Lesch-Nyhan disease with no HPRT1 gene mutation? / ¿Síndrome de Lesch-Nyhan sin mutación genética HPRT1?

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Fuzzy optimization for detecting enzyme targets of human uric acid metabolism.

MOTIVATION: Mathematical modeling and optimization have been used for detecting enzyme targets in human metabolic disorders. Such optimal drug design methods are generally differentiated as two stages, identification and decision-making, to find optimal targets. We developed a unified method named fuzzy equal metabolic adjustment to formulate an optimal enzyme target design problem for drug discovery. The optimization framework combines the identification of enzyme targets and a decision-making strategy simultaneously. The objectives of this algorithm include evaluations of the therapeutic effect of target enzymes, the adverse effects of drugs and the minimum effective dose (MED). RESULTS: An existing generalized mass action system model of human uric acid (UA) metabolism was used to formulate the fuzzy optimization method for detecting two types of enzymopathies: hyperuricemia caused by phosphoribosylpyrophosphate synthetase (PRPPS) overactivity and Lesch-Nyhan syndrome. The fuzzy objectives were set so that the concentrations of the metabolites were as close as possible to the healthy levels. The target design included a diet control of ribose-5-phospahate (R5P). The diet control of R5P served as an extra remedy to reduce phosphate uptake entering the purine metabolic pathway, so that we could obtain a more satisfactory treatment than obtained for those without a diet control. Moreover, enhancing UA excretion resulted in an effective treatment of hyperuricemia caused by PRPPS overactivity. This result correlates with using probenecid and benbromazone, which are uricosuric agents present in current clinical medications. By contrast, the Lesch-Nyhan syndrome required at least three enzyme targets to cure hyperuricemia.

Anestesia en un paciente con síndrome de Lesch-Nyhan / Anaesthesia in a patient with Lesch-Nyhan syndrome

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Self-injurious behaviour in young children with Lesch-Nyhan syndrome.

The early development of self-injurious behaviour in three young boys (aged 17, 25, and 30 months at start of study) with Lesch-Nyhan syndrome was examined by means of parental interviews and by direct observations completed at 3 to 4 monthly intervals over an 18-month period. Results suggest that the self-injury began in a different way from that of other young children with autism and/or developmental disabilities in that, from the start, self-injurious responses were sudden and violent, rather than emerging gradually over time. Drastic measures, such as removal of the teeth or provision of tooth guards, were often taken to prevent further tissue damage. Direct observations showed that the boys' self-injury occurred at lower rates, but their carers were highly concerned about the behaviour. Sequential analysis of the observational data indicated that on some occasions the children were more likely to self-injure during periods of low social interaction, suggesting that their self-injury may have been influenced by environmental factors. The theoretical and practical implications of these findings are discussed.

Germ-line gene modification and disease prevention: some medical and ethical perspectives.

There has been considerable debate about the ethics of human germ-line gene modification. As a result of recent advances in the micromanipulation of embryos and the laboratory development of transgenic mice, a lively discussion has begun concerning both the technical feasibility and the ethical acceptability of human germ-line modification for the prevention of serious disease. This article summarizes some of the recent research on germ-line gene modification in animal models. Certain monogenic deficiency diseases that ultimately might be candidates for correction by germ-line intervention are identified. Several of the most frequently considered ethical issues relative to human germ-line gene modification are considered in the context of professional ethics, parental responsibility, and public policy. Finally, it is suggested that there is merit in continuing the discussion about human germ-line intervention, so that this technique can be carefully compared with alternative strategies for preventing genetic disease.