J G Puig

Hospital Universitario La Paz, Madrid, Madrid, Spain

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Publications (101)360.87 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Since 1984, we have diagnosed at the La Paz University Hospital, Madrid, Spain, 41 patients with hypoxanthine phosphoribosyltransferase (HPRT) activity deficiency. These patients belonged to 34 families. We have also performed molecular and enzymatic diagnosis in three patients from India, one from Belgium, and three from Colombia. About 1/3 of these patients were followed up at La Paz University Hospital at least every year. This fact has allowed us to examine the complete spectrum of HPRT deficiency as well as to perform a more accurate diagnosis and treatment. In the present review, we also summarized our studies on the basis of physiopathology of the neurological manifestation of Lesch Nyhan disease (LND).
    Nucleosides Nucleotides &amp Nucleic Acids 04/2014; 33(4-6):223-232. · 0.71 Impact Factor
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    ABSTRACT: Background: Kidney function progressively deteriorates in patients with familial juvenile hyperuricemiac nephropathy (FJHN, OMIN 162000) and chronic renal disease is commonly associated to dyslipidemia. We report for the first time abrupt renal insufficiency in a patient with FJHN and hypertrygliceridemia following fenofibrate administration.Case report: A 53-year-old man was diagnosed clinically with FJHN at age 24 years which was subsequently confirmed by genotypic analysis of the UMOD gene at age 40 years. His mother and two brothers suffered the disease. At that time, renal size and function were normal, as was his blood pressure and serum lipids. At age 34 years, serum urate was 8.5 mg/dL and creatinine 1.7 mg/dL (GFR, 58 mL/min/1.73 m(2)). He was treated with allopurinol, losartan, and lovastatin. Serum TG levels ranged between 150 and 250 mg/dL. At age 52 years, serum urate was 4.1 mg/dL, creatinine 3.2 mg/dL, LDLc 99 mg/dL (atorvastatin 40 mg/d), and TG 275 mg/dL. Fenofibrate (160 mg/d) was added. One month later, serum creatinine increased to 4.2 mg/dL and TG decreased to 125 mg/dL. He did not complain of muscle pain, weakness, or changes in urinary frequency or color and rabdomyolysis was discarded. Fenofibrate was withheld and three months later serum creatinine decreased to baseline levels (3.2 mg/dL) and TG increased to 197 mg/dL.Conclusion: To our knowledge, this is the first patient with FJHN in whom fenofibrate administration was associated to a further impairment in renal function not attributable to rabdomyolysis.
    Nucleosides Nucleotides &amp Nucleic Acids 04/2014; 33(4-6):181-184. · 0.71 Impact Factor
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    ABSTRACT: Gout is commonly associated with obesity, arterial hypertension, diabetes, and dyslipidemia. However, the prevalence of metabolic syndrome has not been widely recognized in patients with gout. We studied 41 patients (37 males) with primary gout to assess the prevalence and characteristics of the associated metabolic syndrome. Twenty-one patients with gout (51%) showed >or=3 criteria for the metabolic syndrome. Pathological conditions associated were obesity (21/41), high blood pressure (30/41), dyslipidemia (30/41), and fasting plasma glucose >or= 100 mg/dL (22/41). The most frequent triad was the presence of increased waist circumference, elevated fasting plasma glucose, and hypertension. Mean serum urate concentration did not differ significantly in gout patients with the metabolic syndrome (8.5 mg/dl) and without (8.1 mg/dl). Given the complications associated with metabolic syndrome, its diagnosis may determine the long-term treatment of patients with gout.
    Nucleosides Nucleotides &amp Nucleic Acids 06/2010; 29(4-6):325-9. · 0.71 Impact Factor
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    ABSTRACT: Forty-four patients (40 males) with a mean age of 58 years were included in this pilot study. Mean serum urate concentration in patients with and without the metabolic syndrome (MS) was 8.8 mg/dL and 8.1 mg/dL, respectively. Urinary uric acid excretion was 543 mg/day/1.73 m(2) in the former and 609 mg/day/1.73 m(2) in the latter. Uric acid to creatinine ratio was 0.37 mg/mg in patients with the MS and 0.42 mg/mg in those without the MS. Mean serum urate increased from 8.6 mg/dL in subjects with three or more MS components to 10.3 mg/dL in those with five MS components. Serum urate was markedly lower in patients with mild MS (9 patients, 8.6 mg/dL) as compared to severe MS (10 patients, 9.2 mg/dL). In contrast, urinary uric acid to creatinine ratio was 0.42 mg/mg in patients with gout and mild MS and 0.33 mg/mg in gout patients with severe MS. Uric acid underexcretion appears to be more severe in gout patients with the MS. This disturbance appears to be related to the severity of the MS.
