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[PMID]: 29502913
[Au] Autor:Sklirou E; Lichter-Konecki U
[Ad] Address:Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.
[Ti] Title:Inborn Errors of Metabolism with Cognitive Impairment: Metabolism Defects of Phenylalanine, Homocysteine and Methionine, Purine and Pyrimidine, and Creatine.
[So] Source:Pediatr Clin North Am;65(2):267-277, 2018 Apr.
[Is] ISSN:1557-8240
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Phenylketonuria is a defect in phenylalanine metabolism resulting in the excretion of phenylketones and severe intellectual disability. The principle of eliminating the offending amino acid from the diet as a successful treatment strategy was demonstrated. The development of a low methionine diet to treat homocystinuria was established after identifying the transsulfuration pathway resulting in cysteine synthesis. Both conditions are examples of disorders of amino acid metabolism. Lesch-Nyhan syndrome, a rare disorder of purine metabolism resulting in intellectual disability and self-injurious behavior, is a classical inborn error of metabolism. Disorders of creatine biosynthesis are relatively newly described and less known diseases.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1803
[Cu] Class update date: 180305
[Lr] Last revision date:180305
[St] Status:In-Data-Review

  2 / 1341 MEDLINE  
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[PMID]: 29479880
[Au] Autor:Huang J; Zhang C; Guo Q; Zhang X; Ma L; Zhan Y; Chen Y
[Ti] Title:Lesch-Nyhan Syndrome in a Chinese Family with Mutation in the Hypoxanthine-Guanine Phosphoribosyltransferase Gene.
[So] Source:Clin Lab;64(1):197-200, 2018 Jan 01.
[Is] ISSN:1433-6510
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:BACKGROUND: Lesch-Nyhan syndrome (LNS) is a congenital X-linked recessive neurogenetic disorder caused by mutations in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene. The main clinical manifestation includes hyperuricemia, juvenile-onset gouty arthritis, and neurological developmental disorders. Studies have reported more than 400 HPRT gene mutation sites, but the incidence of LNS in the Chinese population is extremely low. METHODS: Here we report a 16-year-old male patient who suffered neurological dysfunction at an early age and gouty arthritis in his youth. RESULTS: No activity of the HPRT enzyme was detected in the erythrocytes. Furthermore, we found a mutation on exon 3 of the HPRT gene in the patient and his mother (exon 3: c.143G>A), which resulted in arginine to histidine (p.R48H) substitution in the encoded protein. The same mutation was reported in several European families, but was found for the first time in a Chinese family. CONCLUSIONS: Clinicians in China have poor experience in diagnosing LNS cases due to the low incidence in China. Therefore, LNS screening for infants or adolescents with hyperuricemia, gouty arthritis, and neurological dysfunction should be performed.
[Pt] Publication type:CASE REPORTS
[Em] Entry month:1802
[Cu] Class update date: 180226
[Lr] Last revision date:180226
[St] Status:In-Data-Review
[do] DOI:10.7754/Clin.Lab.2017.170813

  3 / 1341 MEDLINE  
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[PMID]: 29227296
[Au] Autor:Harris JC
[Ad] Address:The Johns Hopkins University School of Medicine, Charlotte R. Bloomberg Children's Center, Baltimore, Maryland, USA.
[Ti] Title:Lesch-Nyhan syndrome and its variants: examining the behavioral and neurocognitive phenotype.
[So] Source:Curr Opin Psychiatry;31(2):96-102, 2018 Mar.
[Is] ISSN:1473-6578
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:PURPOSE OF REVIEW: Lesch-Nyhan Syndrome (LNS) is a metabolic disorder involving mutations in the HGPRT1 gene that result in hyperuricemia, intellectual disability, a dystonic movement disorder, and compulsive self-injury with self-mutilation. The aim of this review is to summarize recent research that documents the extended behavioral, neurologic, and neurocognitive phenotype in classic LNS, to describe milder variants of HGprt deficiency that do not self-injure and have less severe neurological and cognitive deficits, and to provide an update on treatment for associated psychiatric and behavioral disorders. RECENT FINDINGS: Psychiatric management utilizes combined behavioral and pharmacological treatment in conjunction with protective equipment and dental management to avert self-injury. Pharmacological management focuses on stabilization of mood and anxiety management. S-adenosylmethionine (SAMe), a physiological intermediate in methylation and transsulfuration, has shown beneficial effects in carefully selected patients who can tolerate the drug. Deep brain stimulation is shown in several case reports and series to reduce or eliminate self-injury and aggression, and in some cases, modify dystonia. SUMMARY: This review highlights progress in our understanding of the behavioral and neurocognitive phenotype of Lesch-Nyhan syndrome (HGprt deficiency) and its variants, describes psychiatric and behavioral management, and discusses prospects for new therapies.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1712
[Cu] Class update date: 180131
[Lr] Last revision date:180131
[St] Status:In-Data-Review
[do] DOI:10.1097/YCO.0000000000000388

