Record 1 of 21 in MEDLINE(R) on CD 2001/07-2001/11
TITLE: Molecular analysis of HPRT1(+) somatic cell hybrids derived from a carrier of an HPRT1 mutation responsible for Lesch-Nyhan syndrome.
AUTHOR: Rivero,-M-B; Olicio,-R; Lima,-C-R; Bonvicino,-C-R; Moreira,-M-A; Llerena,-J-C; Seuanez,-H-N
ADDRESS OF AUTHOR: Divisao de Genetica, Instituto Nacional de Cancer, Rio de Janeiro, Brazil.
SOURCE: Am-J-Med-Genet. 2001 Sep 15; 103(1): 48-55
INTERNATIONAL STANDARD SERIAL NUMBER: 0148-7299
PUBLICATION YEAR: 2001
LANGUAGE: English
COUNTRY OF PUBLICATION: United-States
ABSTRACT: Heterozygous carriers of HPRT1 mutations responsible for Lesch-Nyhan syndrome can be detected by analysis of somatic cell hybrids derived from peripheral blood lymphocytes and Hprt1-negative cells of rodent origin followed by selection in culture medium containing hypoxanthine, aminopterine, and thymidine (HAT). The parental origin of the X chromosome containing the normal HPRT1 allele in HPRT1(+) hybrid cell lines can be determined by molecular haplotyping attributable to highly polymorphic X-linked markers. We used this procedure to study a presumed carrier whose paternal active X chromosome always segregated in the cell hybrids derived from her. Conversely, her maternal X chromosome was systematically absent in most cell hybrids, or when present, it was inactive and coexisted with an active, paternal X chromosome. These results clearly demonstrated that the proband was a heterozygous carrier of a mutation responsible for HPRT1 deficiency. Copyright 2001 Wiley-Liss, Inc.
MAJOR MESH DESCRIPTORS: *Heterozygote-; *Hypoxanthine-Phosphoribosyltransferase-genetics; *Lesch-Nyhan-Syndrome-genetics
MINOR MESH DESCRIPTORS: Adult-; DNA-genetics; Family-Health; Haplotypes-; Heterozygote-Detection-methods; Hybrid-Cells; Hypoxanthine-Phosphoribosyltransferase-deficiency; Lesch-Nyhan-Syndrome-enzymology; Lesch-Nyhan-Syndrome-pathology; Mutation-; X-Chromosome-genetics
CHECKTAGS: Animal; Case-Report; Female; Human; Support,-Non-U.S.-Gov't
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: genetics; methods; deficiency; enzymology; pathology
CAS REGISTRY NUMBER OR EC NUMBER: 9007-49-2; EC 2.4.2.8
NAME OF SUBSTANCE: DNA; Hypoxanthine-Phosphoribosyltransferase
SUBSET: Index-Medicus
UPDATE CODE: 20011004
ACCESSION NUMBER: 21446337
RECORD FEATURES: ABSTRACT (AB)
Record 2 of 21 in MEDLINE(R) on CD 2001/07-2001/11
TITLE: Investigation of the functional role of active site loop II in a hypoxanthine phosphoribosyltransferase.
AUTHOR: Lee,-C-C; Medrano,-F-J; Craig,-S-P 3rd; Eakin,-A-E
ADDRESS OF AUTHOR: Laboratory of Molecular Parasitology and Drug Design, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7360, USA.
SOURCE: Biochim-Biophys-Acta. 2001 Jul 27; 1537(1): 63-70
INTERNATIONAL STANDARD SERIAL NUMBER: 0006-3002
PUBLICATION YEAR: 2001
LANGUAGE: English
COUNTRY OF PUBLICATION: Netherlands
ABSTRACT: Hypoxanthine phosphoribosyltransferases (HPRTs) are of biomedical interest because defects in the enzyme from humans can result in gouty arthritis or Lesch-Nyhan syndrome, and in parasites these enzymes are potential targets for antiparasite chemotherapy. In HPRTs, a long flexible loop (active site loop II) closes over the active site during the enzyme catalyzed reaction. Functional roles for this loop have been proposed but have yet to be substantiated. For the present study, seven amino acids were deleted from loop II of the HPRT from Trypanosoma cruzi to probe the functional role of this active site loop in catalysis. The mutant enzyme (Deltaloop II) was expressed in bacteria, purified by affinity chromatography, and kinetic constants were determined for substrates of both forward (purine salvage) and reverse (pyrophosphorolysis) reactions catalyzed by the enzyme. Loop II deletion resulted in moderate (0.6-2.7-fold) changes in the Michaelis constants (K(m)s) for substrates other than pyrophosphate (PP(i)), for which there was a 5.8-fold increase. In contrast, k(cat) values were severely affected by loop deletion, with rates that were 240-840-fold below those for the wild-type enzyme. Together with previously reported structural data, these results are consistent with active site loop II participating in transition-state stabilization by precise positioning of the substrates for in line nucleophilic attack and in the liberation of PP(i) as a product of the salvage reaction.
MAJOR MESH DESCRIPTORS: *Hypoxanthine-Phosphoribosyltransferase-metabolism; *Trypanosoma-cruzi-enzymology
MINOR MESH DESCRIPTORS: Binding-Sites; Catalysis-; Diphosphates-metabolism; Gene-Deletion; Guanine-metabolism; Hypoxanthine-metabolism; Hypoxanthine-Phosphoribosyltransferase-chemistry; Hypoxanthine-Phosphoribosyltransferase-genetics; Inosine-Monophosphate-metabolism; Kinetics-; Models,-Molecular; Mutation-; Phosphoribosyl-Pyrophosphate-metabolism
CHECKTAGS: Animal; Support,-U.S.-Gov't,-P.H.S.
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: metabolism; chemistry; genetics; enzymology
CAS REGISTRY NUMBER OR EC NUMBER: 0; 131-99-7; 68-94-0; 73-40-5; 7540-64-9; EC 2.4.2.8
NAME OF SUBSTANCE: Diphosphates; Inosine-Monophosphate; Hypoxanthine; Guanine; Phosphoribosyl-Pyrophosphate; Hypoxanthine-Phosphoribosyltransferase
CONTRACT OR GRANT NUMBERS: AI38919AINIAID; AI45021AINIAID
SUBSET: Index-Medicus
UPDATE CODE: 20010927
ACCESSION NUMBER: 21369432
RECORD FEATURES: ABSTRACT (AB)
Record 3 of 21 in MEDLINE(R) on CD 2001/07-2001/11
TITLE: Ocular motor dysfunction in Lesch-Nyhan disease.
AUTHOR: Jinnah,-H-A; Lewis,-R-F; Visser,-J-E; Eddey,-G-E; Barabas,-G; Harris,-J-C
ADDRESS OF AUTHOR: Department of Neurology, Johns Hopkins Hospital, Baltimore, MD 21287, USA.
SOURCE: Pediatr-Neurol. 2001 Mar; 24(3): 200-4
INTERNATIONAL STANDARD SERIAL NUMBER: 0887-8994
PUBLICATION YEAR: 2001
LANGUAGE: English
COUNTRY OF PUBLICATION: United-States
ABSTRACT: Eye movements were assessed in 22 patients with varying degrees of hypoxanthine-guanine phosphoribosyltransferase deficiency. Ocular motility was clinically normal in seven patients with moderate enzyme deficiency but grossly abnormal in 15 patients with severe enzyme deficiency. In patients with severe deficiency, fixation was interrupted by frequent unwanted saccades toward minor visual distractions. Voluntary saccades were associated with an initial head movement and/or eyeblink in all of these patients. When head motion was prevented, voluntary saccades were often delayed and sometimes absent. In contrast, saccade speed, reflexive saccades, and other reflexive eye movements appeared clinically normal. Four patients with severe enzyme deficiency also experienced mild blepharospasm, and two had ocular tics. These disturbances of ocular motility are consistent with dysfunction of the basal ganglia or its connections with ocular motor centers in the prefrontal cortex or midbrain.
