ABSTRACT
BACKGROUND: Patients with deficient hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity present hyperuricemia and/or hyperuricosuria, with a variable degree of neurological manifestations. Hyperuricemia in HPRT deficiency is due to uric acid overproduction and is frequently treated with allopurinol. Renal uric acid excretion is sharply increased in these patients. In recent years, several renal tubular urate transporter single nucleotide polymorphisms (SNPs), including those of the GLUT9, ABCG2 and URAT1 genes, have been described that influence the renal handling of uric acid and modulate serum urate levels. In the present study, we analyzed whether GLUT9, ABCG2 and URAT1 gene SNPs are able to influence uric acid levels and allopurinol response in patients with HPRT deficiency. METHODS: Three SNPs, URAT1 rs11231825, GLUT9 rs16890979 and ABCG2 rs2231142, previously associated in our population with hyperuricemia and gout, were analyzed in 27 patients with HPRT deficiency treated with allopurinol for at least 5 years. RESULTS: Patients with HPRT deficiency having allele A of rs16890979 in the GLUT9 gene present with a lower serum urate concentration at diagnosis, before allopurinol treatment is instituted, and need lower allopurinol doses to maintain serum urate levels between 268 and 446 µmol/L (4.5 and 7.5 mg/dL). No relationship between rs2231142 in the ABCG2 gene or rs11231825 in the URAT1 gene and serum urate levels or allopurinol response was found in our patients with HPRT deficiency. CONCLUSIONS: GLUT9 SNPs influence the renal handling of uric acid and modulate serum urate levels and the response to treatment in patients with uric acid overproduction due to HPRT deficiency.
Subject(s)
Glucose Transport Proteins, Facilitative/genetics , Gout/genetics , Hyperuricemia/genetics , Lesch-Nyhan Syndrome/genetics , Polymorphism, Single Nucleotide , Uric Acid/blood , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Adolescent , Adult , Allopurinol/therapeutic use , Biomarkers/blood , Child , Child, Preschool , Genetic Predisposition to Disease , Glucose Transport Proteins, Facilitative/metabolism , Gout/blood , Gout/diagnosis , Gout/drug therapy , Gout Suppressants/therapeutic use , Humans , Hyperuricemia/blood , Hyperuricemia/diagnosis , Hyperuricemia/drug therapy , Lesch-Nyhan Syndrome/blood , Lesch-Nyhan Syndrome/diagnosis , Lesch-Nyhan Syndrome/drug therapy , Middle Aged , Neoplasm Proteins/genetics , Organic Anion Transporters/genetics , Organic Cation Transport Proteins/genetics , Phenotype , Renal Elimination , Treatment Outcome , Young AdultABSTRACT
The neurological manifestations of Lesch-Nyhan disease (LND) have been attributed to the effect of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency on nervous system development. An increase has been reported in the levels of 5-aminoimidazole-4-carboxamide-1-ß-D-ribotide (AICAR) and its triphosphate form ZTP in the red blood cells of patients with LND. AICAR accumulation in the brain has been hypothesized as the cause of some of the neurological symptoms of patients with LND. In this study, we examined the effect of AICAR on the differentiation of neurons in the well-established human NTERA-2 cl.D1 (NT2/D1) embryonic carcinoma neurogenesis model. NT2/D1 cells were differentiated along neuroectodermal lineages after exposure to 10-µM retinoic acid (RA), with or without the addition of 25-µM AICAR to the culture medium. The effect of AICAR on RA differentiation were examined through changes in the expression of genes essential to neuronal differentiation, as well as genes from the Wnt/ß-catenin, transforming growth factor beta (TGFß) and sonic hedgehog (SHH) pathways. Results: RA-induced differentiation in the NT2/D1 cells significantly increased the expression of MAP2, NRG1, NRP1, NRP2, NEUROG1 and EN1 genes (genes linked to neural differentiation) compared with undifferentiated NT2/D1 cells. We found that AICAR increased the expression of the SHH gene and the WNT2 and WNT7B genes but did not influence the expression of genes whose overexpression characterize early neurodevelopmental processes. Conclusion: The relevance of the AICAR related changes in the SHH and Wnt/ß-catenin pathway genes expression in the physiopathology of LND warrants further exploration.