  4 / 1341 MEDLINE  
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[PMID]: 29305058
[Au] Autor:Zizzo MG; Frinchi M; Nuzzo D; Jinnah HA; Mudò G; Condorelli DF; Caciagli F; Ciccarelli R; Di Iorio P; Mulè F; Belluardo N; Serio R
[Ad] Address:Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; ATeN (Advanced Technologies Network Center), University of Palermo, Viale delle Scienze, Palermo, Italy.
[Ti] Title:Altered gastrointestinal motility in an animal model of Lesch-Nyhan disease.
[So] Source:Auton Neurosci;, 2017 Dec 20.
[Is] ISSN:1872-7484
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Mutations in the HGPRT1 gene, which encodes hypoxanthine-guanine phosphoribosyltransferase (HGprt), housekeeping enzyme responsible for recycling purines, lead to Lesch-Nyhan disease (LND). Clinical expression of LND indicates that HGprt deficiency has adverse effects on gastrointestinal motility. Therefore, we aimed to evaluate intestinal motility in HGprt knockout mice (HGprt¯). Spontaneous and neurally evoked mechanical activity was recorded in vitro as changes in isometric tension in circular muscle strips of distal colon. HGprt¯ tissues showed a lower in amplitude spontaneous activity and atropine-sensitivity neural contraction compared to control mice. The responses to carbachol and to high KCl were reduced, demonstrating a widespread impairment of contractility. L-NAME was not able in the HGprt¯ tissues to restore the large amplitude contractile activity typical of control. In HGprt¯ colon, a reduced expression of dopaminergic D1 receptor was observed together with the loss of its tonic inhibitory activity present in control-mice. The analysis of inflammatory and oxidative stress in colonic tissue of HGprt¯ mice revealed a significant increase of lipid peroxidation associated with over production of oxygen free radicals. In conclusion, HGprt deficiency in mice is associated with a decrease in colon contractility, not dependent upon reduction of acetylcholine release from the myenteric plexus or hyperactivity of inhibitory signalling. By contrast the increased levels of oxidative stress could partially explain the reduced colon motility in HGprt¯ mice. Colonic dysmotility observed in HGprt¯ mice may mimic the gastrointestinal dysfunctions symptoms of human syndrome, providing a useful animal model to elucidate the pathophysiology of this problem in the LND.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180106
[Lr] Last revision date:180106
[St] Status:Publisher

  5 / 1341 MEDLINE  
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[PMID]: 29185864
[Au] Autor:Nguyen KV; Naviaux RK; Nyhan WL
[Ad] Address:a Department of Medicine, Biochemical Genetics and Metabolism, The Mitochondrial and Metabolic Disease Center, School of Medicine , University of California, San Diego , CA , USA.
[Ti] Title:Novel mutation in the human HPRT1 gene and the Lesch-Nyhan disease.
[So] Source:Nucleosides Nucleotides Nucleic Acids;36(11):704-711, 2017 Nov 02.
[Is] ISSN:1532-2335
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Lesch-Nyhan disease (LND) is a rare X-linked inherited neurogenetic disorder of purine metabolism in which the enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt) is defective. The authors report a novel point mutation that led to HGprt-related neurological dysfunction (HND) in a family in which there was a missense mutation in exon 6 of the coding region of the HPRT1 gene: g.34938G>T, c.403G>T, p.D135Y. Molecular diagnosis is consistent with the genetic heterogeneity of the HPRT1 gene responsible for HGprt deficiency. It allows fast, accurate carrier detection and genetic counseling.
[Mh] MeSH terms primary: Hypoxanthine Phosphoribosyltransferase/genetics
Lesch-Nyhan Syndrome/enzymology
Lesch-Nyhan Syndrome/genetics
Mutation, Missense
[Mh] MeSH terms secundary: Base Sequence
Child, Preschool
Exons/genetics
Female
Humans
Hypoxanthine Phosphoribosyltransferase/metabolism
Male
Pedigree
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:EC 2.4.2.8 (Hypoxanthine Phosphoribosyltransferase)
[Em] Entry month:1801
[Cu] Class update date: 180101
[Lr] Last revision date:180101
[Js] Journal subset:IM
[Da] Date of entry for processing:171130
[St] Status:MEDLINE
[do] DOI:10.1080/15257770.2017.1395037