MAJOR MESH DESCRIPTORS: *Lesch-Nyhan-Syndrome-complications; *Ocular-Motility-Disorders-complications
MINOR MESH DESCRIPTORS: Adolescence-; Adult-; Child-; Fixation,-Ocular-physiology; Ocular-Motility-Disorders-diagnosis; Ocular-Motility-Disorders-physiopathology; Saccades-physiology
CHECKTAGS: Female; Human; Male; Support,-U.S.-Gov't,-P.H.S.
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: physiology; complications; diagnosis; physiopathology
CONTRACT OR GRANT NUMBERS: HD33095HDNICHD; K0801985PHS
SUBSET: Index-Medicus
UPDATE CODE: 20010823
ACCESSION NUMBER: 21197784
RECORD FEATURES: ABSTRACT (AB)
Record 4 of 21 in MEDLINE(R) on CD 2001/07-2001/11
TITLE: [The effect of risperidone on the self-mutilation of Lesch-Nyhan syndrome]
AUTHOR: Saito,-Y; Yamashita,-S; Kaneko,-K; Kimura,-S; Osawa,-M
SOURCE: No-To-Hattatsu. 2001 May; 33(3): 281-2
INTERNATIONAL STANDARD SERIAL NUMBER: 0029-0831
PUBLICATION YEAR: 2001
LANGUAGE: Japanese; Non-English
COUNTRY OF PUBLICATION: Japan
MAJOR MESH DESCRIPTORS: *Dopamine-Antagonists-therapeutic-use; *Lesch-Nyhan-Syndrome-drug-therapy; *Risperidone-therapeutic-use; *Self-Mutilation-drug-therapy
MINOR MESH DESCRIPTORS: Child-
CHECKTAGS: Case-Report; Human; Male
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: therapeutic-use; drug-therapy
CAS REGISTRY NUMBER OR EC NUMBER: 0; 106266-06-2
NAME OF SUBSTANCE: Dopamine-Antagonists; Risperidone
SUBSET: Index-Medicus
UPDATE CODE: 20010719
ACCESSION NUMBER: 21283975
Record 5 of 21 in MEDLINE(R) on CD 2001/01-2001/06
TITLE: Decelerated rate of dendrite outgrowth from dopaminergic neurons in primary cultures from brains of hypoxanthine phosphoribosyltransferase-deficient knockout mice.
AUTHOR: Boer,-P; Brosh,-S; Wasserman,-L; Hammel,-I; Zoref-Shani,-E; Sperling,-O
ADDRESS OF AUTHOR: Felsenstein Medical Research Center, Rabin Medical Center, Petah-Tikva, Israel.
SOURCE: Neurosci-Lett. 2001 Apr 27; 303(1): 45-8
INTERNATIONAL STANDARD SERIAL NUMBER: 0304-3940
PUBLICATION YEAR: 2001
LANGUAGE: English
COUNTRY OF PUBLICATION: Ireland
ABSTRACT: Lesch-Nyhan syndrome (LNS), caused by the complete deficiency of hypoxanthine phosphoribosyltransferase (HPRT), is characterized by a neurological deficit, the etiology of which is still unclear. Evidence has accumulated indicating that it reflects dopamine deficiency associated with defective arborization of dopaminergic dendrites. We monitored the differentiation in vitro of dopaminergic neurons, cultured from HPRT-deficient knockout mice. The HPRT-deficient dopaminergic neurons exhibited a decelerated rate of outgrowth of dendrites in comparison to that of control neurons resulting, after 8 days in culture, in 32% smaller average total length of dendrites per neuron (P<0.025). The results suggest that the abnormal dendrite outgrowth in LNS reflects a defective developmental process.
MAJOR MESH DESCRIPTORS: *Brain-physiology; *Dendrites-physiology; *Dopamine-deficiency; *Hypoxanthine-Phosphoribosyltransferase-deficiency
MINOR MESH DESCRIPTORS: Cells,-Cultured; Lesch-Nyhan-Syndrome-physiopathology; Mice-; Mice,-Inbred-C57BL; Mice,-Knockout; Neurons-physiology
CHECKTAGS: Animal; Support,-Non-U.S.-Gov't
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: physiology; deficiency; physiopathology
CAS REGISTRY NUMBER OR EC NUMBER: 51-61-6; EC 2.4.2.8
NAME OF SUBSTANCE: Dopamine; Hypoxanthine-Phosphoribosyltransferase
SUBSET: Index-Medicus
UPDATE CODE: 20010628
ACCESSION NUMBER: 21195893
RECORD FEATURES: ABSTRACT (AB)
Record 6 of 21 in MEDLINE(R) on CD 2001/01-2001/06
TITLE: Molecular description of three macro-deletions and an Alu-Alu recombination-mediated duplication in the HPRT gene in four patients with Lesch-Nyhan disease.
AUTHOR: Brooks,-E-M; Branda,-R-F; Nicklas,-J-A; O'Neill,-J-P
ADDRESS OF AUTHOR: Genetics Laboratory, University of Vermont, 32 N. Prospect Street, Burlington, VT 05401, USA.
SOURCE: Mutat-Res. 2001 May 9; 476(1-2): 43-54
INTERNATIONAL STANDARD SERIAL NUMBER: 0027-5107
PUBLICATION YEAR: 2001
LANGUAGE: English
COUNTRY OF PUBLICATION: Netherlands
ABSTRACT: Mutations in the HPRT gene cause a spectrum of diseases that ranges from hyperuricemia alone to hyperuricemia with profound neurological and behavioral dysfunction. The extreme phenotype is termed Lesch-Nyhan syndrome. In 271 cases in which the germinal HPRT mutation has been characterized, 218 different mutations have been found. Of these, 34 (13%) are large- (macro-) deletions of one exon or greater and four (2%) are partial gene duplications. The deletion breakpoint junctions have been defined for only three of the 34 macro-deletions. The molecular basis of two of the four duplications has been defined. We report here the breakpoint junctions for three new deletion mutations, encompassing exons 4-8 (20033bp), exons 4 and 5 (13307bp) and exons 5 and 6 (9454bp), respectively. The deletion breakpoints were defined by a combination of long polymerase chain reaction (PCR) amplifications, and conventional PCR and DNA sequencing. All three deletions are the result of non-homologous recombinations. A fourth mutation, a duplication of exons 2 and 3, is the result of an Alu-mediated homologous recombination between identical 19bp sequences in introns 3 and 1. In toto, two of three germinal HPRT duplication mutations appear to have been caused by Alu-mediated homologous recombination, while only one of six deletion mutations appears to have resulted from this type of recombination mechanism. The other five deletion mutations resulted from non-homologous recombination. With this admittedly limited number of characterized macro-mutations, Alu-mediated unequal homologous recombinations account for at least 8% (3 of 38) of the macro-alterations and 1% (3 of 271) of the total HPRT germinal mutations.