    Nucleosides Nucleotides &amp Nucleic Acids 06/2010; 29(4-6):330-4. · 0.71 Impact Factor
  • R J Torres, M G Garcia, J G Puig
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    ABSTRACT: Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity is an inborn error of purine metabolism associated with uric acid overproduction and a continuum spectrum of neurological manifestations depending on the degree of enzyme deficiency. The complete deficiency causes Lesch-Nyhan syndrome (LNS). Partial HPRT-deficient patients can show a variable degree of neurological manifestations. Both diseases have been associated with mutations in the HPRT1 gene. Documented mutations in HPRT deficiency show a high degree of heterogeneity in type and location within the gene. In fact, more than 300 disease-associated mutations have been described. Splice mutations accounts for more that 16% of HPRT mutations and in most cases cause a complete LNS phenotype. A 16 year-old boy consulted to La Paz University Hospital because of hyperuricemia (9.4 mg/dL). At age one year he was given a diagnosis of dystonic cerebral palsy. Although he usually employs a wheelchair, under certain circumstances, he is able to stand up and walk by himself. He has never showed self injurious behavior. This patient presented a splice mutation (NM_000194.2: c.552 -2 A > G) causing exon 5 exclusion. An exon-5 specific PCR was designed, and a minor amount of normally spliced HPRT mRNA was found. Normally spliced HPRT mRNA was quantified by real-time PCR in this patient, in control subjects, and in two Lesch Nyhan patient with splice mutations excluding exon 4 (patient B) and exon 8 (patient C) who had clinically a Lesch Nyhan disease phenotype. A minor amount of normally spliced HPRT mRNA was found in all the patients. No correlation was found between the percentage of the normally spliced HPRT mRNA and the phenotype. We conclude that the partial HPRT deficient phenotype of this patient can not be explained by the finding of a minor amount of normally splice HPRT mRNA. It is possible that the amount of normally splice mRNA vary among different tissues.
    Nucleosides Nucleotides &amp Nucleic Acids 06/2010; 29(4-6):295-300. · 0.71 Impact Factor
  • M G Garcia, R J Torres, J G Puig
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    ABSTRACT: Lesch-Nyhan syndrome is an X-linked recessive inborn error of metabolism due to a complete deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity (OMIM 300322). Partial deficiency of HPRT (OMIM 300323) is characterized by the effects of excess uric acid synthesis and a continuum spectrum of neurological manifestations, without the manifestations of full-blown Lesch-Nyhan syndrome. Both diseases have been associated with mutations in the HPRT1 gene. We have described one Lesch-Nyhan patient and four partial HPRT deficient patients with a normal HPRT1 coding region. These patients showed markedly decreased HPRT mRNA expression, but no mutation in their genomic regulatory sequences from HPRT1 gene. In this study, we analyzed the promoter region methylation status of the HPRT1 gene in these five HPRT deficient patients. Methods: DNA was bisulphite modified and a 620 bp fragment including 320 bp 5' to start codon was amplified and sequenced. The methylation status of 35 CpG island 5' to start codon and 28 CpG island 3' to start codon were investigated in male controls, female controls, patients, and the patient's mothers. Primer pairs were designed for methylated-specific and unmethylated-specific amplification and PCR was performed employing DNA bisulphite treated as template. Results: No alterations in the methylation pattern of the HPRT1 promoter were found in the five HPRT deficient patients. Conclusions: The promoter region methylation status of these five HPRT deficient patients was similar to that of normal subjects. Thus, some other genetic alteration must explain a reduced enzyme activity with a normal gene coding region.
