Classic Lesch-Nyhan Syndrome Research Articles

Lesch-Nyhan syndrome and its variants: examining the behavioral and neurocognitive phenotype.

Lesch-Nyhan Syndrome (LNS) is a metabolic disorder involving mutations in the HGPRT1 gene that result in hyperuricemia, intellectual disability, a dystonic movement disorder, and compulsive self-injury with self-mutilation. The aim of this review is to summarize recent research that documents the extended behavioral, neurologic, and neurocognitive phenotype in classic LNS, to describe milder variants of HGprt deficiency that do not self-injure and have less severe neurological and cognitive deficits, and to provide an update on treatment for associated psychiatric and behavioral disorders. Psychiatric management utilizes combined behavioral and pharmacological treatment in conjunction with protective equipment and dental management to avert self-injury. Pharmacological management focuses on stabilization of mood and anxiety management. S-adenosylmethionine (SAMe), a physiological intermediate in methylation and transsulfuration, has shown beneficial effects in carefully selected patients who can tolerate the drug. Deep brain stimulation is shown in several case reports and series to reduce or eliminate self-injury and aggression, and in some cases, modify dystonia. This review highlights progress in our understanding of the behavioral and neurocognitive phenotype of Lesch-Nyhan syndrome (HGprt deficiency) and its variants, describes psychiatric and behavioral management, and discusses prospects for new therapies.

Variable Expression of HPRT Deficiency in 5 Members of a Family With the Same Mutation

Lesch-Nyhan disease is an inborn error of purine metabolism that results from deficiency of the activity of hypoxanthine phosphoribosyltransferase (HPRT). In the classic disease, the activity of the enzyme is completely deficient; the patient has mental retardation, spasticity, dystonia, and self-injurious behavior, as well as elevated concentrations of uric acid in blood and urine and its consequences of nephropathy, urinary tract calculi, and tophaceous gout. The HPRT gene is located on the X chromosome, and its expression is usually X-linked recessive. There are variant HPRT enzymes with some activity, and milder clinical expression, but the rule has been that each mutation produces a stereotypical pattern of clinical disease. To document a family in which a single mutation has led to 3 different phenotypes in 5 individuals. Case reports. Settings A foundation devoted to the investigation and care of patients with rare diseases and a university-based biochemical genetics laboratory. Clinical and biochemical observations of predominantly 1 generation of a family. A mutation (IVS6 + 2) led to deletion of exon 6. In 1 patient, the phenotype was that of classic Lesch-Nyhan syndrome, while the patient's brother and uncle had a much milder disease, which was difficult to distinguish from good health; 2 cousins had an intermediate phenotype. It is no longer true that a given mutation in the HPRT gene will lead to a reproducible pattern of clinical expression.

Novel genetic mutations responsible for the HPRT deficiency and the clinical phenotypes in Japanese.

ConclusionWe have identified six novel mutations in Japanese families of HPRT deficiency manifesting different clinical phenotypes. A missense mutation (Y195C) was identified in a patient with hyperuricemia and gout (Case 1). In Cases 2 and 3 with mild neurological symptoms, missense mutations L147P and K159E were detected, respectively. A point mutation 532+2T>C causing splicing error was found in a severe form of partial HPRT deficiency (Case 4). Two mutations causing splicing error, 609+1delGT (Case 5) and 610-−1G>A (Case 6), resulted in the classic Lesch-Nyhan syndrome.

Fisiopatología de las manifestaciones neurológicas en la deficiencia de hipoxantina-guanina fosforribosiltransferasa

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. 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. 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.

Clinical symptoms of patients with partial HPRT deficiency.

Since the first description of partial Hypoxanthine-Guanine-Phosphoribosyl-transferase (HPRT) deficiency in 1967 by Kelley, Seegmiller and coworkers a large number of cases has been described. The clinical picture has been quite variable, reaching from asymptomatic hyperuricemia to very severe disease with arthritis, nephrolithiasis and neurological symptoms. In contrast to classical Lesch-Nyhan syndrome selfmutilation is not observed in patients with partial HPRT deficiency.

The spectrum of HPRT deficiency: an update.

Since the discovery that a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) was responsible for the Lesch-Nyhan syndrome (1, 2), a number of HPRT-deficient patients with greatly varying phenotypes have been reported. These have included patients with the classic Lesch-Nyhan syndrome, those with the neurological manifestations and normal intelligence, and those with uric acid overproduction and its consequences as their only clinical symptoms. In 1981 we reported that an inverse correlation exists between HPRT activity and the severity of the accompanying symptoms, if the enzyme activity is measured in intact cells (3). We have now studied many more patients by this method and have a better idea of the degree of enzyme deficiency at which the various symptoms appear. In the course of these studies, two new phenotypes of HPRT deficiency have been identified, and in each case the degree of HPRT deficiency found in these patients appears to be appropriate for the respective phenotype.