MAJOR MESH DESCRIPTORS: *Hypoxanthine-Phosphoribosyltransferase-genetics; *Lesch-Nyhan-Syndrome-enzymology; *Lesch-Nyhan-Syndrome-genetics; *Mutation-
MINOR MESH DESCRIPTORS: Alu-Elements; Base-Sequence; Cells,-Cultured; DNA-Primers-genetics; DNA,-Complementary-genetics; Databases,-Factual; Exons-; Gene-Duplication; Introns-; Molecular-Sequence-Data; Polymerase-Chain-Reaction; Recombination,-Genetic; Sequence-Deletion; Sequence-Homology,-Nucleic-Acid
CHECKTAGS: Case-Report; Human; Male; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: genetics; enzymology
CAS REGISTRY NUMBER OR EC NUMBER: 0; 0; EC 2.4.2.8
NAME OF SUBSTANCE: DNA-Primers; DNA,-Complementary; Hypoxanthine-Phosphoribosyltransferase
CONTRACT OR GRANT NUMBERS: RO1CA41843CANCI
SUBSET: Index-Medicus
UPDATE CODE: 20010614
ACCESSION NUMBER: 21235552
RECORD FEATURES: ABSTRACT (AB)
Record 7 of 21 in MEDLINE(R) on CD 2001/01-2001/06
TITLE: GTP cyclohydrolase I feedback regulatory protein-dependent and -independent inhibitors of GTP cyclohydrolase I.
AUTHOR: Yoneyama,-T; Wilson,-L-M; Hatakeyama,-K
ADDRESS OF AUTHOR: Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA.
SOURCE: Arch-Biochem-Biophys. 2001 Apr 1; 388(1): 67-73
INTERNATIONAL STANDARD SERIAL NUMBER: 0003-9861
PUBLICATION YEAR: 2001
LANGUAGE: English
COUNTRY OF PUBLICATION: United-States
ABSTRACT: GTP cyclohydrolase I feedback regulatory protein (GFRP) mediates the feedback inhibition of GTP cyclohydrolase I activity by (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) through protein complex formation. Since guanine and BH4 have a common pyrimidine ring structure, we examined the inhibitory effect of guanine and its analogs on the enzyme activity. Guanine, 8-hydroxyguanine, 8-methylguanine, and 8-bromoguanine inhibited the enzyme activity in a GFRP-dependent and pH-dependent manner and induced complex formation between GTP cyclohydrolase I and GFRP. The type of inhibition by this group is a mixed type. All these properties were shared with BH4. In striking contrast, inhibition by 8-azaguanine and 8-mercaptoguanine was GFRP-independent and pH-independent. The type of inhibition by 8-azaguanine and 8-mercaptoguanine was a competitive type. The two compounds did not induce complex formation between the enzyme and GFRP. These results demonstrate that guanine compounds of the first group bind to the BH4-binding site of the GTP cyclohydrolase I/GFRP complex, whereas 8-azaguanine and 8-mercaptoguanine bind to the active site of the enzyme. 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.
MAJOR MESH DESCRIPTORS: *GTP-Cyclohydrolase-chemistry; *GTP-Cyclohydrolase-metabolism; *Guanine-analogs-and-derivatives; *Guanosine-analogs-and-derivatives
MINOR MESH DESCRIPTORS: Adjuvants,-Immunologic-pharmacology; Antimetabolites,-Antineoplastic-pharmacology; Azaguanine-pharmacology; Binding-Sites; Binding,-Competitive; Chromatography,-Gel; Dose-Response-Relationship,-Drug; Guanine-metabolism; Guanine-pharmacology; Guanosine-pharmacology; Guanosine-Triphosphate-metabolism; Hydrogen-Ion-Concentration; Inhibitory-Concentration-50; Kinetics-; Lesch-Nyhan-Syndrome-metabolism; Models,-Chemical; Parkinson-Disease-metabolism; Rats-; Thionucleosides-pharmacology
CHECKTAGS: Animal; Support,-U.S.-Gov't,-P.H.S.
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: pharmacology; chemistry; metabolism; analogs-and-derivatives
CAS REGISTRY NUMBER OR EC NUMBER: 0; 0; 0; 118-00-3; 134-58-7; 23662-75-1; 29836-03-1; 4016-63-1; 5614-64-2; 73-40-5; 86-01-1; EC 3.5.4.16
NAME OF SUBSTANCE: Adjuvants,-Immunologic; Antimetabolites,-Antineoplastic; Thionucleosides; Guanosine; Azaguanine; 8-methylguanine; 8-thioguanosine; 8-bromoguanosine; 8-hydroxyguanine; Guanine; Guanosine-Triphosphate; GTP-Cyclohydrolase
CONTRACT OR GRANT NUMBERS: DK51257DKNIDDK
SUBSET: Index-Medicus
UPDATE CODE: 20010614
ACCESSION NUMBER: 21258588
RECORD FEATURES: ABSTRACT (AB)
Record 8 of 21 in MEDLINE(R) on CD 2001/01-2001/06
TITLE: Human genetic disorders, a phylogenetic perspective.
AUTHOR: Martinez,-J; Dugaiczyk,-L-J; Zielinski,-R; Dugaiczyk,-A
ADDRESS OF AUTHOR: Department of Biochemistry, University of California, Riverside, CA 92521, USA.
SOURCE: J-Mol-Biol. 2001 May 11; 308(4): 587-96
INTERNATIONAL STANDARD SERIAL NUMBER: 0022-2836
PUBLICATION YEAR: 2001
LANGUAGE: English
COUNTRY OF PUBLICATION: England
ABSTRACT: When viewed from the perspective of time, human genetic disorders give new insights into their etiology and evolution. Here, we have correlated a specific set of Alu repetitive DNA elements, known to be the basis of certain genetic defects, with their phylogenetic roots in primate evolution. From a differential distribution of Alu repeats among primate species, we identify the phylogenetic roots of three human genetic diseases involving the LPL, ApoB, and HPRT genes. The different phylogenetic age of these genetic disorders could explain the different susceptibility of various primate species to genetic diseases. Our results show that LPL deficiency is the oldest and should affect humans, apes, and monkeys. ApoB deficiency should affect humans and great apes, while a disorder in the HPRT gene (leading to the Lesch-Nyhan syndrome) is unique to human, chimpanzee, and gorilla. Similar results can be obtained for cancer. We submit that de novo transpositions of Alu elements, and saltatory appearances of Alu-mediated genetic disorders, represent singularities, places where behavior changes suddenly. Alus' propensity to spread, not only increased the regulatory and developmental complexity of the primate genome, it also increased its instability and susceptibility to genetic defects and cancer. The dynamic spread not only provided markers of primate phylogeny, it must have actively shaped the course of that phylogeny. Copyright 2001 Academic Press.