    Nucleosides Nucleotides &amp Nucleic Acids 06/2010; 29(4-6):301-5. · 0.71 Impact Factor
  • Source
    M G García, J G Puig, R J Torres
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    ABSTRACT: Self-injurious behavior is the most outstanding feature of Lesch-Nyhan syndrome and has recently been ascribed to an obsessive-compulsive behavior. Lesch-Nyhan syndrome results from the complete enzyme deficiency of hypoxanthine-guanine phosphoribosyl transferase (HPRT) but the link between abnormal purine metabolism and its neurological and behavioral manifestations remains largely unknown. Previous studies led us to hypothesize that adenosine and dopamine receptor expression could be altered in HPRT-deficient cells. To test this hypothesis, we examined mRNA expressions of adenosine (ADORA2A and ADORA2B) and dopamine receptors (DRD1 and DRD2 like), and dopamine transporter (DAT1) in peripheral blood lymphocytes (PBLs) from Lesch-Nyhan patients. We also examined the influence of hypoxanthine in these expressions. As compared to normal PBLs, both ADORA2A and DRD5 expression were abnormal in PBLs from Lesch-Nyhan patients. In contrast, DAT1 expression was similar to control values in HPRT deficient PBLs. These results indicate an abnormal adenosine and dopamine receptor expression in HPRT-deficient cells and suggest disrupted adenosine and dopamine neurotransmission may have a significant role in the pathogenesis of the neurological manifestations of Lesch-Nyhan syndrome.
    Brain Behavior and Immunity 08/2009; 23(8):1125-31. · 5.61 Impact Factor
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    ABSTRACT: Thirty-five patients (23 males) with asymptomatic hyperuricemia for at least two years underwent two-dimensional ultrasonography of knees and ankles. Urate deposits (tophi) in tendons, synovium, and other soft tissues were detected in 12 patients (34%). Increased vascularity (inflammation) was evident in 8 of these patients (23%). Tophi were more frequently found in knees than in ankles and were especially prevalent in the distal patellar tendon. The presence of tophi was unrelated to the known duration of hyperuricemia (mean, 5 years). Ultrasonography allows detection of tophi and inflammation in a third and in a fourth, respectively, of asymptomatic hyperuricemic patients.
    Nucleosides Nucleotides &amp Nucleic Acids 07/2008; 27(6):592-5. · 0.71 Impact Factor
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    ABSTRACT: Neurobehavioral manifestations of complete HPRT deficiency include severe action dystonia, choreathetosis, alteration of executive functions, and self-injurious behavior. Dystonic manifestations are also present in patients with partial HPRT deficiency. Pathophysiology of these manifestations is unknown. Guanidinoacetate is a neurotoxin implicated in certain dystonic syndromes. We have examined guanidinoacetate and creatine levels in urine from 11 HPRT deficient patients (9 with Lesch-Nyhan syndrome and 2 with partial deficiency). Urinary guanidinoacetate and creatine levels in HPRT deficient patients were within the normal range. Guanidinoactetate alteration does not seem to be implicated in the pathogenesis of the neurological disease associated with HPRT deficiency.
    Nucleosides Nucleotides &amp Nucleic Acids 07/2008; 27(6):575-7. · 0.71 Impact Factor
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    ABSTRACT: This report describes a 75-year-old Caucasian man with extensive urate deposits and severe gouty arthropathy that confined him to a wheelchair. Since age 50, he suffered multiple acute gout flares and progressive deformities in his hands, feet, knees, and elbows (tophi). Serum creatinine was 1.4 mg/dL and serum urate 9.4 mg/dL. Conditions known to increase uric acid production (psoriasis, chronic bronchitis) and to decrease uric acid excretion (hypothyroidism, metabolic syndrome, and nephroangiosclerosis) may operate in a single patient, illustrating the dramatic clinical course of untreated gout.
    Nucleosides Nucleotides &amp Nucleic Acids 07/2008; 27(6):604-7. · 0.71 Impact Factor
  • R J Torres, J G Puig
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    ABSTRACT: We have studied 36 patients with HPRT deficiency, 25 with Lesch-Nyhan syndrome and 11 with partial HPRT deficiency (grades 1 to 3). Patients diagnosed with HPRT deficiency have increased 50% since 2000. The most relevant recent advances have been made in molecular diagnosis. Nevertheless, enzyme determinations are still essential for the diagnosis of HPRT deficiency. Therapy for the neurological manifestations of HPRT deficiency has not advanced. Allopurinol remains the drug of choice to diminish uric acid overproduction, but the optimal allopurinol dose must be established in each patient to prevent xanthine or uric acid urolithiasis, a process aided by sequential determination of urinary oxypurines and uric acid.
    Nucleosides Nucleotides &amp Nucleic Acids 07/2008; 27(6):564-9. · 0.71 Impact Factor
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    ABSTRACT: We studied the associations between serum urate levels (determined in 503 subjects from a population of 1,344 subjects living in northern Madrid) and both the metabolic syndrome (MS) (defined by the Adult Treatment Panel III criteria) and C-reactive protein (CRP, determined in 382 subjects). MS was diagnosed in 25% (95%CI, 21-28%) and was associated with hyperuricemia (p<0.001). There was a graded increase in serum urate levels with increasing number of MS components. Urate concentrations significantly correlated with waist circumference (r=0,455, p<0.01). Serum urate was not independently associated with CRP levels. This study shows that serum urate levels are associated with the presence of MS and each of its features.
