J García Puig

Hospital Universitario La Paz, Madrid, Madrid, Spain

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Publications (205)481.2 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.ResultsA 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.
    Orphanet Journal of Rare Diseases 12/2014; 9(1):190. · 4.32 Impact Factor
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    Revista Española de Cardiología. 11/2014;
  • Revista Española de Cardiología (English Edition). 11/2014;
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    Revista Clínica Española 10/2014; · 2.01 Impact Factor
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    ABSTRACT: 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.
    The Journal of rheumatology. 08/2014;
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    ABSTRACT: 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.
    Movement Disorders Clinical Practice. 06/2014;
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    ABSTRACT: The biennial 15(th) 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.
    Nucleosides Nucleotides &amp Nucleic Acids 04/2014; 33(4-6):165-173. · 0.71 Impact Factor
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    ABSTRACT: 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 m(2) versus 546 ± 221 mg/day/1,73 m(2); 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.
    Nucleosides Nucleotides &amp Nucleic Acids 04/2014; 33(4-6):185-191. · 0.71 Impact Factor
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    ABSTRACT: 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.
    Nucleosides Nucleotides &amp Nucleic Acids 04/2014; 33(4-6):174-180. · 0.71 Impact Factor
  • Juan G Puig, Rosa J Torres
    The Lancet Neurology 12/2013; 12(12):1129-31. · 23.92 Impact Factor
  • The American journal of medicine 08/2013; · 5.30 Impact Factor
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    ABSTRACT: 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.
    Brain 08/2013; · 10.23 Impact Factor
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    ABSTRACT: Objectives To evaluate the night-time drop in blood pressure in patients with light hypertension and to determine its possible relationship with damage in key organs. Design Cross-sectional study. Setting Eight urban health centres. Patients Four hundred and eighteen adults with light-moderate hypertension. Interventions a) Blood pressure reading on three visits; b) ambulatory monitoring of pressure for 24 hours; c) echocardiograph (in 219 patients); d) albuminuria determination (in 134 patients). A night-time drop in blood pressure was defined as the difference between day and night ambulatory pressures; and relative drop, as the night-time pressure drop as a percentage of the day-time pressure. Results Night-time drop in systolic and diastolic pressures was 13.6 (10.7) and 12.1 (8.6) mmHg, respectively. The predictive factors of night-time drop in blood pressure were, directly, daily ambulatory blood pressure (p < 0.05) and female gender (p < 0.05) and, inversely, age (p < 0.05). No association was observed between nighttime drop in blood pressure and left ventricular mass. Only in women was an independent relationship found, inversely, between night-time drop in blood pressure and urinary excretion of albumin (p < 0.05). Conclusions Relative night-time drop in blood pressure is greater in women than in men, diminishes with age and depends on the day-time ambulatory pressure. In women a minor night-time drop in blood pressure is associated with greater organic damage.
    Atención Primaria. 08/2013; 26(9):607–613.
  • Revista Clínica Española 08/2013; 200(1):35–36. · 2.01 Impact Factor
  • M.a Ángeles Martínez López, Juan García Puig
    Medicina Clínica. 07/2013; 115(6):221–223.
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    ABSTRACT: 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.
    Gene 10/2012; · 2.20 Impact Factor
  • The Journal of Rheumatology 09/2012; 39(9):1901. · 3.26 Impact Factor
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    ABSTRACT: 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.
    Journal of Inherited Metabolic Disease 03/2012; 35(6):1129-35. · 4.07 Impact Factor
  • Medicina Clínica 02/2012; 138(3):138. · 1.25 Impact Factor
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    ABSTRACT: Objective To estimate the prevalence of diabetes mellitus and impaired fasting glycemia in an adult population living in Madrid (Spain).
    Gaceta Sanitaria - GAC SANIT. 01/2012;

Publication Stats

927 Citations
481.20 Total Impact Points

Institutions

  • 1981–2014
    • Hospital Universitario La Paz
      • Servicio de Medicina Interna
      Madrid, Madrid, Spain
  • 2010–2013
    • Emory University
      Atlanta, Georgia, United States
  • 2009–2011
    • Madrid Salud
      Madrid, Madrid, Spain
  • 1988–2011
    • Universidad Autónoma de Madrid
      • • Departamento de Medicina Preventiva y Salud Pública y Microbiología
      • • Facultad de Medicina
      • • Departamento de Medicina
      Madrid, Madrid, Spain
  • 2008
    • Instituto de Salud Carlos III
      Madrid, Madrid, Spain
  • 2007
    • University of Naples Federico II
      Napoli, Campania, Italy
  • 2004
    • Hospital Universitario de Móstoles
      Madrid, Madrid, Spain