MAJOR MESH DESCRIPTORS: *Genetic-Predisposition-to-Disease-genetics; *Hereditary-Diseases-genetics; *Phylogeny-; *Primates-genetics
MINOR MESH DESCRIPTORS: Alu-Elements-genetics; Apolipoproteins-B-deficiency; Apolipoproteins-B-genetics; Base-Sequence; Evolution,-Molecular; Exons-genetics; Genetics,-Population; Genotype-; Globins-genetics; Hypoxanthine-Phosphoribosyltransferase-deficiency; Hypoxanthine-Phosphoribosyltransferase-genetics; Introns-genetics; Lipoprotein-Lipase-deficiency; Lipoprotein-Lipase-genetics; Molecular-Sequence-Data; Mutagenesis,-Insertional-genetics; Neoplasms-genetics; Point-Mutation-genetics
CHECKTAGS: Animal; Human; Support,-Non-U.S.-Gov't
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: genetics; deficiency
CAS REGISTRY NUMBER OR EC NUMBER: 0; 9004-22-2; EC 2.4.2.8; EC 3.1.1.34
NAME OF SUBSTANCE: Apolipoproteins-B; Globins; Hypoxanthine-Phosphoribosyltransferase; Lipoprotein-Lipase
SECONDARY SOURCE IDENTIFIER: GENBANK/AF358268; GENBANK/AF358269; GENBANK/AF358270; GENBANK/AF358271; GENBANK/AF358272; GENBANK/AF358273; GENBANK/AF358845; GENBANK/AF358846; GENBANK/AF358847; GENBANK/AF358848; GENBANK/AF358849; GENBANK/AF358850; GENBANK/AF358851; GENBANK/AF358852; GENBANK/AF358853; GENBANK/AF358854; GENBANK/AF358855; GENBANK/AF358856
SUBSET: Index-Medicus
UPDATE CODE: 20010607
ACCESSION NUMBER: 21248984
RECORD FEATURES: ABSTRACT (AB)
Record 9 of 21 in MEDLINE(R) on CD 2001/01-2001/06
TITLE: The spectrum of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. Clinical experience based on 22 patients from 18 Spanish families.
AUTHOR: Puig,-J-G; Torres,-R-J; Mateos,-F-A; Ramos,-T-H; Arcas,-J-M; Buno,-A-S; O'Neill,-P
ADDRESS OF AUTHOR: La Paz University Hospital, Divisions of Internal Medicine, Madrid, Spain. med027514@nacom.es
SOURCE: Medicine-(Baltimore). 2001 Mar; 80(2): 102-12
INTERNATIONAL STANDARD SERIAL NUMBER: 0025-7974
PUBLICATION YEAR: 2001
LANGUAGE: English
COUNTRY OF PUBLICATION: United-States
ABSTRACT: The enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) catalyzes the reutilization of hypoxanthine and guanine to the purine nucleotides IMP and GMP, respectively. HPRT deficiency is an X-linked disorder characterized by uric acid overproduction and variable neurologic impairment. The complete deficiency of HPRT is diagnostic of Lesch-Nyhan syndrome manifested by choreoathetosis, spasticity, mental retardation, and self-injurious behavior. In some HPRT-deficient patients the enzyme defect appeared to be "partial" and the neurologic symptoms mild to severe (Kelley-Seegmiller syndrome). This has prompted the classification of HPRT deficiency in 2 distinct groups: Lesch-Nyhan syndrome and Kelley-Seegmiller syndrome, which has created much confusion. A spectrum of clinical consequences of HPRT deficiency has been recognized in small series of patients, but the complete spectrum of the neurologic disorder has not been described in a single series of patients examined by the same observers. We analyzed our experience with 22 patients belonging to 18 different families with HPRT deficiency diagnosed at "La Paz" University Hospital in Madrid over the past 16 years. The clinical spectrum of these HPRT-deficient Spanish patients was similar to the different phenotypes occasionally reported in the literature, in some cases diagnosed as Lesch-Nyhan "variants." The clinical, biochemical, enzymatic, and molecular genetic studies on these 22 patients allowed us to delineate a new classification of HPRT deficiency. Based on the neurologic symptoms, dependency for personal care, HPRT activity in hemolysate and in intact erythrocytes, and predicted protein size, patients were classified into 4 groups: Group 1 (2 patients), normal development with no neurologic symptoms, HPRT activity was detectable in hemolysates and in intact erythrocytes, and the mutation did not affect the predicted protein size. Group 2 (3 patients) mild neurologic symptoms that did not prevent independent lives, HPRT activity was detectable in intact erythrocytes, and the protein size was normal. Group 3 (2 patients), severe neurologic impairment that precluded an independent life, no residual HPRT activity, and normal protein size. Group 4 (15 patients), clinical characteristics of Lesch-Nyhan syndrome (some may not show self-injurious behavior), no residual HPRT activity, and in most (7 of 8 patients in whom the mutation could be detected) the mutation affected the predicted protein size. This classification of HPRT deficiency into 4 groups may be more useful in terms of accuracy, reproducibility, assessment for treatment trials and prognosis. The study of this Spanish series allows us to conclude that HPRT deficiency may be manifested by a wide spectrum of neurologic symptoms; the overall severity of the disease is associated with mutations permitting some degree of residual enzyme activity; and mutation analysis provides a valuable tool for prognosis, carrier identification, and prenatal diagnosis.
MAJOR MESH DESCRIPTORS: *Hypoxanthine-Phosphoribosyltransferase-deficiency
MINOR MESH DESCRIPTORS: Adolescence-; Adult-; Child-; Child,-Preschool; Heterozygote-Detection; Infant-; Lesch-Nyhan-Syndrome-blood; Lesch-Nyhan-Syndrome-genetics; Lesch-Nyhan-Syndrome-physiopathology; Metabolism,-Inborn-Errors-blood; Metabolism,-Inborn-Errors-classification; Metabolism,-Inborn-Errors-genetics; Metabolism,-Inborn-Errors-physiopathology; Mutation-genetics; Pedigree-; Phenotype-; Purines-blood; Spain-epidemiology
CHECKTAGS: Female; Human; Male; Support,-Non-U.S.-Gov't
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: deficiency; blood; genetics; physiopathology; classification; epidemiology
CAS REGISTRY NUMBER OR EC NUMBER: 0; EC 2.4.2.8
NAME OF SUBSTANCE: Purines; Hypoxanthine-Phosphoribosyltransferase
SUBSET: Abridged-Index-Medicus; Index-Medicus
UPDATE CODE: 20010503
ACCESSION NUMBER: 21202854
RECORD FEATURES: ABSTRACT (AB)
Record 10 of 21 in MEDLINE(R) on CD 2001/01-2001/06
TITLE: Lesch-Nyhan syndrome presenting as acute renal failure secondary to obstructive uropathy.
AUTHOR: Ankem,-M; Glazier,-D-B; Barone,-J-G
ADDRESS OF AUTHOR: Division of Urology, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
SOURCE: Urology. 2000 Dec 20; 56(6): 1056
INTERNATIONAL STANDARD SERIAL NUMBER: 1527-9995
PUBLICATION YEAR: 2000
LANGUAGE: English
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Lesch-Nyhan syndrome is a rare genetic disorder characterized by mental retardation, self-mutilation, choreoathetosis, and hyperuricemia. The disease is caused by a mutation in the hypoxanthine-guanine phosphoribosyltransferase gene and is transmitted as a sex-linked recessive disorder. Since hyperuricemia is the primary metabolic problem caused by a hypoxanthine-guanine phosphoribosyltransferase mutation, urologic evaluation and treatment is often necessary for children with this disease. We report a 3-year-old boy who presented with anuric renal failure secondary to bilateral obstructing uric acid calculi. The evaluation of T lymphocytes revealed a hypoxanthine-guanine phosphoribosyltransferase mutation consistent with Lesch-Nyhan syndrome. The diagnosis and urologic management of this disorder is discussed.
MAJOR MESH DESCRIPTORS: *Anuria-diagnosis; *Kidney-Calculi-diagnosis; *Kidney-Failure,-Acute-diagnosis; *Lesch-Nyhan-Syndrome-diagnosis
MINOR MESH DESCRIPTORS: Anuria-etiology; Child,-Preschool; Kidney-Calculi-complications; Lesch-Nyhan-Syndrome-blood; Uric-Acid-blood
CHECKTAGS: Case-Report; Human; Male
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: diagnosis; etiology; complications; blood
CAS REGISTRY NUMBER OR EC NUMBER: 69-93-2
NAME OF SUBSTANCE: Uric-Acid
SUBSET: Index-Medicus
UPDATE CODE: 20010215
ACCESSION NUMBER: 20566213
RECORD FEATURES: ABSTRACT (AB)
Record 11 of 21 in MEDLINE(R) on CD 2001/01-2001/06
TITLE: Cytosolic 5'-nucleotidase hyperactivity in erythrocytes of Lesch-Nyhan syndrome patients.