    Nucleosides Nucleotides &amp Nucleic Acids 06/2008; 27(6):620-3. · 0.71 Impact Factor
  • C Prior, R J Torres, J G Puig
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    ABSTRACT: Lesch-Nyhan (LN) syndrome is associated with deficient hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity, but the connection between the aberrant purine metabolism and the neurological symptoms remains largely unknown. The aim of this study was to determine adenosine transporter subtypes affected by HPRT deficiency and by the associated hypoxanthine excess. Nucleoside transporter types (depending on their sodium dependence and 10 microm nitrobenzylthioinosine, NBTI, sensitivity) involved in adenosine transport were compared between peripheral blood lymphocytes (PBL) obtained from nine LN patients, PBL(LN) (2-21 years) and from nine controls, PBL(C) (2-23 years) under basal conditions and after 25 microm hypoxanthine incubation. We found four types of adenosine transporters in PBL: equilibrative and concentrative transporters that are either sensitive (ENT1 or cs) or insensitive (ENT2 or ci) to NBTI. Adenosine ENT1 uptake was the predominant transporter in both PBL(C) (55%) and PBL(LN) (46%). Under basal conditions no significant differences were found in adenosine transport between PBL(C) and PBL(LN). Incubation of PBL with 25 microm hypoxanthine markedly decreased total adenosine transport in both cell types. Hypoxanthine affected equilibrative transport (mainly ENT2 type) in PBL(LN) and PBL(C). Only in PBL(C) was concentrative transport affected by hypoxanthine. Expressions of human (h) ENT1 and hENT2 mRNA were not significantly modified by hypoxanthine incubation in PBL(C). This study contributes to further knowledge of the defective adenosine transport found in PBL(LN). Increased hypoxanthine levels, similar to those reported in HPRT deficient patients, reduced adenosine uptake by 32% in PBL(LN) as compared to normal transport.
    European Journal of Clinical Investigation 12/2007; 37(11):905-11. · 3.37 Impact Factor
  • C Prior, R J Torres, J G Puig
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    ABSTRACT: We postulated that increased levels of hypoxanthine, a main characteristic of hypoxanthine phosphoribosyltransferase (HPRT) deficiency, may influence adenosine function which could be related to some of the neurological features of the Lesch-Nyhan syndrome. We have examined the effect of hypoxanthine on different adenosine transporters in peripheral blood lymphocytes from control subjects. Increased hypoxanthine concentrations (25 microM) significantly decreased adenosine transport. The equilibrative adenosine transporters (79.6% of the adenosine transport), both NBTI sensitive and NBTI insensitive, were affected significantly. In contrast, the concentrative adenosine transporters were not influenced by hypoxanthine. These results supports the hypothesis that increased hypoxanthine levels influence equilibrative (predominantly NBTI-insensitive type) adenosine transporters.
    Nucleosides Nucleotides &amp Nucleic Acids 02/2006; 25(9-11):1065-9. · 0.71 Impact Factor
  • R J Torres, C Prior, J G Puig
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    ABSTRACT: Allopurinol is used widely for the treatment of purine disorders such as gout, but efficacy and safety of allopurinol has not been analyzed systematically in an extensive series of patients with HPRT deficiency. From 1984 to 2004 we have diagnosed 30 patients with HPRT deficiency. Eighteen patients (12 with Lesch-Nyhan syndrome or complete HPRT deficiency, and 6 with partial HPRT deficiency) were treated with allopurinol (mean dose, 6.44 mg/Kg of weight per day) and followed-up for at least 12 months (mean follow-up 7,6 years per patient). Mean age at diagnosis was 7 years (range, 5 months to 35 years). Treatment with allopurinol was associated to a mean reduction of serum urate concentration of 50%, and was normalized in all patients. Mean urinary uric acid excretion was reduced by 75% from baseline values, and uric acid to creatinine ratio was close or under 1.0 in all patients. In contrast, hypoxanthine and xanthine urinary excretion rates increased by a mean of 6 and 10 times, respectively, compared to baseline levels. These modifications were similar in patients with complete or partial HPRT deficiency. In 2 patients xanthine stones were documented despite allopurinol dose adjustments to prevent markedly increased oxypurine excretion rates. Neurological manifestations did not appear to be influenced by allopurinol therapy. Allopurinol is a very efficacy and fairly safety drug for the treatment of uric acid overproduction in patients with complete and partial HPRT deficiency. Allopurinol was associated with xanthine lithiasis.
