[The genetic diagnosis of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency. A study of 12 cases]. / Diagnóstico genético de la deficiencia de hipoxantina-guanina fosforribosiltransferasa (HGPRT). Estudio de 12 casos.

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency is transmitted as an X-linked recessive trait. Female carriers are asymptomatic and the carrier diagnosis is usually performed by determining HGPRT activity in hair roots. This technique does not allow a non-carrier state diagnosis with absolute certainty and has other limitations such as obtaining non-viable hair roots. The knowledge of the genetic mutation in three Spanish families with HGPRT deficiency, enabled us to perform the genetic diagnosis of the carrier state in 10 female subjects at risk and one female fetus. The genetic diagnosis has been performed by analyzing the differences between the mutant and the normal allele with respect to the restriction pattern. When the restriction pattern showed no differences, this has been created by directed mutagenesis. With this methodology we confirmed that a newborn of a known carrier female of HGPRT deficiency was healthy. In all cases the diagnosis could be established with great fiability in a mean time of 24 to 48 hours. We report the first genetic diagnosis of the carrier state for the HGPRT deficiency performed in Spain.

[Physiopathology of neurological signs of hypoxanthine-guanine phosphoribosyltransferase deficiency]. / Fisiopatología de las manifestaciones neurológicas en la deficiencia de hipoxantina-guanina fosforribosiltransferasa.

OBJECTIVE: Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is characterized by an increase in renal uric acid excretion, usually with hyperuricemia and may be associated with more or less important neurological symptoms. Based on a series of 20 patients from 16 Spanish families we propose that HPRT deficiency could be clinically classified in four different groups. In the more severe form (classic Lesch-Nyhan syndrome) HPRT deficiency is characterized by choreoathetosis, spasticity, mental retardation and compulsive self-mutilation behavior. The pathophysiology of the neurological symptoms remains unclear and there is no effective therapy. This review is intended to provide a research strategy for a better knowledge of the neurological pathophysiology of HPRT deficiency. DEVELOPMENT: We have analyzed the knowledge on the neurological symptoms of HPRT deficiency. This knowledge comes from histopathological studies of the brains from Lesch-Nyhan patients, chemical studies of the cerebrospinal fluid, experimental animal models (pharmacologic and lesioning and genetic approaches), and human in vivo studies with positron-emission tomography. CONCLUSIONS: The observed findings suggest that the neurological symptoms of Lesch-Nyhan syndrome could be related with the neonatal neuronal and/or dopaminergic terminations damage. This damage could be due to lost or reorganization of dopaminergic system, and is associated with a reduced dopamine levels and with hypersensitivity of the D1 subclass dopamine receptors.

[Treatment of Lesch-Nyhan syndrome]. / Tratamiento del síndrome de Lesch-Nyhan.

AIM: We have reviewed the treatments employed to alleviate the different manifestations of the Lesch Nyhan syndrome, the adverse reactions related to these treatments, and the prospectives of future therapeutic approaches now under active research. DEVELOPMENT: Lesch Nyhan syndrome is an X linked inherited disorder of purine metabolism caused by the deficiency of the enzyme hypoxanthine guanine phosphoribosyltransferase (HPRT). Clinical features include overproduction of uric acid and a neurologic syndrome related to the severity of the enzyme defect. CONCLUSIONS: Treatment with xanthine oxidase inhibitors is effective for the control of the elevated renal excretion of uric acid, but there is no specific treatment for the neurologic symptoms. Due to the low frequency of the syndrome and to the incomplete understanding of the pathophysiologic mechanisms underlying the neurologic manifestations, the treatments employed are merely symptomatic.

[Usefulness of bone remodelling biochemical markers in the diagnosis and follow-up of Paget's bone disease, primary hyperparathyroidism, tumor hypercalcemia, and postmenopausal osteoporosis. II. Bone resorption markers]. / Utilidad de los marcadores bioquímicos de remodelamiento óseo en el diagnóstico y seguimiento de la enfermedad ósea de Paget, hiperparatiroidismo primario, hipercalcemia tumoral y osteoporosis postmenopáusica. II. Marcadores de reabsorción ósea.

