Disease relevance of Lesch-Nyhan Syndrome

• Partial HPRT deficiencies are associated with gouty arthritis, while absence of activity results in Lesch-Nyhan syndrome (L-N) [1].
• A 15-year-old male with a long history of self-mutilation resembling the Lesch-Nyhan syndrome, but with normal uric acid levels, was treated with naloxone [2].
• Diagnoses in the patients included gout in seven; Sjögren syndrome in two; medullary sponge kidney in two; primary aldosteronism in two; and Lesch-Nyhan syndrome, hyperparathyroidism, glycogen storage disease type XI, Wilson disease, and pseudo-Bartter syndrome in one each [3].
• A rat neuroma cell line (B103 4C), deficient of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), was utilized as a model tissue in search for the biochemical basis of the Lesch-Nyhan syndrome (LNS) [4].
• Hypoxanthine impairs morphogenesis and enhances proliferation of a neuroblastoma model of Lesch Nyhan syndrome [5].

Psychiatry related information on Lesch-Nyhan Syndrome

• Complete hypoxanthine-guanine phosphoribosyl-transferase (HPRT) deficiency in humans results in the Lesch-Nyhan syndrome which is characterized, among other features, by compulsive self-injurious behavior [6].
• The Lesch-Nyhan syndrome is a rare inborn error of purine metabolism associated with hyperuricacidemia, mental retardation, and an insatiable urge for self-mutilation, especially of the extremities [7].

High impact information on Lesch-Nyhan Syndrome

• BACKGROUND: Lesch-Nyhan disease is a rare, devastating, X-linked recessive disorder of purine synthesis [8].
• A rationalization of the effects on stability and activity of naturally occurring single amino acid mutations of HGPRTase is presented, including a discussion of several mutations at the active site that lead to Lesch-Nyhan syndrome [9].
• Production of a model for Lesch-Nyhan syndrome in hypoxanthine phosphoribosyltransferase-deficient mice [10].
• The disruption of the balance between the functions of GABA, dopamine, and acetylcholine neurons in the extrapyramidal system probably accounts for some of the symptoms observed in the Lesch-Nyhan syndrome (e.g., choreoathetosis) [11].
• Lesch-Nyhan syndrome: low dopamine-beta-hydroxylase activity and diminished sympathetic response to stress and posture [12].

Chemical compound and disease context of Lesch-Nyhan Syndrome

• Phosphoribosylpyrophosphate overproduction, a new metabolic abnormality in the Lesch Nyhan syndrome [13].
• Patients with Lesch-Nyhan syndrome with virtually no hypoxanthine phosphoribosyltransferase activity demonstrate significantly low plasma activity of dopamine-beta-hydroxylase but normal basal levels of norepinephrine [12].
• Microencapsulated xanthine oxidase as experimental therapy in Lesch-Nyhan disease [14].
• A 24-hour urinary uric acid to creatinine ratio greater than 0.75 was found in six of nine patients with a partial deficiency of hypoxanthine-guanine phosphoribosyltransferase and in all patients with Lesch-Nyhan syndrome [15].
• Serial determinations of spinal fluid homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were made in four patients with the Lesch-Nyhan syndrome over a 5-year period [16].

Biological context of Lesch-Nyhan Syndrome

• To test the hypothesis that genes on the silent X chromosome reactivate as a consequence of ageing, we examined the X-linked hypoxanthine phosphoribosyltransferase (HPRT) locus in 41 women who are heterozygous for mutations at this locus, leading to severe deficiency of the enzyme (Lesch-Nyhan syndrome) [17].
• Thus, APRT-HPRT-deficient mice, which are devoid of any purine salvage pathways, show no novel phenotype and are not a model for the behavioral abnormalities associated with the Lesch-Nyhan syndrome as previously suggested [6].
• Molecular description of a hypoxanthine phosphoribosyltransferase gene deletion in Lesch-Nyhan syndrome [18].
• A slight decrease in the Km for phosphoribosylpyrophosphate was observed in the case of heterozygotes for the Lesch-Nyhan syndrome [19].
• Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency: identification of point mutations in Japanese patients with Lesch-Nyhan syndrome and hereditary gout and their permanent expression in an HPRT-deficient mouse cell line [20].

Anatomical context of Lesch-Nyhan Syndrome

• To derive an animal model for the Lesch-Nyhan syndrome, we have used cultured mouse embryonic stem cells, mutagenized by retroviral insertion and selected for loss of HPRT activity, to construct chimaeric mice [21].
• Phosphoribosylpyrophosphate synthetase is elevated in fibroblasts from patients with the Lesch-Nyhan syndrome [22].
• The purpose of this review is to summarize emerging evidence that the neurobehavioral features of Lesch-Nyhan disease (LND), a developmental disorder caused by congenital deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), may be attributable to dysfunction of the basal ganglia [23].
• Use of phytohaemagglutinin stimulated lymphocytes to study effects of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency on polynucleotide and protein synthesis in the Lesch-Nyhan syndrome [24].
• However, in neutrophils obtained from a patient with Lesch-Nyhan syndrome, which lacked hypoxanthine-guanine phosphoribosyl transferase activity neither hypoxanthine nor guanosine had any rescue effect [25].

Gene context of Lesch-Nyhan Syndrome

• HPRT-APRT-deficient mice are not a model for lesch-nyhan syndrome [6].
• In this research we demonstrate a model for Lesch-Nyhan disease by mutating the HPRT1 gene in human ES cells using homologous recombination [26].
• Finally, the possible implications in Lesch-Nyhan syndrome and Parkinson diseases of the inhibition of GTP cyclohydrolase I by guanine and 8-hydroxyguanine are discussed [27].
• In the present study, disruption of the MAOA gene was evaluated in males with mental retardation with and without a history of sexually deviant behavior, as well as normal controls, healthy males, and patients with other diseases (Parkinson disease, Lesch-Nyhan syndrome) [28].
• It is concluded that the HPRT and APRT activities measured in the pre-embryos studied here are likely to be maternally inherited, and that use of a direct assay for HPRT activity for the pre-implantation diagnosis of Lesch-Nyhan disease would be premature [29].

Analytical, diagnostic and therapeutic context of Lesch-Nyhan Syndrome

• A potential animal model for Lesch-Nyhan syndrome through introduction of HPRT mutations into mice [21].
• Preimplantation diagnosis of deficiency of hypoxanthine phosphoribosyl transferase in a mouse model for Lesch-Nyhan syndrome [30].
• Hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) is the locus of Lesch-Nyhan syndrome, the activator of the prodrugs 6-mercaptopurine and allopurinol, and a target for antiparasitic chemotherapy [31].
• We report the results of carrier and prenatal diagnosis for hypoxanthine guanine phosphoribosyltransferase (HPRT) deficiency, Lesch-Nyhan syndrome, by carrier testing of 83 women and prenatal analysis of 26 pregnancies [32].
• More specific examples of enzyme encapsulation include the microencapsulation of xanthine oxidase for Lesch-Nyhan disease; phenylalanine ammonia lyase for pheny, ketonuria and microencapsulation of multienzyme systems with cofactor recycling for multistep enzyme conversions [33].

References