  6 / 1341 MEDLINE  
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[PMID]: 28877755
[Au] Autor:Jasinge E; Kularatnam GAM; Dilanthi HW; Vidanapathirana DM; Jayasena KLSPKM; Chandrasiri NDPD; Indika NLR; Ratnayake PD; Gunasekara VN; Fairbanks LD; Stiburkova B
[Ad] Address:Department of Chemical Pathology, Lady Ridgeway Hospital for Children, Dr Danister De Silva Mawatha, Colombo 8, Sri Lanka. eresha.jasinge@gmail.com.
[Ti] Title:Uric acid, an important screening tool to detect inborn errors of metabolism: a case series.
[So] Source:BMC Res Notes;10(1):454, 2017 Sep 06.
[Is] ISSN:1756-0500
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: Uric acid is the metabolic end product of purine metabolism in humans. Altered serum and urine uric acid level (both above and below the reference ranges) is an indispensable marker in detecting rare inborn errors of metabolism. We describe different case scenarios of 4 Sri Lankan patients related to abnormal uric acid levels in blood and urine. CASE 1: A one-and-half-year-old boy was investigated for haematuria and a calculus in the bladder. Xanthine crystals were seen in microscopic examination of urine sediment. Low uric acid concentrations in serum and low urinary fractional excretion of uric acid associated with high urinary excretion of xanthine and hypoxanthine were compatible with xanthine oxidase deficiency. CASE 2: An 8-month-old boy presented with intractable seizures, feeding difficulties, screaming episodes, microcephaly, facial dysmorphism and severe neuro developmental delay. Low uric acid level in serum, low fractional excretion of uric acid and radiological findings were consistent with possible molybdenum cofactor deficiency. Diagnosis was confirmed by elevated levels of xanthine, hypoxanthine and sulfocysteine levels in urine. CASE 3: A 3-year-10-month-old boy presented with global developmental delay, failure to thrive, dystonia and self-destructive behaviour. High uric acid levels in serum, increased fractional excretion of uric acid and absent hypoxanthine-guanine phosphoribosyltransferase enzyme level confirmed the diagnosis of Lesch-Nyhan syndrome. CASE 4: A 9-year-old boy was investigated for lower abdominal pain, gross haematuria and right renal calculus. Low uric acid level in serum and increased fractional excretion of uric acid pointed towards hereditary renal hypouricaemia which was confirmed by genetic studies. CONCLUSION: Abnormal uric acid level in blood and urine is a valuable tool in screening for clinical conditions related to derangement of the nucleic acid metabolic pathway.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1709
[Cu] Class update date: 170915
[Lr] Last revision date:170915
[St] Status:In-Process
[do] DOI:10.1186/s13104-017-2795-2