Subject(s)
Aminoimidazole Carboxamide/analogs & derivatives , Neurogenesis/drug effects , Ribonucleotides , Aminoimidazole Carboxamide/pharmacology , Cell Differentiation/drug effects , Gene Expression Regulation/drug effects , Hedgehog Proteins/genetics , Humans , Microtubule-Associated Proteins/genetics , Neurogenesis/genetics , Neurons/cytology , Ribonucleotides/pharmacology , Signal Transduction , Transforming Growth Factors/genetics , beta Catenin/geneticsABSTRACT
X chromosome inactivation (XCI) ratios of normal females can range from a highly skewed ratio of 0:100 to a 50:50 ratio. In several X-linked disorders, female carriers present skewed X inactivation. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is an X-linked disorder. Males are affected and present with the complete Lesch-Nyhan disease (LND) or with a partial phenotype (Lesch-Nyhan variant, LNV). Female carriers are usually asymptomatic. The aim of the present study was to analyze the XCI pattern of HPRT-deficiency carrier females. As a group, 75% of HPRT-deficiency carrier females presented skewed XCI. Moreover, skewed XCI is significantly more frequent in LND carriers (83%) than in LNV (0-50%, depending on the phenotype severity). The ratios of the preferentially inactivated allele of carrier females were significantly higher than the ratios of the preferentially inactivated allele of noncarrier females (89.4±15, n=52 vs 65.2±12, n=52; P<0.0001). For carrier diagnosis, the presence of skewed XCI presents a sensitivity of 75% with a specificity of 85%. In LND families, the presence of skewed XCI is more sensitive for carrier diagnosis than in LNV families; however, we believe that this test is not accurate for carrier diagnostic purposes.
Subject(s)
Hypoxanthine Phosphoribosyltransferase/genetics , Lesch-Nyhan Syndrome/genetics , X Chromosome Inactivation/genetics , Aged , Aged, 80 and over , Female , Heterozygote , Humans , Middle Aged , PhenotypeABSTRACT
We report two Lesch-Nyhan Disease (LND) patients who developed new forms of self-injurious behavior following total dental extraction. Patients 1 and 2 were submitted to total teeth extraction at the age of 13 and 8 years, respectively, due to continuous self-biting, not prevented by mouth guards. Severity of dystonia was markedly reduced and quality of life improved. After 12 and 17 months, respectively, patient 1 started rubbing one foot against other and scratching toenails with his hands, and patient 2 stuck his legs and feet against hard objects. These forms of self-injury behavior could be easily prevented with protective materials, according to the mothers.
Subject(s)
Lesch-Nyhan Syndrome/diagnosis , Self-Injurious Behavior/diagnosis , Adolescent , Child , Humans , Lesch-Nyhan Syndrome/psychology , Lesch-Nyhan Syndrome/surgery , Male , Quality of Life , Self-Injurious Behavior/prevention & control , Tooth ExtractionABSTRACT
OBJECTIVES: An international double-blind, parallel-group, randomized controlled trial was performed to determine the efficacy and safety of a new first-line strategy in mild to moderate hypertension based on a single-pill combination of perindopril/amlodipine versus a validated stepped-care strategy (initiation with valsartan monotherapy, up-titrating to valsartan/amlodipine after 2 months). METHODS: At inclusion, patients received perindopril/amlodipine 3.5/2.5âmg or valsartan 80âmg. At 1, 2, and 3 months, patients were up-titrated if they had uncontrolled hypertension (≥140/90âmmHg). The up-titration steps were: perindopril/amlodipine 7/5âmg, 14/10âmg, and 14/10âmg + indapamide sustained release 1.5âmg; or valsartan 160âmg, valsartan/amlodipine 160/5âmg, and 160/10âmg. The two groups were similar at baseline (55.5 years, 53% men, blood pressure 163.5/100.2âmmHg); 881 perindopril/amlodipine and 876âvalsartan/amlodipine patients were analyzed for efficacy. RESULTS: After 1 month, the rate of controlled hypertension was 33% with perindopril/amlodipine versus 27% with valsartan/amlodipine (estimate of difference, +6.1%; Pâ=â0.005); this between-strategy difference remained significant at every visit (Pâ<â0.05). After 3 months, blood pressure was 137.8â±â12.4/83.3â±â8.7 and 139.7â±â13.3/84.8â±â9.0âmmHg, respectively, with greater reductions from baseline with perindopril/amlodipine (primary endpoint -2.0/-1.5âmmHg; both Pâ<â0.001). Similar results were observed at all other visits (all Pâ≤â0.001). The safety of the two strategies was equivalent. CONCLUSIONS: The three-step strategy of initiation with single-pill perindopril/amlodipine produces greater reductions in blood pressure, and better and quicker rates of control of hypertension. This can be expected to be associated with benefits beyond blood pressure control, notably improved compliance and better cardioprotection.