Rapid detection of the exact changes in bone remodelling is exceptionally important. In this paper, the latest bone remodelling biochemical markers are reviewed. Some of them have already been used for a long time, and their utility has been widely demonstrated. The newest ones, in experimental stage, can be used as a complement to the others. The bone remodelling markers reviewed are: 1) Alkaline phosphatase; 2) osteocalcin; 3) other noncollagen of bone matrix such as osteonectin, GLA-protein of the matrix, osteopontine and alpha 2-HS-glycoprotein; 4) Procollagenous and other collagenous peptides of the matrix (C terminal of type I procollagen and urinary elimination of non-dialysis hydroxyproline. Amongst the bone resorption markers studied are: 1) Calcium/creatinine urinary quotient; 2) Tartrate resistant acid phosphatase; 3) Urinary hydroxyproline; 4) Other substance derived from collagen disruption such as hydroxylysine glycoside, piridinolinic intermolecular bridges and the enzymatic activity of proline iminopeptidase. We endeavored to collect all the most important references on the matter, especially those relating to Paget's disease of the bone, primary hyperparathyroidism, tumoral hypercalcemia and postmenopausal osteoporosis.

[The usefulness of biochemical markers of bone remodelling in the diagnosis and follow-up of Paget's disease of bone, primary hyperparathyroidism, tumoral hypercalcemia and postmenopausal osteoporosis. I. The markers of bone formation]. / Utilidad de los marcadores bioquímicos de remodelamiento óseo en el diagnóstico y seguimiento de la enfermedad ósea de Paget, hiperparatiroidismo primario, hipercalcemia tumoral y osteoporosis postmenopáusica. I. Marcadores de formación ósea.

Rapid detection of the exact changes in bone remodelling is exceptionally important. In this paper, the latest bone remodelling biochemical markers are reviewed. Some of them have already been used for a long time, and their utility has been widely demonstrated. The newest ones, in experimental stage, can be used as a complement to the others. The bone remodelling markers reviewed are: 1) Alkaline phosphatase; 2) osteocalcin; 3) Other noncollagen of bone matrix such as osteonectin, GLA-protein of the matrix, osteopontine and alpha 2-HS-glycoprotein; 4) Procollagenous and other collagenous peptides of the matrix (C terminal of type-I procollagen and urinary elimination of nondialysis hydroxyproline. Amongst the bone resorption markers studied are: 1) Calcium/creatinine urinary quotient; 2) Tartrate resistant acid phosphatase; 3) Urinary hydroxyproline; 4) Other substances derived from collagen disruption such as hydroxilysin glycoside, piridinolinic intermolecular bridges and the enzymatic activity of proline iminopeptidase. We endeavoured to collect all the most important references on the matter, especially those relating to Paget's disease of the bone, primary hyperparathyroidism, tumoral hypercalcemia and postmenopausal osteoporosis.

[Hyperoxaluria and renal calculi]. / Hiperoxaluria y litiasis renal.

Urolithiasis is one of the most frequent causes of morbidity in developed countries and its incidence is close to 5%. In our experience, 67.4% of urinary stones contain calcium oxalate as the main component, and hyperoxaluria plays an important role in the pathophysiology of this type of stone. The mechanisms responsible for the increment in urinary excretion of oxalate could involve oxalic acid synthesis. This increase could be due either to an increment of its endogenous formation or to an exogenous load of its precursors. Furthermore, an increased intestinal oxalate absorption is a frequent cause of hyperoxaluria and urolithiasis. Ingestion of oxalate rich foods, imbalance in the supply of other nutrients that influence oxalic acid absorption and GI disorders with malabsorption and/or decreased degradation of intraluminal oxalate can increase intestinal oxalate transport and cause hyperoxaluria. In this article we review the physiological mechanisms that control the oxalate pool: endogenous synthesis, exogenous supply, intestinal absorption and renal excretion of oxalic acid. We analyze the causes and the pathophysiological mechanisms that increase urinary oxalate excretion. We describe a protocol for the biochemical study of patients with hyperoxaluria and the therapeutic measures to reduce urinary oxalate are reviewed. Finally, possible research that may provide further insight into oxalate metabolism in patients with hyperoxaluria are discussed.

