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Dr. Huseyin Mehmet (London, England) is a lecturer in neurobiology at the Weston Laboratory, a division of Paediatrics, Obstetrics and Gynecology at the Imperial College of Science, Technology and Medicine, Hammersmith Hospital. He is doing research which may eventually have an important impact on infants with MSUD. He will be sharing more on his research as a speaker at Symposium 2002.

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by a deficiency in branched chain a-ketoacid dehydrogenase, leading to the accumulation of the branched chain amino-acids (BCAA), leucine, valine and isoleucine, and a corresponding increase in their a-keto-acid derivatives (BCKA), a-keto isocaproic acid, a-keto valeric acid, and a-keto-?-methyl-n-valeric acid levels. Acute neurological deterioration in children is often associated with increased plasma and cerebrospinal fluid (CSF) concentrations of BCAA and BCKA. Magnetic resonance imaging studies in MSUD children have confirmed extensive white matter loss and neuronal injury.

Although the underlying mechanisms of cellular toxicity are not known, there is direct evidence that BCKA affect mitochondrial enzymes resulting in impaired energy metabolism. It has recently been demonstrated by a number of laboratories, including our own, that reduced mitochondrial function can trigger cell death by apoptosis (a well conserved and highly regulated mechanism of cell death used for the removal of unnecessary, surplus, aged or damaged cells). From a therapeutic point, apoptosis is attractive since it can be inhibited at specific stages, in some cases resulting in tissue recovery. Since concentrations of BCAA are increased in the CSF, we hypothesized that pathological changes in the central nervous system of MSUD children may reflect a neurotoxic effect of BCAA and BCKA triggering inappropriate apoptosis of neural cells.

Our results (recently published in Molecular Biology of the Cell) showed that increased concentrations of MSUD metabolites, in particular a-keto isocaproic acid (KICA), specifically induced apoptosis in glial and neuronal cells in culture. Apoptosis was associated with a reduction in cell respiration and, significantly, KICA also triggered neuronal apoptosis in vivo following intracerebral injection into the developing rat brain. These findings suggest that in MSUD children, neurodegeneration may result, at least in part, from mitochondrial damage due to the accumulation of BCAA and BCKA.

In the future, we aim to focus on the precise mechanism of KICA toxicity. We have already ascertained that KICA-induced apoptosis is not accompanied by the release of cytochrome c from mitochondria to the cytosol, a common occurrence in apoptotic cells. This suggests that an alternative pathway for apoptotic execution exists. Our goal is to dissect this death pathway in vulnerable brain cells exposed to physiological combinations of BCAA and BCKA.

With this approach, we hope to identify appropriate therapeutic targets to inhibit or delay apoptosis. If this strategy succeeds, there are potential implications for cerebroprotection in MSUD children. The brains of babies are less than one fifth the size of adults'. Saving a few thousand brain cells in MSUD babies from apoptotic death would result in millions of cells in the adult that would otherwise have been wiped out by the accumulation of BCAA /BCKA. In this way, the neurological deficit associated with MSUD would be minimized.

Our findings may also have implications for disease management. Diet is critical in MSUD patients and the vast majority of patients manage the disease successfully by carefully restricting BCAA intake. Nevertheless, even with the most diligent care, children can sometimes undergo a metabolic crisis. These episodes can result in brain damage if undetected and untreated. Understandably, the constant threat can put immense strain on the families of MSUD children. If our preliminary findings are confirmed, anti apoptotic therapy may be a way to minimize cell damage resulting from BCAA/BCKA accumulation. We hope that the potential clinical applications of our research can offer these children and their families the chance of a better quality of life.

Melvin Carruth

This letter is a tribute to my brother Melvin Carruth! We believe he is one of the oldest living African Americans with Maple Syrup Urine Disease.

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A Child's Life

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