    Nucleosides Nucleotides &amp Nucleic Acids 02/2006; 25(9-11):1077-82. · 0.71 Impact Factor
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    ABSTRACT: Since 1993 we have studied 5 Spanish families with familial nephropathy associated with hyperuricemia (FJHN). Among these families, 24 patients have been identified. All patients had some combination of hyperuricemia, gout, renal insufficiency, arterial hypertension, and reduced kidney size. The clinical presentation in the different families and in the members of the same family was heterogeneous. Allopurinol treatment did not appear to influence renal disease. From a clinical perspective, this syndrome is a distinctive interstitial nephropathy, inherited as an autosomal dominant trait, that progresses to renal failure and is not halted nor prevented by allopurinol therapy. In 2003, genetic linkage analysis in 3 of the 5 families showed linkage of FJHN to 16p 11.2. One family was not analyzed and one family did not show linkage to this region confirming the genetic heterogeneity of this syndrome. A mutation in UMOD gene was found in these 3 families as the cause of the FJHN. The mutations cluster in exon 4 and exon 5 and were point mutation that results in an amino acid change in the uromodulin or Tamm Horsfall protein. This fact allowed in 2004, the presymptomatic genetic diagnosis of an 8-years-old boy belonging to one of these 3 Spanish families. We conclude that in families with a history of renal failure and/or gout in which FJHN is suspected, UMOD mutation screening may enable a definite diagnosis. When a mutation is found, family members can be tested for a UMOD mutation and pre-symptomatic diagnosis may allow counseling to prevent or halt the progression to renal insufficiency.
    Nucleosides Nucleotides &amp Nucleic Acids 02/2006; 25(9-11):1295-300. · 0.71 Impact Factor
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    ABSTRACT: We have analysed adenosine transport and [3H] NBTI binding in peripheral blood lymphocytes obtained from Lesch-Nyhan patients, in basal conditions and following 24 h incubation with hypoxanthine. We found that adenosine transport and [3H] NBTI binding were significantly decreased in PBL-LN with respect to PBL-C in basal conditions. Following 25 microM hypoxanthine incubation, adenosine transport is decreased in PBL-LN with respect to basal transport, however, [3H] NBTI binding in PBL-LN was not decreased following hypoxanthine incubation.
    Nucleosides Nucleotides &amp Nucleic Acids 11/2004; 23(8-9):1193-6. · 0.71 Impact Factor
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    ABSTRACT: We have measured hypoxanthine effect on cAMP levels in PBL in basal conditions (no agonist), and with the addition of 2-(p-[2-carboxyethyl] phenylethylamino)-5'-N-ethylcarboxamidoadenosine (CGS-21680, a specific A2 receptor agonist). We have found that hypoxanthine, at 25 microM and 50 microM concentrations, increases cAMP levels in PBL in basal and A2 agonist stimulated conditions.
    Nucleosides Nucleotides &amp Nucleic Acids 11/2004; 23(8-9):1181-3. · 0.71 Impact Factor
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    ABSTRACT: We have examined the effect of hypoxanthine on adenosine transport and [3H] NBTI binding in peripheral blood lymphocytes (PBL) cultures. Pre-incubation with hypoxanthine originates a dose dependent decrease of adenosine transport and [3H] NBTI binding sites in PBL.
    Nucleosides Nucleotides &amp Nucleic Acids 11/2004; 23(8-9):1177-9. · 0.71 Impact Factor
  • Source
    J G Puig, R J Torres
    QJM: monthly journal of the Association of Physicians 08/2004; 97(7):457-8. · 2.36 Impact Factor

Publication Stats

720 Citations
360.87 Total Impact Points


  • 1988–2014
    • Hospital Universitario La Paz
      • Servicio de Medicina Interna
      Madrid, Madrid, Spain
  • 1989–2001
    • Universidad Autónoma de Madrid
      Madrid, Madrid, Spain
  • 2000
    • University of Vermont
      • Department of Microbiology and Molecular Genetics
      Burlington, VT, United States
  • 1993
    • Hospital Universitario Madrid Montepríncipe
      Madrid, Madrid, Spain