Subject(s)
Amlodipine, Valsartan Drug Combination/therapeutic use , Amlodipine/therapeutic use , Antihypertensive Agents/administration & dosage , Hypertension/drug therapy , Perindopril/therapeutic use , Adult , Aged , Blood Pressure/drug effects , Double-Blind Method , Drug Combinations , Drug Therapy, Combination , Female , Humans , Indapamide/administration & dosage , Male , Middle Aged , Valsartan/administration & dosageABSTRACT
An international double-blind, parallel-group,randomized controlled trial was performed to determinethe efficacy and safety of a new first-line strategy in mildto moderate hypertension based on a single-pillcombination of perindopril/amlodipine versus a validatedstepped-care strategy (initiation with valsartanmonotherapy, up-titrating to valsartan/amlodipine after2 months).Methods: At inclusion, patients received perindopril/amlodipine 3.5/2.5mg or valsartan 80 mg. At 1, 2, and3 months, patients were up-titrated if they haduncontrolled hypertension ( 140/90 mmHg). The uptitrationsteps were: perindopril/amlodipine 7/5 mg,14/10 mg, and 14/10mg R indapamide sustained release1.5 mg; or valsartan 160 mg, valsartan/amlodipine160/5 mg, and 160/10 mg. The two groups were similarat baseline (55.5 years, 53% men, blood pressure163.5/100.2 mmHg); 881 perindopril/amlodipine and876 valsartan/amlodipine patients were analyzed forefficacy.Results: After 1 month, the rate of controlledhypertension was 33% with perindopril/amlodipine versus27% with valsartan/amlodipine (estimate of difference,R6.1%; P»0.005); this between-strategy differenceremained significant at every visit (P<0.05). After 3months, blood pressure was 137.8 12.4/83.3 8.7 and139.7 13.3/84.8 9.0 mmHg, respectively, with greaterreductions from baseline with perindopril/amlodipine(primary endpoint 2.0/ 1.5 mmHg; both P<0.001).Similar results were observed at all other visits (allP 0.001). The safety of the two strategies wasequivalent.Conclusions: The three-step strategy of initiation withsingle-pill perindopril/amlodipine produces greaterreductions in blood pressure, and better and quicker ratesof control of hypertension. This can be expected to beassociated with benefits beyond blood pressure control,notably improved compliance and better cardioprotection.Keywords: amlodipine, hypertension, perindopril, singlepillcombination, valsartan...
Subject(s)
Hypertension , Morbidity , PerindoprilABSTRACT
BACKGROUND: Phosphoribosyl pyrophosphate synthetase (PRS) I deficiency is a rare medical condition caused by missense mutations in PRPS1 that lead to three different phenotypes: Arts Syndrome (MIM 301835), X-linked Charcot-Marie-Tooth (CMTX5, MIM 311070) or X-linked non-syndromic sensorineural deafness (DFN2, MIM 304500). All three are X-linked recessively inherited and males affected display variable degree of central and peripheral neuropathy. We applied whole exome sequencing to a three-generation family with optic atrophy followed by retinitis pigmentosa (RP) in all three cases, and ataxia, progressive peripheral neuropathy and hearing loss with variable presentation. METHODS: Whole exome sequencing was performed in two affecteds and one unaffected member of the family. Sanger sequencing was used to validate and segregate the 12 candidate mutations in the family and to confirm the absence of the novel variant in PRPS1 in 191 controls. The pathogenic role of the novel mutation in PRPS1 was assessed in silico and confirmed by enzymatic determination of PRS activity, mRNA expression and sequencing, and X-chromosome inactivation. RESULTS: A novel missense mutation was identified in PRPS1 in the affected females. Age of onset, presentation and severity of the phenotype are highly variable in the family: both the proband and her mother have neurological and ophthalmological symptoms, whereas the phenotype of the affected sister is milder and currently confined to the eye. Moreover, only the proband displayed a complete lack of expression of the wild type allele in leukocytes that seems to correlate with the degree of PRS deficiency and the severity of the phenotype. Interestingly, optic atrophy and RP are the only common manifestations to all three females and the only phenotype correlating with the degree of enzyme deficiency. CONCLUSIONS: These results are in line with recent evidence of the existence of intermediate phenotypes in PRS-I deficiency syndromes and demonstrate that females can exhibit a disease phenotype as severe and complex as their male counterparts.