Clinical correlations in partial hypoxanthine guanine phosphoribosyltransferase deficiency

Erythrocyte assays for hypoxanthine guanine phosphoribosyltransferase (HGPRT) activity performed on two male half-siblings with hyperuricemia, produced results consistent with classic Lesch-Nyhan syndrome. Due to the absence of neurologic abnormalities, cognitive deficits, or self-mutilation, HGPRT activity was measured by intact fibroblast assay which revealed partial enzyme deficiency. The presence of an unstable mutant enzyme may have led to the discrepancy between the erythrocyte and fibroblast studies. This discrepancy emphasizes the difficulty in assaying this enzyme solely utilizing red blood cell studies to determine a patient's course. In order to provide an accurate prognosis and relevant genetic counseling, measurement of this enzyme utilizing intact fibroblasts is critical after establishing a diagnosis of HGPRT deficiency in a hyperuricemic male lacking typical clinical manifestations of Lesch-Nyhan syndrome, but having enzyme activity of erythrocytes consistent with the diagnosis.

L8FLOURODEOXYGLUCOSE PET SCANNING IN HPRT DEFICIENCY: 150

The Lesch-Nyhan syndrome (LNS) results from the virtually complete deficiency of hypoxanthine phosphoribosyltransferase (HPRT); partial deficiency of HPRT results in gout. The metabolic mechanisms for neurologic dysfunction in the more severe HPRT deficiency states remain unclear. Previous attempts to assess therapy for LNS also have been limited due to the lack of non-invasive measures of metabolic and neurochemical function in the CNS. In an effort to develop such measures, we have examined the local glucose metabolic rate (LGMR) using the positron emitter 18Flourodeoxyglucose (FDG) with positron emission tomography (PET) scanning in 10 normal subjects and in four HPRT deficient individuals. One subject had partial HPRT deficiency with gout and no clinical neurologic disease. Two subjects had no detectable RBC HPRT and age-related, progressive neurologic dysfunction. The fourth subject had the classical LNS. LGMR in the basal ganglia was normal in the first subject without neurologic disease and reduced in the regions of the basal ganglia in both partially deficient subjects with neurologic disease. LGMR was severely reduced in the basal ganglia of the subject with LNS. From these initial studies we conclude that the severity of neurologic dysfunction appears to be proportional to the degree of HPRT deficiency and that PET scanning of the basal ganglia with 18FDG may provide a sensitive non-invasive measure of metabolic derangement resulting from HPRT deficiency. This study suggests for the first time a characteristic abnormality in CNS metabolism unique to HPRT deficiency with neurologic dysfunction.

Studies in fibroblasts of patients with the Lesch-Nyhan syndrome and HPRT variants. Correlation of HPRT activity with hypoxanthine utilization and growth in selection media.

In the present study, hypoxanthine phosphoribosyltransferase (HPRT) has been investigated in fibroblasts of 19 patients from 16 different families with HPRT deficiency, concerning activity, incorporation of 14C-hypoxanthine, and growth in 8-azaguanine and HAT (hypoxanthine, azaserine, thymidine containing) selection media. According to these data we could classify the patients into 5 groups (patients with classical Lesch-Nyhan syndrome and patients with HPRT variants of types A, B, C, D). In 3 groups (patients with classical Lesch-Nyhan syndrome, HPRT variants C and D), a correlation of residual HPRT activity with the incorporation of 14C-hypoxanthine as well as growth in 8-azaguanine and HAT selection was observed. The variant A, from a patient with the classical Lesch-Nyhan syndrome, exhibited higher HPRT activity than that from all the other patients with the Lesch-Nyhan syndrome. However, the values of hypoxanthine incorporation and growth in selection media were as in the classical syndrome. The cells of variant B were resistant to azaguanine and grew in HAT selection media in the range of control cells, but had HPRT residual activities similar to those of variants A and C. For the characterization of the genetic heterogeneity of HPRT, it seems necessary to study the enzymatic properties in cell extracts as well as the purine uptake and proliferation of cells in different selection media.

Lesch-Nyhan Syndrome: Biochemical Characterization of a Case with Attenuated Behavioral Manifestation

The activity and kinetic properties of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) were studied in fibroblasts from a Lesch-Nyhan syndrome (LNS) variant, with complete HGPRT deficiency in hemolysates, but with attenuated behavioral manifestation of the syndrome. The mutant HGPRT exhibited a 100-fold increase in Km for substrate phosphoribosyl-pyrophosphate, manifest in markedly decreased enzyme activity, being 2.5% of normal in cell extracts and about 0.6% of normal in intact cells. This degree of residual activity of the mutant enzyme is within the range found in patients with classical LNS.

Lesch-Nyhan syndrome: altered kinetic properties of mutant enzyme.

Hypoxanthine-guanine phosphoribosyltransferase is virtually inactive in erythrocytes from patients with the classical Lesch-Nyhan syndrome. In one such patient, activity of this enzyme ranged from 8 to 34 percent of normal in erythrocytes when assayed with a very high concentration of magnesium 5-phosphoribosyl-1-pyrophosphate. In addition, the mutant enzyme exhibited sigmoidal kinetics with this substrate as well as an increased Michaelis constant for both guanine and hypoxanthine. These findings provide the first evidence for genetic heterogeneity within the group of patients with the Lesch-Nyhan syndrome.