, K., Skvorak, K.; Paul, H., Homanics, G.; (2009). Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease. Brain: A Journal of Neurology, Vol. 132, Issue 4, p903- 903, 1p