Subject(s)
Hearing Loss/genetics , Peripheral Nervous System Diseases/genetics , Phenotype , Purine-Pyrimidine Metabolism, Inborn Errors/genetics , Retinitis Pigmentosa/genetics , Ribose-Phosphate Pyrophosphokinase/deficiency , Amino Acid Sequence , Female , Hearing Loss/complications , Hearing Loss/diagnosis , Humans , Male , Molecular Sequence Data , Mutation, Missense/genetics , Pedigree , Peripheral Nervous System Diseases/complications , Peripheral Nervous System Diseases/diagnosis , Protein Structure, Secondary , Purine-Pyrimidine Metabolism, Inborn Errors/complications , Purine-Pyrimidine Metabolism, Inborn Errors/diagnosis , Retinitis Pigmentosa/complications , Retinitis Pigmentosa/diagnosis , Ribose-Phosphate Pyrophosphokinase/genetics , SyndromeABSTRACT
Patients with Lesch-Nyhan disease (LND) often engage in self-injurious biting. This problem requires difficult management choices, sometimes including removal of the teeth. Although many health care professionals are reluctant to remove teeth in a child because of the permanent negative cosmetic consequences of the edentulous state, disfigurement of the face and tongue from self-biting can be worse. We analyzed the records of 5 LND patients who used mouth guards to spare the teeth. Success was variable, and dental extraction ultimately was required in 4 cases. We also reviewed previously published cases on the use of dental devices to spare teeth in LND. Various devices have been recommended, but failure rates are high, and tooth extraction often is still needed. Although dental extraction is not required in all cases, it should not be delayed when biting is severe.
ABSTRACT
OBJECTIVE: Primary gout has been associated with single-nucleotide polymorphisms (SNP) in several tubular urate transporter genes. No study has assessed the association of reabsorption and secretion urate transporter gene SNP with gout in a single cohort of documented primary patients with gout carefully subclassified as normoexcretors or underexcretors. METHODS: Three reabsorption SNP (SLC22A12/URAT1, SLC2A9/GLUT9, and SLC22A11/OAT4) and 2 secretion transporter SNP (SLC17A1/NPT1 and ABCG2/BRCP) were studied in 104 patients with primary gout and in 300 control subjects. The patients were subclassified into normoexcretors and underexcretors according to their serum and 24-h urinary uric acid levels under strict conditions of dietary control. RESULTS: Compared with control subjects, patients with gout showed different allele distributions of the 5 SNP analyzed. However, the diagnosis of underexcretor was only positively associated with the presence of the T allele of URAT1 rs11231825, the G allele of GLUT9 rs16890979, and the A allele of ABCG2 rs2231142. The association of the A allele of ABCG2 rs2231142 in normoexcretors was 10 times higher than in underexcretors. The C allele of NPT1 rs1165196 was only significantly associated with gout in patients with normal uric acid excretion. CONCLUSION: Gout with uric acid underexcretion is associated with transporter gene SNP related mainly to tubular reabsorption, whereas uric acid normoexcretion is associated only with tubular secretion SNP. This finding supports the concept of distinctive mechanisms to account for hyperuricemia in patients with gout with reduced or normal uric acid excretion.