  7 / 1341 MEDLINE  
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[PMID]: 28712454
[Au] Autor:Gasperini M; Findlay GM; McKenna A; Milbank JH; Lee C; Zhang MD; Cusanovich DA; Shendure J
[Ad] Address:Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: gasperim@uw.edu.
[Ti] Title:CRISPR/Cas9-Mediated Scanning for Regulatory Elements Required for HPRT1 Expression via Thousands of Large, Programmed Genomic Deletions.
[So] Source:Am J Hum Genet;101(2):192-205, 2017 Aug 03.
[Is] ISSN:1537-6605
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The extent to which non-coding mutations contribute to Mendelian disease is a major unknown in human genetics. Relatedly, the vast majority of candidate regulatory elements have yet to be functionally validated. Here, we describe a CRISPR-based system that uses pairs of guide RNAs (gRNAs) to program thousands of kilobase-scale deletions that deeply scan across a targeted region in a tiling fashion ("ScanDel"). We applied ScanDel to HPRT1, the housekeeping gene underlying Lesch-Nyhan syndrome, an X-linked recessive disorder. Altogether, we programmed 4,342 overlapping 1 and 2 kb deletions that tiled 206 kb centered on HPRT1 (including 87 kb upstream and 79 kb downstream) with median 27-fold redundancy per base. We functionally assayed programmed deletions in parallel by selecting for loss of HPRT function with 6-thioguanine. As expected, sequencing gRNA pairs before and after selection confirmed that all HPRT1 exons are needed. However, HPRT1 function was robust to deletion of any intergenic or deeply intronic non-coding region, indicating that proximal regulatory sequences are sufficient for HPRT1 expression. Although our screen did identify the disruption of exon-proximal non-coding sequences (e.g., the promoter) as functionally consequential, long-read sequencing revealed that this signal was driven by rare, imprecise deletions that extended into exons. Our results suggest that no singular distal regulatory element is required for HPRT1 expression and that distal mutations are unlikely to contribute substantially to Lesch-Nyhan syndrome burden. Further application of ScanDel could shed light on the role of regulatory mutations in disease at other loci while also facilitating a deeper understanding of endogenous gene regulation.
[Mh] MeSH terms primary: CRISPR-Cas Systems/genetics
Gene Expression Regulation/genetics
Hypoxanthine Phosphoribosyltransferase/genetics
Regulatory Sequences, Nucleic Acid/genetics
Sequence Deletion/genetics
[Mh] MeSH terms secundary: Cell Line
HEK293 Cells
Humans
Hypoxanthine Phosphoribosyltransferase/biosynthesis
Lesch-Nyhan Syndrome/genetics
RNA, Guide/genetics
Thioguanine/metabolism
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (RNA, Guide); EC 2.4.2.8 (Hypoxanthine Phosphoribosyltransferase); FTK8U1GZNX (Thioguanine)
[Em] Entry month:1709
[Cu] Class update date: 170907
[Lr] Last revision date:170907
[Js] Journal subset:IM
[Da] Date of entry for processing:170718
[St] Status:MEDLINE

  8 / 1341 MEDLINE  
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[PMID]: 28524722
[Au] Autor:Nguyen KV; Silva S; Troncoso M; Naviaux RK; Nyhan WL
[Ad] Address:a Department of Medicine, Biochemical Genetics and Metabolism, The Mitochondrial and Metabolic Disease Center, School of Medicine , University of California , San Diego , California , USA.
[Ti] Title:Lesch-Nyhan disease in two families from Chiloé Island with mutations in the HPRT1 gene.
[So] Source:Nucleosides Nucleotides Nucleic Acids;36(7):452-462, 2017 Jul 03.
[Is] ISSN:1532-2335
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Lesch-Nyhan disease (LND) is a rare X-linked inherited neurogenetic disorder of purine metabolism in which the enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt) is defective. The authors report two independent point mutations leading to splicing errors: IVS 2 +1G>A, c.134 +1G>A, and IVS 3 +1G>A, c.318 +1G>A in the hypoxanthine-phosphoribosyltransferase1 (HPRT1) gene which result in exclusion of exon 2 and exon 3 respectively, in the HGprt enzyme protein from different members of two Chiloé Island families. Molecular analysis has revealed the heterogeneity of genetic mutation of the HPRT1 gene responsible for the HGprt deficiency. It allows fast, accurate carrier detection and genetic counseling.
[Mh] MeSH terms primary: Hypoxanthine Phosphoribosyltransferase/genetics
Islands
Lesch-Nyhan Syndrome/enzymology
Lesch-Nyhan Syndrome/genetics
Mutation
Pedigree
[Mh] MeSH terms secundary: Adolescent
Adult
Base Sequence
Chile
Exons/genetics
Female
Humans
Male
Young Adult
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:EC 2.4.2.8 (Hypoxanthine Phosphoribosyltransferase)
[Em] Entry month:1711
[Cu] Class update date: 171113
[Lr] Last revision date:171113
[Js] Journal subset:IM
[Da] Date of entry for processing:170520
[St] Status:MEDLINE
[do] DOI:10.1080/15257770.2017.1315434

