PMC:1448208 / 32692-34524 JSONTXT

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The phenotypic behavior of homozygous mouse pups resembles symptoms seen in newborn classic MSUD patients. These include signs of neurologic dysfunction such as seizures, stupor, lethargy, loss of motor activity, and respiratory difficulties [1]. These neurologic symptoms may result from reduced levels of glutamate, glutamine, alanine, and other similar neuroactive amino acids, which are considered the culprit for MSUD encephalopathies in patients [1,37]. Finally, nearly all of the homozygous pups died within 72 hours of birth. This neonatal lethality is likely due to the accumulation of BCAA to neurotoxic levels, ketoacidosis, brain edema, dehydration, and malnutrition as observed in the MSUD calf [17] and in classic MSUD patients [1]. Heterozygous knockouts were normal and had normal levels of BCAA despite having approximately half of BCKDH enzymatic activity. From the characterization studies completed thus far, the null mutation mouse accurately represents a model of classic MSUD and appears to be a faithful model of the human disease with respect to several biochemical phenotypes 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