AUTHOR: Pesi,-R; Micheli,-V; Jacomelli,-G; Peruzzi,-L; Camici,-M; Garcia-Gil,-M; Allegrini,-S; Tozzi,-M-G
ADDRESS OF AUTHOR: Dipartimento di Fisiologia e Biochimica, Universita di Pisa, Italy.
SOURCE: Neuroreport. 2000 Jun 26; 11(9): 1827-31
INTERNATIONAL STANDARD SERIAL NUMBER: 0959-4965
PUBLICATION YEAR: 2000
LANGUAGE: English
COUNTRY OF PUBLICATION: ENGLAND
ABSTRACT: Lesch-Nyhan syndrome is a metabolic-neurological syndrome caused by the X-linked deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Metabolic consequences of HGPRT deficiency have been clarified, but the connection with the neurological manifestations is still unknown. Much effort has been directed to finding other alterations in purine nucleotides in different cells of Lesch-Nyhan patients. A peculiar finding was the measure of appreciable amount of Z-nucleotides in red cells. We found significantly higher IMP-GMP-specific 5'-nucleotidase activity in the erythrocytes of seven patients with Lesch-Nyhan syndrome than in healthy controls. The same alteration was found in one individual with partial HGPRT deficiency displaying a severe neurological syndrome, and in two slightly hyperuricemic patients with a psychomotor delay. Since ZMP was a good substrate of 5'-nucleotidase producing Z-riboside, we incubated murine and human cultured neuronal cells with this nucleoside and found that it is toxic for our models, promoting apoptosis. This finding suggests an involvement of the toxicity of the Z-riboside in the pathogenesis of neurological disorders in Lesch-Nyhan syndrome and possibly in other pediatric neurological syndromes of uncertain origin.
MAJOR MESH DESCRIPTORS: *5'-Nucleotidase-blood; *Aminoimidazole-Carboxamide-analogs-and-derivatives; *Cytosol-enzymology; *Erythrocytes-enzymology; *Lesch-Nyhan-Syndrome-blood
MINOR MESH DESCRIPTORS: 5'-Nucleotidase-metabolism; Adolescence-; Adult-; Aminoimidazole-Carboxamide-pharmacology; Apoptosis-; Autistic-Disorder-blood; Child-; Hypoxanthine-Phosphoribosyltransferase-metabolism; Mice-; Middle-Age; Nervous-System-Diseases-blood; Reference-Values; Ribonucleosides-pharmacology; Ribonucleotides-pharmacology; Tumor-Cells,-Cultured-drug-effects; Uric-Acid-blood
CHECKTAGS: Animal; Female; Human; Male; Support,-Non-U.S.-Gov't
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: blood; metabolism; analogs-and-derivatives; pharmacology; enzymology; drug-effects
CAS REGISTRY NUMBER OR EC NUMBER: 0; 0; 2627-69-2; 3031-94-5; 360-97-4; 69-93-2; EC 2.4.2.8; EC 3.1.3.5
NAME OF SUBSTANCE: Ribonucleosides; Ribonucleotides; acadesine; AICA-ribonucleotide; Aminoimidazole-Carboxamide; Uric-Acid; Hypoxanthine-Phosphoribosyltransferase; 5'-Nucleotidase
SUBSET: Index-Medicus
UPDATE CODE: 20001222
ACCESSION NUMBER: 20339086
RECORD FEATURES: ABSTRACT (AB)
Record 12 of 21 in MEDLINE(R) on CD 2001/01-2001/06
TITLE: New mutations of the HPRT gene in Lesch-Nyhan syndrome.
AUTHOR: Mak,-B-S; Chi,-C-S; Tsai,-C-R; Lee,-W-J; Lin,-H-Y
ADDRESS OF AUTHOR: Department of Pediatrics, Taichung Veterans General Hospital;, Taichung, Taiwan.
SOURCE: Pediatr-Neurol. 2000 Oct; 23(4): 332-5
INTERNATIONAL STANDARD SERIAL NUMBER: 0887-8994
PUBLICATION YEAR: 2000
LANGUAGE: English
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Lesch-Nyhan syndrome is an X-linked recessive disorder involving the purine metabolism, with resultant hyperuricemia, choreoathetosis, self-mutilation, and profound neurologic dysfunction. A deficiency of the enzyme hypoxanthine guanine phosphoribosyl-transferase is responsible for the disease. The human HPRT gene is located at Xq26-27 and consists of 57 base pairs. At least 2,000 mutations throughout the HPRT gene coding region from exon 1-9 have been reported. Four patients from three Chinese families were diagnosed with Lesch-Nyhan syndrome according to the clinical and laboratory findings. DNA studies revealed the first family (Patients 1 and 2) had a missense mutation in exon 3 of the HPRT encoding region. This novel mutation occurs in the hot spot of the HPRT gene. The second family (Patient 3) was found to have a missense mutation in exon 8 of the HPRT gene. The third family (Patient 4) carried a mutation in the splicing region of intron 4 of the HPRT gene. All three mutations were de novo.
MAJOR MESH DESCRIPTORS: *Hypoxanthine-Phosphoribosyltransferase-genetics; *Lesch-Nyhan-Syndrome-genetics; *Mutation,-Missense-genetics
MINOR MESH DESCRIPTORS: Base-Sequence-genetics; Child-; Child,-Preschool; Pedigree-; Sequence-Analysis,-DNA
CHECKTAGS: Case-Report; Human; Male
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: genetics
CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8
NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase
SUBSET: Index-Medicus
UPDATE CODE: 20001220
ACCESSION NUMBER: 20521399
RECORD FEATURES: ABSTRACT (AB)
Record 13 of 21 in MEDLINE(R) on CD 2001/01-2001/06
TITLE: Neurotransmitter changes in the pathophysiology of Lesch-Nyhan syndrome.
AUTHOR: Saito,-Y; Takashima,-S
ADDRESS OF AUTHOR: Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan.
SOURCE: Brain-Dev. 2000 Sep; 22 Suppl 1S122-31
INTERNATIONAL STANDARD SERIAL NUMBER: 0387-7604
PUBLICATION YEAR: 2000
LANGUAGE: English
COUNTRY OF PUBLICATION: NETHERLANDS
ABSTRACT: The neurological symptoms of Lesch-Nyhan syndrome (LNS) are assumed to result from the neurotransmitter changes in this disorder. Among them, the dopaminergic system is believed to play a role in the self-injurious behavior through receptor supersensitivity. However, the precise mechanism underlying the dopamine supersensitivity remains unclear. An increased serotonergic action in the striatum may be crucial for the appearance of self-injurious behavior, and pharmacological evidence suggests the efficacy of serotonin agonists/antagonists for the treatment of the self-mutilation in LNS.
