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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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 μM) 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 25µM 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 25µM and 50µM concentrations, increases cAMP levels in PBL in basal and A2 agonist stimulated conditions. [ABSTRACT FROM AUTHOR]