  9 / 1341 MEDLINE  
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[PMID]: 28357186
[Au] Autor:Tewari N; Mathur VP; Sardana D; Bansal K
[Ad] Address:Pedodontics & Preventive Dentistry, Center for Dental Education and Research, All India Institute of Medical Sciences, New Delhi, India.
[Ti] Title:Lesch-Nyhan syndrome: The saga of metabolic abnormalities and self-injurious behavior.
[So] Source:Intractable Rare Dis Res;6(1):65-68, 2017 Feb.
[Is] ISSN:2186-3644
[Cp] Country of publication:Japan
[La] Language:eng
[Ab] Abstract:Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder of purine metabolism caused by a mutation in Xq26.2-q26.3 (OMIM 308000.0004). The presence of the diagnostic triad, signs of self-injurious behavior (SIB) and results of pedigree analysis and novel molecular biology & genetic testing, confirms the diagnosis of LNS. With a level of hypoxanthine guanine phosphoribosyl-transferase 1 (HPRT1) enzyme activity < 2%, patients develop neurological, neurocognitive, and neuromotor symptoms along with SIB. Described here is a case of 4-year-old boy who was diagnosed with LNS. The boy displayed SIB, biting of the lips and fingers, and he had cerebral venous sinus thrombosis caused by LNS.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1703
[Cu] Class update date: 170816
[Lr] Last revision date:170816
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.5582/irdr.2016.01076

  10 / 1341 MEDLINE  
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[PMID]: 28282408
[Au] Autor:Zennaro C; Tonon F; Zarattini P; Clai M; Corbelli A; Carraro M; Marchetti M; Ronda L; Paredi G; Rastaldi MP; Percudani R
[Ad] Address:Department of Medical, Surgery and Health Sciences, Università degli Studi di Trieste, Trieste, Italy.
[Ti] Title:The renal phenotype of allopurinol-treated HPRT-deficient mouse.
[So] Source:PLoS One;12(3):e0173512, 2017.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Excess of uric acid is mainly treated with xanthine oxidase (XO) inhibitors, also called uricostatics because they block the conversion of hypoxanthine and xanthine into urate. Normally, accumulation of upstream metabolites is prevented by the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. The recycling pathway, however, is impaired in the presence of HPRT deficiency, as observed in Lesch-Nyhan disease. To gain insights into the consequences of purine accumulation with HPRT deficiency, we investigated the effects of the XO inhibitor allopurinol in Hprt-lacking (HPRT-/-) mice. Allopurinol was administered in the drinking water of E12-E14 pregnant mothers at dosages of 150 or 75 µg/ml, and mice sacrificed after weaning. The drug was well tolerated by wild-type animals and heterozygous HPRT+/- mice. Instead, a profound alteration of the renal function was observed in the HPRT-/- model. Increased hypoxanthine and xanthine concentrations were found in the blood. The kidneys showed a yellowish appearance, diffuse interstitial nephritis, with dilated tubules, inflammatory and fibrotic changes of the interstitium. There were numerous xanthine tubular crystals, as determined by HPLC analysis. Oil red O staining demonstrated lipid accumulation in the same location of xanthine deposits. mRNA analysis showed increased expression of adipogenesis-related molecules as well as profibrotic and proinflammatory pathways. Immunostaining showed numerous monocyte-macrophages and overexpression of alpha-smooth muscle actin in the tubulointerstitium. In vitro, addition of xanthine to tubular cells caused diffuse oil red O positivity and modification of the cell phenotype, with loss of epithelial features and appearance of mesenchymal characteristics, similarly to what was observed in vivo. Our results indicate that in the absence of HPRT, blockade of XO by allopurinol causes rapidly developing renal failure due to xanthine deposition within the mouse kidney. Xanthine seems to be directly involved in promoting lipid accumulation and subsequent phenotype changes of tubular cells, with activation of inflammation and fibrosis.
[Mh] MeSH terms primary: Allopurinol/pharmacology
Lesch-Nyhan Syndrome/drug therapy
Nephritis/drug therapy
Xanthine Oxidase/antagonists & inhibitors
Xanthine/metabolism
[Mh] MeSH terms secundary: Animals
Hypoxanthine Phosphoribosyltransferase/genetics
Lesch-Nyhan Syndrome/genetics
Lesch-Nyhan Syndrome/metabolism
Lesch-Nyhan Syndrome/pathology
Mice
Mice, Knockout
Nephritis/genetics
Nephritis/metabolism
Nephritis/pathology
Xanthine Oxidase/genetics
Xanthine Oxidase/metabolism
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:1AVZ07U9S7 (Xanthine); 63CZ7GJN5I (Allopurinol); EC 1.17.3.2 (Xanthine Oxidase); EC 2.4.2.8 (Hypoxanthine Phosphoribosyltransferase)
[Em] Entry month:1708
[Cu] Class update date: 170922
[Lr] Last revision date:170922
[Js] Journal subset:IM
[Da] Date of entry for processing:170311
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173512


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