MAJOR MESH DESCRIPTORS: *Lesch-Nyhan-Syndrome-pathology; *Lesch-Nyhan-Syndrome-physiopathology; *Neurotransmitters-physiology; *Self-Mutilation-physiopathology
MINOR MESH DESCRIPTORS: Brain-pathology; Brain-physiopathology; Neurons-metabolism; Neurons-pathology; Receptors,-Dopamine-metabolism; Synapses-metabolism; Synapses-pathology
CHECKTAGS: Animal; Human
PUBLICATION TYPE: Journal-Article; Review; Review,-Tutorial
SUBHEADINGS: pathology; physiopathology; metabolism; physiology
CAS REGISTRY NUMBER OR EC NUMBER: 0; 0
NAME OF SUBSTANCE: Neurotransmitters; Receptors,-Dopamine
SUBSET: Index-Medicus
UPDATE CODE: 20001107
ACCESSION NUMBER: 20442019
RECORD FEATURES: ABSTRACT (AB)
Record 14 of 21 in MEDLINE(R) on CD 2001/01-2001/06
TITLE: Dopamine function in Lesch-Nyhan disease.
AUTHOR: Nyhan,-W-L
ADDRESS OF AUTHOR: Department of Pediatrics, University of California, San Diego, California, USA. wnyhan@ucsd.edu
SOURCE: Environ-Health-Perspect. 2000 Jun; 108 Suppl 3409-11
INTERNATIONAL STANDARD SERIAL NUMBER: 0091-6765
PUBLICATION YEAR: 2000
LANGUAGE: English
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Lesch-Nyhan disease is a disorder of purine metabolism resulting from mutations in the gene for hypoxanthine guanine phosphoribosyl transferase on the X chromosome. It is characterized by hyperuricemia and all of its consequences, as in gout; but in addition, patients have impressive disease of the central nervous system. This includes spasticity, involuntary movements, and retardation of motor development. The behavioral phenotype is best remembered by self-injurious biting behavior with attendant destruction of tissue. The connection between aberrant metabolism of purines and these neurologic and behavioral features of the disease is not clear. Increasing evidence points to imbalance of neurotransmitters. There is increased excretion of the serotonin metabolite 5-hydroxyindoleacetic acid in the urine. There are decreased quantities and activities of a number of dopaminergic functions. Positron emission tomography scanning has indicated deficiency in the dopamine transporter.
MAJOR MESH DESCRIPTORS: *Dopamine-metabolism; *Lesch-Nyhan-Syndrome-metabolism
MINOR MESH DESCRIPTORS: Hydroxyindoleacetic-Acid-urine; Hypoxanthine-Phosphoribosyltransferase-metabolism; Lesch-Nyhan-Syndrome-physiopathology; Phenotype-; Tomography,-Emission-Computed
CHECKTAGS: Human
PUBLICATION TYPE: Journal-Article; Review; Review,-Tutorial
SUBHEADINGS: metabolism; urine; physiopathology
CAS REGISTRY NUMBER OR EC NUMBER: 51-61-6; 54-16-0; EC 2.4.2.8
NAME OF SUBSTANCE: Dopamine; Hydroxyindoleacetic-Acid; Hypoxanthine-Phosphoribosyltransferase
SUBSET: Index-Medicus
UPDATE CODE: 20001023
ACCESSION NUMBER: 20312769
RECORD FEATURES: ABSTRACT (AB)
Record 15 of 21 in MEDLINE (R) 2000
TITLE: Elevated UTP and CTP content in cultured neurons from HPRT-deficient transgenic mice.
AUTHOR: Brosh,-S; Boer,-P; Sperling,-O; Zoref-Shani,-E
ADDRESS OF AUTHOR: Felsenstein Medical Research Center, Rabin Medical Center, Petah-Tikva, Israel.
SOURCE: J-Mol-Neurosci. 2000 Feb-Apr; 14(1-2): 87-91
INTERNATIONAL STANDARD SERIAL NUMBER: 0895-8696
PUBLICATION YEAR: 2000
LANGUAGE: English
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8.; HPRT) catalyzes the salvage synthesis of inosine-5'-monophosphate (IMP) and guanosine-5'-monophosphate (GMP) from the purine bases hypoxanthine and guanine, respectively. Complete deficiency of HPRT activity is associated with the Lesch-Nyhan syndrome (LNS), characterized by excessive purine production and severe neurological manifestations. The etiology of the metabolic consequences of HPRT deficiency is clarified, but that of the neurological manifestations is not yet understood. HPRT-deficient mice represent an experimental animal model of LNS. In search for a possible metabolic abnormality in LNS brains, connecting the neurological deficit to HPRT deficiency, the purine and pyrimidine nucleotide content of cultured neurons, prepared from HPRT-deficient transgenic mice, was now determined. The HPRT-deficient neuronal cultures exhibited a significantly elevated content of the pyrimidine nucleotides UTP (1.33-fold the normal level, p = 0.0002) and CTP (1.28-fold the normal level, p = 0.02), but normal content of the purine nucleotides ATP and GTP. This abnormality in neuronal pyrimidine nucleotide content may be associated with the pathophysiology of the neurological deficit in LNS.
MAJOR MESH DESCRIPTORS: *Cytidine-Triphosphate-metabolism; *Hypoxanthine-Phosphoribosyltransferase-genetics; *Neurons-metabolism; *Uridine-Triphosphate-metabolism
MINOR MESH DESCRIPTORS: Brain-cytology; Cells,-Cultured; Embryo-; Hypoxanthine-Phosphoribosyltransferase-deficiency; Lesch-Nyhan-Syndrome-genetics; Mice-; Mice,-Inbred-C57BL; Mice,-Transgenic
CHECKTAGS: Animal; Support,-Non-U.S.-Gov't
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: cytology; metabolism; deficiency; genetics
CAS REGISTRY NUMBER OR EC NUMBER: 63-39-8; 65-47-4; EC 2.4.2.8
NAME OF SUBSTANCE: Uridine-Triphosphate; Cytidine-Triphosphate; Hypoxanthine-Phosphoribosyltransferase
SUBSET: Index-Medicus
UPDATE CODE: 20001218
ACCESSION NUMBER: 20311087
RECORD FEATURES: ABSTRACT (AB)
Record 16 of 21 in MEDLINE (R) 2000
TITLE: Characterization of the dopamine defect in primary cultures of dopaminergic neurons from hypoxanthine phosphoribosyltransferase knockout mice.
AUTHOR: Smith,-D-W; Friedmann,-T
ADDRESS OF AUTHOR: Center for Molecular Genetics, Room 122, Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0634, USA. dwsmith@ucsd.edu
SOURCE: Mol-Ther. 2000 May; 1(5 Pt 1): 486-91
INTERNATIONAL STANDARD SERIAL NUMBER: 1525-0016
PUBLICATION YEAR: 2000
LANGUAGE: English
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Lesch-Nyhan disease (LND) is an X-linked metabolic disorder caused by lack of activity of the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT) and characterized by hyperuricemia and debilitating neurological manifestations. The mechanisms underlying the neuropathology are not well understood and the principal neurochemical lesion characterized to date is a deficiency of the dopamine system in the basal ganglia. To facilitate the study of mechanism(s) by which HPRT deficiency causes the dopamine defect, we have compared the survival and dopamine phenotype of primary cultures of dopamine neurons derived from HPRT-deficient mice with the dopaminergic neurons from wild-type mice. The survival of dopaminergic neurons from both sources was promoted to an equal extent by glial cell line-derived neurotrophic factor (GDNF), a potent survival factor for dopamine neurons in vitro. Although the survival of the HPRT-deficient neurons was indistinguishable from that of cells derived from wild-type counterparts, the HPRT-deficient cells demonstrated a persistent deficiency of dopamine content and dopamine uptake with increasing neuritic differentiation, indicating that GDNF does not restore the normal phenotype in HPRT-deficient dopamine neurons despite its well-known protective and regenerative properties in several neurodegeneration models. Nevertheless, the demonstration that GDNF trophic support promotes the survival of these dopaminergic neurons will facilitate gaining a better understanding of the neuropathological mechanisms of LND by allowing a more extensive analysis of the cells central to the Lesch-Nyhan phenotype, the dopaminergic neurons of the basal ganglia.