Lithogenic risk factors for renal stones in patients with Crohn's disease.

OBJECTIVES: Calcium oxalate kidney stones are more common in patients with Crohn's disease (CD). The aims of this study were to verify the prevalence of the main risk factors for calcium oxalate nephrolithiasis in patients with CD and to evaluate the degree of urinary relative supersaturation for calcium oxalate (CaOx), dihydrogen uric acid (DHUA) and monohydrogen calcium phosphate (MHCaP). SUBJECTS AND STUDY PROTOCOL: 42 patients with CD (22 male and 20 female, aged 15-72 years) and 18 controls (8 male and 10 female, aged 26-65) were studied. Nine patients were evaluated during an active episode and 33 in a quiescent phase. All patients had normal glomerular filtration rate. All subjects collected a 24-hr urine sample and fasting venous blood was drawn. Good compliance of urine collection was assessed by the Cockcroft and Gault formula. In urine pH and oxalate (Ox), calcium (Ca), phosphate (P), uric acid (UA), citrate (Cit), magnesium (Mg), sulphate (Sulph), sodium, potassium and chloride concentrations were measured and their excretions calculated. Urinary RS index was obtained using the software EQUIL93. RESULTS: A decreased urinary volume (61.9%) was the most frequent finding. A decreased excretion of Cit, Mg and Sulph (38.1%, 31.0% and 31.0%, respectively) and increased excretion of P, Ox, UA and Ca (33.3%, 23.8%, 16.7% and 14.3%, respectively) were found. Thirty four patients (81.0%) showed at least 2 lithogenic risk factors and only 2 patients showed none. Urine of patients had a higher urinary CaOx and DHUA relative super saturation. Patients studied in an active episode showed a higher urinary CaOx and MHCaP RS than those studied in the quiescent period. CONCLUSIONS: The majority of patients with CD have a multifactorial high risk for calcium oxalate and a single patient usually has several metabolic disturbances which are more evident in an active episode.

[Biochemical, enzymatic and genetic study of hypoxanthine guanine phosphoribosyl transferase (HPRT) deficiency]. / Estudio bioquímico, enzimático y genético de la deficiencia de hipoxantina guanina fosforribosiltransferasa (HPRT).

OBJECTIVE: The objective of this study was to analyze the diagnosis of HPRT deficiency, perform a thorough purine metabolism study and to establish the carrier and prenatal diagnosis in 16 HPRT deficient families. PATIENTS AND METHODS: Plasma and urinary concentrations of uric acid, creatinine and oxypurines, APRT and HPRT activities in hemolysates and HPRT in intact erythrocytes and adenine 8-C14 urinary excretion were analyzed. Carrier diagnosis was made by hair root enzyme analysis and genetic studies. RESULTS: These studies allowed the diagnosis of HPRT deficiency in 20 patients. Carrier diagnosis could be performed in 23 women at risk and in a 9 week old female fetus. CONCLUSIONS: The study results suggest that HPRT deficiency accounts for increased purine nucleotide degradation. This increase results in elevated urinary and plasma concentrations of hypoxanthine, xanthine and uric acid. The clinical severity of the disease is not related to the degree of urinary or plasma concentrations of oxypurines. Hair root analysis generally allows the diagnosis of carrier status, but the carrier state cannot be fully excluded in women at risk. When the familial mutation causing the defect in HPRT is known, analysis of the differences in the restriction pattern of the HPRT gene (natural or due to directed mutagenesis) allow a rapid and reliable diagnosis of carrier status and HPRT deficiency.

