Hypothesized deficiency of guanine-based purines may contribute to abnormalities of neurodevelopment, neuromodulation, and neurotransmission in Lesch-Nyhan syndrome
| Autor: | Katrice D. Long, Stephen I. Deutsch, John Mastropaolo, Richard B. Rosse, Judy Eller |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Pharmacology
Inosine monophosphate medicine.medical_specialty Hypoxanthine Phosphoribosyltransferase Lesch-Nyhan Syndrome Guanosine Biology medicine.disease Synaptic Transmission chemistry.chemical_compound Glutamatergic Endocrinology chemistry Biochemistry Hypoxanthine-guanine phosphoribosyltransferase Internal medicine Guanosine monophosphate medicine Animals Humans Pharmacology (medical) Neurology (clinical) Lesch–Nyhan syndrome Purine metabolism |
| Zdroj: | Clinical neuropharmacology. 28(1) |
| ISSN: | 0362-5664 |
| Popis: | The Lesch-Nyhan syndrome is a devastating sex-linked recessive disorder resulting from almost complete deficiency of the activity of hypoxanthine phosphoribosyltransferase (HPRT). The enzyme deficiency results in an inability to synthesize the nucleotides guanosine monophosphate and inosine monophosphate from the pu- rine bases guanine and hypoxanthine, respectively, via the ''salvage'' pathway and an accelerated biosynthesis of these purines via the de novo pathway. The syndrome is characterized by neurologic man- ifestations, including the very dramatic symptom of compulsive self- mutilation. The neurologic manifestations may result, at least in part, from a mixture of neurodevelopmental (eg, a failure to ''arborize''do- paminergic synaptic terminals) and neurotransmitter (eg, disruption of GABA and glutamate receptor-mediated neurotransmission) con- sequences. HPRT deficiency results in elevated extracellular levels of hypoxanthine, which can bind to the benzodiazepine agonist rec- ognition site on the GABAA receptor complex, and the possibility of diminished levels of guanine-based purines in discrete ''pools'' involved in synaptic transmission. In addition to their critical roles in metabolism, gene replication and expression, and signal transduction, guanine-based purines may be important regulators of the synaptic availability of L-glutamate. Guanine-based purines may also have im- portant trophic functions in the CNS. The investigation of the Lesch- Nyhan syndrome may serve to clarify these and other important neu- rotransmitter, neuromodulatory, and neurotrophic roles that guanine- based purines play in the central nervous system, especially the developing brain. A widespread and general deficiency of guanine- based purines would lead to impaired transduction of a variety of signals that depend on GTP-protein-coupled second messenger systems. This is less likely in view of a prominent localized path- ologic effect of HPRT deficiency on presynaptic dopaminergic projections to the striatum. A possible more circumscribed effect of a deficiency of guanine-based purines could be interference with modulation of glutamatergic neurotransmission. Guanosine has been shown to be an important modulator of glutamatergic neurotrans- mission, promoting glial reuptake of L-glutamate. A deficiency of guanosine could lead to dysregulated glutamatergic neurotransmis- sion, including possible excitotoxic damage. Unfortunately, although the biochemical lesion has been known for quite some time (ie, HPRT deficiency), therapeutically beneficial interventions for these affected children and adults have not yet emerged based on this elucidation. Conceivably, guanosine or its analogues and excitatory amino acid receptor antagonists could participate in the pharmacotherapy of this devastating disorder. |
| Databáze: | OpenAIRE |
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