MAJOR MESH DESCRIPTORS: *Dopamine-metabolism; *Hypoxanthine-Phosphoribosyltransferase-deficiency; *Hypoxanthine-Phosphoribosyltransferase-genetics; *Neurons-enzymology
MINOR MESH DESCRIPTORS: Basal-Ganglia-metabolism; Cells,-Cultured; Chromatography,-High-Pressure-Liquid; Immunohistochemistry-; Mesencephalon-physiology; Mice-; Mice,-Inbred-C57BL; Mice,-Knockout; Nerve-Tissue-Proteins-pharmacology; Neurites-physiology; Neurons-drug-effects; Phenotype-; Survival-Rate
CHECKTAGS: Animal; Female; Male; Pregnancy; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: metabolism; deficiency; genetics; physiology; pharmacology; drug-effects; enzymology
CAS REGISTRY NUMBER OR EC NUMBER: 0; 0; 51-61-6; EC 2.4.2.8
NAME OF SUBSTANCE: Nerve-Tissue-Proteins; glial-cell-line-derived-neurotrophic-factor; Dopamine; Hypoxanthine-Phosphoribosyltransferase
SUBSET: Index-Medicus
UPDATE CODE: 20001218
ACCESSION NUMBER: 20394336
RECORD FEATURES: ABSTRACT (AB)
Record 17 of 21 in MEDLINE (R) 2000
TITLE: Lesch-Nyhan disease and the basal ganglia.
AUTHOR: Visser,-J-E; Bar,-P-R; Jinnah,-H-A
ADDRESS OF AUTHOR: Laboratory of Experimental Neurology, Rudolf Magnus Institute for Neurosciences, Utrecht University, Utrecht, Netherlands.
SOURCE: Brain-Res-Brain-Res-Rev. 2000 Apr; 32(2-3): 449-75
INTERNATIONAL STANDARD SERIAL NUMBER: 0165-0173
PUBLICATION YEAR: 2000
LANGUAGE: English
COUNTRY OF PUBLICATION: NETHERLANDS
ABSTRACT: 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. Affected individuals have severe motor disability described by prominent extrapyramidal features that are characteristic of dysfunction of the motor circuits of the basal ganglia. They also display disturbances of ocular motility, cognition, and behavioral control that may reflect disruption of other circuits of the basal ganglia. Though neuropathologic studies of autopsy specimens have revealed no obvious neuroanatomical abnormalities in LND, neurochemical studies have demonstrated 60-90% reductions in the dopamine content of the basal ganglia. In addition, recent PET studies have documented significant reductions in dopamine transporters and [18F]fluorodopa uptake in the basal ganglia. These findings support the proposal that many of the neurobehavioral features of LND might be related to dysfunction of the basal ganglia.
MAJOR MESH DESCRIPTORS: *Basal-Ganglia-pathology; *Lesch-Nyhan-Syndrome-pathology
MINOR MESH DESCRIPTORS: Basal-Ganglia-Diseases-pathology; Basal-Ganglia-Diseases-psychology; Lesch-Nyhan-Syndrome-psychology
CHECKTAGS: Animal; Human; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.
PUBLICATION TYPE: Journal-Article; Review; Review,-Academic
SUBHEADINGS: pathology; psychology
CONTRACT OR GRANT NUMBERS: K08198503PHS
SUBSET: Index-Medicus
UPDATE CODE: 20001218
ACCESSION NUMBER: 20225534
RECORD FEATURES: ABSTRACT (AB)
Record 18 of 21 in MEDLINE (R) 2000
TITLE: A review of behavioral treatments used for Lesch-Nyhan syndrome.
AUTHOR: Olson,-L; Houlihan,-D
ADDRESS OF AUTHOR: University of South Carolina, USA.
SOURCE: Behav-Modif. 2000 Apr; 24(2): 202-22
INTERNATIONAL STANDARD SERIAL NUMBER: 0145-4455
PUBLICATION YEAR: 2000
LANGUAGE: English
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Lesch-Nyhan syndrome is a genetic disorder resulting in hyperuricemia, choreoathetosis, mental retardation, and self-mutilation. The most salient feature of this disorder is the self-injurious behavior (SIB). Although the utility of behavioral interventions with SIB has been well documented, behavioral interventions with Lesch-Nyhan syndrome have been limited in number and long-term success. This article reviews the behavioral treatments that have been used in treating individuals with Lesch-Nyhan syndrome and discusses the strengths and weaknesses of these methods. Suggestions for future directions in the use of behavioral interventions for controlling SIB in Lesch-Nyhan syndrome are provided.
MAJOR MESH DESCRIPTORS: *Behavior-Therapy-methods; *Lesch-Nyhan-Syndrome-psychology; *Lesch-Nyhan-Syndrome-therapy; *Restraint,-Physical-methods; *Self-Injurious-Behavior-prevention-and-control
MINOR MESH DESCRIPTORS: Child-; Extinction-Psychology; Models,-Psychological; Reinforcement-Psychology
CHECKTAGS: Case-Report; Human
PUBLICATION TYPE: Journal-Article; Review; Review,-Tutorial
SUBHEADINGS: methods; psychology; therapy; prevention-and-control
SUBSET: Index-Medicus
UPDATE CODE: 20001218
ACCESSION NUMBER: 20264801
RECORD FEATURES: ABSTRACT (AB)
Record 19 of 21 in MEDLINE (R) 2000
TITLE: An unexpected affected female patient in a classical Lesch-Nyhan family.
AUTHOR: De-Gregorio,-L; Nyhan,-W-L; Serafin,-E; Chamoles,-N-A
ADDRESS OF AUTHOR: Department of Pediatrics, University of California at San Diego, La Jolla, California 92093, USA.
SOURCE: Mol-Genet-Metab. 2000 Mar; 69(3): 263-8
INTERNATIONAL STANDARD SERIAL NUMBER: 1096-7192
PUBLICATION YEAR: 2000
LANGUAGE: English
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Lesch-Nyhan disease is a genetic disorder of purine metabolism caused by defective activity of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT), resulting from mutation in the corresponding gene on the long arm of the X chromosome (Xq26). The classical phenotype, which includes spasticity, involuntary movements, developmental disability, and self-injurious behavior, occurs exclusively in males, while heterozygous, carrier females are clinically normal. We analyzed an Argentine family in which there were male and female siblings with clinically identical classic features of Lesch-Nyhan disease. The mother and an older daughter were carriers and had normal phenotypes. We identified the HPRT mutation in the family. It is a C --> T transition at position 508 of the cDNA (c.508 C --> T) that changes the CGA codon for Arg(169) to the TGA stop codon (R169X). The female patient was karyotypically normal and heterozygous for the mutation. She inherited the HPRT mutation from her mother, but she also had unexpected nonrandom inactivation of the paternal X chromosome carrying the normal HPRT gene. This additional genetic alteration is the cause of the clinical expression of disease in this female patient. Copyright 2000 Academic Press.