Subject(s)
Gout/genetics , Hyperuricemia/genetics , Organic Anion Transporters/genetics , Polymorphism, Single Nucleotide , Uric Acid/urine , Aged , Alleles , Female , Gout/urine , Humans , Hyperuricemia/urine , Male , Middle AgedABSTRACT
The biennial 15th symposium on Purine and Pyrimidine metabolism was held in Madrid, June 2013 (PP13). During the meeting, several novel developments on the diagnosis, pathophysiology, and treatment of several inborn errors of purine and pyrimidine metabolism were presented. These ranged from new drugs for gout to enzyme replacement therapies for mitochondrial diseases. A relatively novel aspect in this meeting was the interest in purine and pyrimidine metabolism in nonmammalian systems, such as parasites, mycoplasms, and bacteria. Development of novel analogs for parasite infections, cardiovascular diseases, inflammatory diseases, and cancer were also discussed.
Subject(s)
Purine-Pyrimidine Metabolism, Inborn Errors/drug therapy , Purine-Pyrimidine Metabolism, Inborn Errors/metabolism , Purines/metabolism , Purines/therapeutic use , Pyrimidines/metabolism , Pyrimidines/therapeutic use , Awards and Prizes , Humans , Purines/chemistry , Pyrimidines/chemistryABSTRACT
BACKGROUND AND OBJECTIVES: Pharmacologic urate lowering therapy (ULT), at full maintenance doses, has been associated with acute gout arthritis (in up to 80% of patients). The American College of Rheumatology has recently advocated gradually titrating the maintenance dose upward to chosen serum urate target. Few studies have examined the efficacy and safety of a ULT in primary gout. PATIENTS AND METHODS: The ULT regimen examined included allopurinol (50 mg/day, with increases of 50 mg/month up to 300 mg/day) and colchicine, as prophylaxis to prevent acute gouty attacks. The efficacy and safety of this regimen was examined in 42 patients in whom allopurinol was withheld for ≥3 months and restarted after this assessment and followed up for 12 months. The efficacy and safety of the ULT regimen was related to the serum urate decrease and to the incidence of acute gout flares, respectively. RESULTS: Fifty-nine patients (mean age 59 years, 56 men) with primary gout received the gradually titrated ULT regimen. Baseline serum urate was (mean±SD) 8.4±0.8 mg/dL. At 3, 6, 9, and 12 months serum urate fell by a mean of 1.8, 2.5, 2.7, and 2.5 mg/dL, respectively (p<0.001). A serum urate level<6.0 mg/dL was achieved by 38/59 (64%) patients. During the 12 months following the start of the ULT we documented 10 acute arthritis episodes (17% of patients). CONCLUSIONS: A gradually titrated hypouricemic regimen for 6 months in patients with primary gout appears to be effective and safe.
Subject(s)
Gout/blood , Gout/drug therapy , Safety , Uric Acid/blood , Adult , Aged , Aged, 80 and over , Female , Hospitals , Humans , Male , Middle AgedABSTRACT
BACKGROUND AND OBJECTIVES: Primary gout has traditionally been associated with obesity, arterial hypertension, and abnormal lipid and glucose homeostasis, but we do not know the prevalence of these vascular risk factors in patients with primary gout from a Mediterranean country. PATIENTS AND METHOD: All patients with primary gout and 2 or more acute arthritis episodes documented by a physician were selected for the study. The diagnosis of MS required ≥3 criteria (ATP III). Patients were classified in two groups: decreased (underexcretors) and normal (normoexcretors) uric acid excretion related to serum urate levels. RESULTS: One hundred and four patients (mean age, 59 years; 100 males) with primary gout were included in the study. MS was diagnosed in 38 subjects (37%). The most frequent triad defining MS was an increased waist circumference, blood pressure, and trygliceride levels. The prevalence of type 2 diabetes mellitus (T2D) was significantly higher in patients with the MS (21/38, 55%) as compared with subjects without the MS (3/66, 5%; p<0.001). Mean serum urate level in patients with and without MS was identical (8.1 mg/dL), but mean 24-hour uric acid excretion was significantly lower in the former than in the latter (444±110 mg/24-hour/1,73 m2 versus 546±221 mg/day/1,73 m2; p=0.009). CONCLUSIONS: The condition of the MS occurs in about one-third of the patients with primary gout. Increased waist circumference, blood pressure, and triglycerides levels is the most frequent MS triad. Diminished urinary uric acid excretion is more severe in gout patients with the MS.