Disfunción endotelial e hiperuricemia: papel de la enzima xantina oxidasa / Endothelial dysfunction and hyperuricemia:role of xanthine-oxidase enzyme

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Hipertensión e hiperuricemia / Hypertension and hyperuricemia

La asociación entre hipertensión e hiperuricemia es conocida. Los sujetos hipertensos con hiperuricemia presentan mayor riesgo de eventos cardiovasculares. La fisiopatología de la hiperuricemia en el sujeto hipertenso puede ser múltiple. Por una parte, la menor excreción de uratos puede estar asociada al tratamiento diurético, a la lesión renal hipertensiva (nefroesclerosis) o a la insulinorresistencia que con frecuencia acompaña a la hipertensión arterial. Por otro lado, la disfunción endotelial, presente en la hipertensión arterial, puede ocasionar una hipoxia tisular con aumento de los sustratos para la enzima xantina oxidasa (XO), cuyo producto final es el ácido úrico. Las consecuencias de esta hiperuricemia pueden ser lesiones renales y/o articulares gotosas. Además, la aparición de hiperuricemia denota bien un deterioro de la función renal o bien una sobreactividad de XO. Esta última es una fuente de radicales libres que son causa a su vez de disfunción endotelial y de resistencia a la insulina. La presencia de hiperuricemia en un sujeto hipertenso debe alertarnos para extremar las precauciones en el control global de su riesgo cardiovascular. (AU)

Tratamiento del síndrome de Lesch-Nyhan / Treatment of Lesch-Nyhan syndrome

Objetivo. En este trabajo se revisan los tratamientos empleados hasta la fecha, dirigidos a paliar las diversas manifestaciones características del síndrome de Lesch-Nyhan (SLN), los efectos adversos registrados y las líneas actuales de investigación que abren futuras esperanzas terapéuticas. Desarrollo. El SLN es un defecto congénito del metabolismo de las purinas ocasionado por el déficit de la enzima hipoxantina-guanina fosforribosiltransferasa (HPRT). Desde el punto de vista clínico se caracteriza por hiperuricemia y trastornos neurológicos graves, que parecen relacionarse con la magnitud del defecto enzimático. Conclusiones. La escasa frecuencia del SLN, junto con el desconocimiento de la fisiopatología de los trastornos neurológicos, explica que la terapéutica se fundamente en recomendaciones sintomáticas. Los fármacos inhibidores de la enzima xantina oxidasa ayudan a controlar la excreción elevada de ácido úrico, pero hasta la fecha no se ha encontrado ningún tratamiento eficaz para los síntomas neurológicos (AU)

Clasificación de la deficiencia de hipoxantina-guanina fosforribosiltransferasa (HPRT) basadas en el estudio de 22 pacientes pertenecientes a 18 familias españolas / Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. A new classification based in the study of 22 patients belonging to 18 Spanish families

La deficiencia de HPRT es un trastorno que se hereda ligado al cromosoma X y se caracteriza por producción excesiva de ácido úrico y alteraciones neurológicas variables. La deficiencia completa de HPRT se denomina síndrome de Lesch-Nyhan y se manifiesta por coreatetosis, espasticidad, retraso mental y automutilación. En otros pacientes con déficit de HPRT la deficiencia parece ser “parcial” y los síntomas neurológicos pueden variar de ausentes a severos (síndrome de Kelley-Seegmiller). La deficiencia de HPRT se clasifica en dos grupos –síndrome de Lesch-Nyhan y síndrome de Kelley-Seegmiller–, pero esta clasificación es confusa. Nosotros hemos analizado nuestra experiencia con 22 pacientes con déficit de HPRT pertenecientes a 18 familias españolas diagnosticados en el Hospital “La Paz” de Madrid en los últimos 16 años. Los estudios clínicos, bioquímicos, enzimáticos y moleculares realizados en estos pacientes nos han permitido delinear una nueva clasificación de la deficiencia de HPRT. Esta clasificación según un espectro continuo puede ser de utilidad para un mejor conocimiento de la enfermedad (AU)