MAJOR MESH DESCRIPTORS: *Hypoxanthine-Phosphoribosyltransferase-genetics; *Lesch-Nyhan-Syndrome-genetics
MINOR MESH DESCRIPTORS: Adult-; Argentina-; Cells,-Cultured; Child-; Child,-Preschool; DNA-genetics; DNA-Mutational-Analysis; DNA,-Complementary-chemistry; DNA,-Complementary-genetics; Dosage-Compensation-Genetics; Family-Health; Fatal-Outcome; Hypoxanthine-Phosphoribosyltransferase-deficiency; Lesch-Nyhan-Syndrome-enzymology; Lesch-Nyhan-Syndrome-pathology; Mutation-; Pedigree-; Phenotype-; Point-Mutation; Polymorphism,-Restriction-Fragment-Length; Promoter-Regions-Genetics; Transcription-Factors-genetics; X-Chromosome-genetics
CHECKTAGS: Case-Report; Female; Human; Male; Support,-U.S.-Gov't,-P.H.S.
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: genetics; chemistry; deficiency; enzymology; pathology
CAS REGISTRY NUMBER OR EC NUMBER: 0; 0; 0; 9007-49-2; EC 2.4.2.8
NAME OF SUBSTANCE: DNA,-Complementary; Transcription-Factors; Xist-gene-product; DNA; Hypoxanthine-Phosphoribosyltransferase
CONTRACT OR GRANT NUMBERS: 2P30AI36214AINIAID
SUBSET: Index-Medicus
UPDATE CODE: 20001218
ACCESSION NUMBER: 20232174
RECORD FEATURES: ABSTRACT (AB)
Record 20 of 21 in MEDLINE (R) 2000
TITLE: Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in thirteen Spanish families.
AUTHOR: Torres,-R-J; Mateos,-F-A; Molano,-J; Gathoff,-B-S; O'Neill,-J-P; Gundel,-R-M; Trombley,-L; Puig,-J-G
ADDRESS OF AUTHOR: Division of Clinical Biochemistry, Hospital La Paz, Universidad Autonoma, Madrid, Spain.
SOURCE: Hum-Mutat. 2000 Apr; 15(4): 383
INTERNATIONAL STANDARD SERIAL NUMBER: 1098-1004
PUBLICATION YEAR: 2000
LANGUAGE: English
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: We have determined the molecular basis of hypoxanthine-guanine phosphoribosyltransferase (HPRT; HPRT1) deficiency in eight Lesch-Nyhan patients and in five partially HPRT deficient patients with mild to severe neurologic symptoms. Eight of these thirteen mutations have not been previously described. HPRT Zaragoza II (a GG insertion in exon 2), HPRT Murcia (an AG deletion in exon 4), HPRT Asturias (a A deletion in exon 4) and HPRT Cartagena (a A insertion in exon 6) cause a frame-shift resulting in a premature stop codon. HPRT Sevilla is a splice-site mutation resulting in exon 8 skipping in the HPRT mRNA. HPRT Huelva, Madrid II and Zaragoza I are point mutations that result in single amino-acid changes in the mutated HPRT protein (118G-->A, G40R; 143G-->A, R 48 H; 397G-->A, V133 M, respectively). Three mutations have been previously described in unrelated families, and two mutations have been already published. All mutations that resulted in truncated proteins corresponded to patients with the Lesch-Nyhan phenotype. Characterization of the HPRT mutation allowed us to make carrier detection in 33 women and prenatal diagnosis in two fetuses. Hum Mutat 15:383, 2000. Copyright 2000 Wiley-Liss, Inc.
MAJOR MESH DESCRIPTORS: *Hypoxanthine-Phosphoribosyltransferase-deficiency; *Hypoxanthine-Phosphoribosyltransferase-genetics
MINOR MESH DESCRIPTORS: Alternative-Splicing-genetics; Exons-genetics; Frameshift-Mutation-genetics; Heterozygote-Detection; Lesch-Nyhan-Syndrome-enzymology; Lesch-Nyhan-Syndrome-genetics; Mutagenesis,-Insertional-genetics; Point-Mutation-genetics; Prenatal-Diagnosis; Sequence-Deletion-genetics; Spain-
CHECKTAGS: Female; Human; Pregnancy; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: genetics; deficiency; enzymology
CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8
NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase
CONTRACT OR GRANT NUMBERS: CO6HL39475CONCI
SUBSET: Index-Medicus
UPDATE CODE: 20001218
ACCESSION NUMBER: 20202839
RECORD FEATURES: ABSTRACT (AB)
Record 21 of 21 in MEDLINE (R) 2000
TITLE: Adrenergic and noradrenergic plasma levels in Lesch-Nyhan disease.
AUTHOR: Ernst,-M; Zametkin,-A-J; Pascualvaca,-D; Matochik,-J-A; Eisenhofer,-G; Murphy,-D-L; Cohen,-R-M
ADDRESS OF AUTHOR: Laboratory of Cerebral Metabolism, NIMH, Bethesda, MD, USA.
SOURCE: Neuropsychopharmacology. 2000 Mar; 22(3): 320-6
INTERNATIONAL STANDARD SERIAL NUMBER: 0893-133X
PUBLICATION YEAR: 2000
LANGUAGE: English
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Noradrenergic dysfunction and abnormality in monoamine oxidase (MAO) enzyme activity have been reported previously in Lesch-Nyhan (LN) disease. This study examines peripheral indices of adrenergic, noradrenergic, and MAO function in children and young adults with LN disease (n = 11), and healthy subjects (n = 9). Blood samples, collected in identical conditions prior to a positron emission tomography (PET) study, were assayed for concentrations of epinephrine (EPI), norepinephrine (NE), and 3-methoxy-4-hydroxyphenylglycol (DHPG) (which results from the degradation of NE by monoamine oxidase type A [MAO-A]). The LN subjects had significantly higher EPI levels by 245% (p < .00) and lower DHPG levels by 42% (p < .00) compared to the control group. No group differences were noted in NE plasma levels. Cognitive function (IQ tested by Stanford Binet Intelligence Scale) was associated with EPI in the LN group (r = 0.77, p = .009), but not in the control group. The abnormally high EPI plasma concentrations may indicate another biochemical dysfunction secondary to the absence of the HPRT enzyme in LN patients. Such a biochemical deficit is likely to originate from the adrenal medulla, which is the primary site of EPI synthesis. The adrenal medulla may be directly affected by the absence of hypoxanthine guanine phosphoribosyl transferase (HPRT) enzyme, or may receive inappropriately high descending activation input from the brain. The abnormally low DHPG levels, in the context of normal NE levels, indicates low MAO activity, either as a primary deficit, or as secondary adaptive changes to spare NE levels that would otherwise be too low for adequate noradrenergic function.
MAJOR MESH DESCRIPTORS: *Epinephrine-blood; *Lesch-Nyhan-Syndrome-blood; *Methoxyhydroxyphenylglycol-analogs-and-derivatives; *Norepinephrine-blood
MINOR MESH DESCRIPTORS: Adolescence-; Adult-; Age-Factors; Blood-Pressure; Child-; Lesch-Nyhan-Syndrome-physiopathology; Methoxyhydroxyphenylglycol-blood; Multivariate-Analysis; Pulse-; Reference-Values
CHECKTAGS: Human
PUBLICATION TYPE: Journal-Article
SUBHEADINGS: blood; physiopathology; analogs-and-derivatives
CAS REGISTRY NUMBER OR EC NUMBER: 3343-19-9; 51-41-2; 51-43-4; 534-82-7
NAME OF SUBSTANCE: dihydroxyphenylethylene-glycol; Norepinephrine; Epinephrine; Methoxyhydroxyphenylglycol
SUBSET: Index-Medicus
UPDATE CODE: 20001218
ACCESSION NUMBER: 20157549
RECORD FEATURES: ABSTRACT (AB)