Subject(s)
Gout/complications , Metabolic Syndrome/complications , Metabolic Syndrome/epidemiology , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Mediterranean Region/epidemiology , Middle Aged , PrevalenceABSTRACT
Establishing meaningful relationships between genetic variations and clinical disease is a fundamental goal for all human genetic disorders. However, these genotype-phenotype correlations remain incompletely characterized and sometimes conflicting for many diseases. Lesch-Nyhan disease is an X-linked recessive disorder that is caused by a wide variety of mutations in the HPRT1 gene. The gene encodes hypoxanthine-guanine phosphoribosyl transferase, an enzyme involved in purine metabolism. The fine structure of enzyme has been established by crystallography studies, and its function can be measured with very precise biochemical assays. This rich knowledge of genetic alterations in the gene and their functional effect on its protein product provides a powerful model for exploring factors that influence genotype-phenotype correlations. The present study summarizes 615 known genetic mutations, their influence on the gene product, and their relationship to the clinical phenotype. In general, the results are compatible with the concept that the overall severity of the disease depends on how mutations ultimately influence enzyme activity. However, careful evaluation of exceptions to this concept point to several additional genetic and non-genetic factors that influence genotype-phenotype correlations. These factors are not unique to Lesch-Nyhan disease, and are relevant to most other genetic diseases. The disease therefore serves as a valuable model for understanding the challenges associated with establishing genotype-phenotype correlations for other disorders.
Subject(s)
Genetic Association Studies , Hypoxanthine Phosphoribosyltransferase/genetics , Lesch-Nyhan Syndrome/genetics , Lesch-Nyhan Syndrome/physiopathology , Mutation/genetics , Animals , HumansABSTRACT
Lesch-Nyhan disease (LND) is caused by lack of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity. Mutations in HPRT1 gene show variability in type and location within the gene, and in certain patients the HPRT coding sequence is normal and the molecular defect cannot be found. These patients presented a decreased HPRT1 expression of unknown cause. This is the first report of a carrier and prenatal diagnosis of LND due to a defect in HPRT gene expression regulation.
Subject(s)
Genetic Carrier Screening , Hypoxanthine Phosphoribosyltransferase/genetics , Lesch-Nyhan Syndrome/diagnosis , Lesch-Nyhan Syndrome/genetics , Prenatal Diagnosis , Humans , Infant , Mutation , RNA, Messenger/genetics , Real-Time Polymerase Chain ReactionSubject(s)
Gout/genetics , Organic Anion Transporters/genetics , Organic Cation Transport Proteins/genetics , Aged , Female , Genetic Association Studies , Humans , Male , Middle Aged , Mutation , SpainABSTRACT
Lesch-Nyhan disease (LND) is caused by complete deficiency of the hypoxanthine-guanine phosphoribosyltransferase enzyme. It is characterized by overproduction of uric acid, jointly with severe motor disability and self-injurious behaviour which physiopathology is unknown. These neurological manifestations suggest a dysfunction in the basal ganglia, and three neurotransmitters have been implicated in the pathogenesis of the disease: dopamine, adenosine and serotonin. All of them are implicated in motor function and behaviour, and act by binding to specific G-protein coupled receptors in the synaptic membrane where they seem to be integrated through receptor-receptor interactions. In this work we have confirmed at protein level the previously reported increased expression of DRD5 and the variably aberrant expression of ADORA2A, in LND PBL respect to control PBL. We have also described, for the first time, a decreased expression and protein level of 5-HTR1A in LND PBL respect to control PBL. If these results were confirmed in the Lesch-Nyhan patients basal ganglia cells, this would support the hypothesis that pathogenesis of neurological manifestations of Lesch-Nyhan patients may be related to an imbalance of neurotransmitters, rather than to the isolated disturbance of one of the neurotransmitters, and this fact should be taken into account in the design of pharmacologic treatment for their motor and behavioural disturbances.