Cytosolic 5'-nucleotidase hyperactivity in erythrocytes of Lesch-Nyhan syndrome patients

Lesch-Nyhan syndrome is a metabolic-neurological syndrome caused by the X-linked deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Metabolic consequences of HGPRT deficiency have been clarified, but the connection with the neurological manifestations is still unknown. Much effort has been directed to finding other alterations in purine nucleotides in different cells of Lesch-Nyhan patients. A peculiar finding was the measure of appreciable amount of Z-nucleotides in red cells. We found significantly higher IMP-GMP-specific 5'-nucleotidase activity in the erythrocytes of seven patients with Lesch-Nyhan syndrome than in healthy controls. The same alteration was found in one individual with partial HGPRT deficiency displaying a severe neurological syndrome, and in two slightly hyperuricemic patients with a psychomotor delay. Since ZMP was a good substrate of 5'-nucleotidase producing Z-riboside, we incubated murine and human cultured neuronal cells with this nucleoside and found that it is toxic for our models, promoting apoptosis. This finding suggests an involvement of the toxicity of the Z-riboside in the pathogenesis of neurological disorders in Lesch-Nyhan syndrome and possibly in other pediatric neurological syndromes of uncertain origin.     

Gilles de la Tourette syndrome: further studies and thoughts.

A possible association between the Gilles de la Tourette and Lesch-Nyhan syndromes has recently been postulated. Fourteen patients with Tourette syndrome demonstrated no similarity to Lesch-Nyhan based upon patterns of inheritance, behavioral changes, or alterations of purine metabolism. Despite a strong male predominance, a sex-linked pattern of inheritance could not be confirmed. Self-mutilating behavior was found in 4 male patients but was readily differentiated from that characteristic of the Lesch-Nyhan syndrome. Quantitation of hypoxanthine-guanine phosphoribosyltransferase and isoelectric focusing of its isoenzymes produced results that were indistinguishable from those in controls. We speculate that, pathophysiologically, Tourette syndrome represents an imbalance between the central neurotransmitters dopamine and serotonin rather than an alteration in purine metabolism.     

Gabapentin for self-injurious behavior in Lesch-Nyhan syndrome

Self-injurious behavior is a common clinical problem in children with Lesch-Nyhan syndrome, an X-linked disorder of purine metabolism. This behavior is not observed in other conditions associated with increased serum concentrations of uric acid, hypoxanthine, and xanthine. Various neurotransmitters appear to play a pivotal role in self-injurious behavior. The authors present a patient with Lesch-Nyhan syndrome, whose self-injurious behavior was effectively treated with gabapentin, and discuss possible mechanisms of action.     

Brain benzodiazepine receptor binding and purine concentration in Lesch-Nyhan syndrome

Benzodiazepine receptor [( 3H]flunitrazepam) binding and purine concentration were measured in autopsied cerebral cortex of 4 patients who died with Lesch-Nyhan syndrome. Receptor density was normal in all 4 regions of Lesch-Nyhan cortex examined. However, an enhancement of benzodiazepine receptor affinity (25% reduction in Kd) was found in well-washed parietal and occipital cortex homogenates. Maximal gamma-aminobutyric acid (GABA) stimulation of [3H]flunitrazepam binding was normal in temporal, parietal and occipital cortex but markedly reduced (by 50-80%) in frontal cortex. Increased sensitivity to hypoxanthine inhibition (30% reduction in Ki) was also observed in parietal cortex. The concentrations of the purines hypoxanthine, xanthine and inosine in Lesch-Nyhan parietal cortex were about twice the values measured in control material matched for postmortem time. We suggest that the above-normal concentrations of purines estimated to be present in Lesch-Nyhan brain may be sufficient to significantly affect the ability of the benzodiazepine receptor to modulate GABA-mediated brain mechanisms.     

Abnormal development of hypoxanthine-guanine phosphoribosyltransferase-deficient CNS neuroblastoma.

Lesch-Nyhan syndrome encompasses a host of neurological symptoms, caused by a deficiency of the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). How the absence of this enzymes activity affects development of the nervous system is unknown. In this study, we examined the ability of N2aTG, a HGPRT-deficient neuroblastoma and its HGPRT-positive counterpart to proliferate and differentiate at various densities. In summary, N2aTG cells proliferated less and differentiated more than N2a cells, with the former cells exhibiting enhanced sensitivity to the effects of low-density culture. Given the homogeneity of this neuroblastoma cell line and its use in studies of neuronal development, the present study indicates that N2aTG cells may prove a suitable in vitro model for the study of non-dopaminergic neuronal development in Lesch-Nyhan syndrome.     

Antero-ventral internal pallidum stimulation improves behavioral disorders in Lesch-Nyhan disease.

The Lesch-Nyhan syndrome is an X-linked recessive disorder caused by a deficiency in hypoxanthine-guanine phosphoribosyl transferase, a purine salvage enzyme. Affected individuals exhibit a characteristic neurobehavioral disorder with delayed acquisition of motor skills, dystonia, severe self-mutilations, and aggressive behavior. Deep brain stimulation has been previously proposed for controlling isolated involuntary movements and psychiatric disorders. We applied a double bilateral simultaneous stimulation to limbic and motor internal pallidum in one patient for controlling both behavioral and movement disorders, respectively. The injurious compulsions disappeared; dystonia and dyskinesia were decreased at 28 months follow-up.     

The biochemical basis of the behavioral disorder in the Lesch-Nyhan syndrome

An inherited complete deficiency of hypoxanthine-guanine phosphoribosyltransferase in male children is associated with a severe neurological disorder characterized by chloroform and athetoid movements, hypertonicity, mental retardation, and self-injurious behavior. In the review that follows several possible mechanisms by which the enzyme defect may cause the CNS disorder are discussed. Current evidence suggests that the primary neural deficit in the Lesch-Nyhan syndrome is a deficiency of dopamine in the basal ganglia. It is argued that this neurochemical lesion results from a deficiency of purine nucleotides which impairs arborization of nigrostriatal neurons during perinatal development. Differences in the ontogenetic timing of the neurochemical lesion may be partly responsible for the different neurological symptoms displayed by persons afflicted with the Lesch-Nyhan and Parkinson's syndromes.     

Behavioral and neurochemical evaluation of a transgenic mouse model of Lesch-Nyhan syndrome

Two transgenic strains of mutant mice lacking hypoxanthine-guanidine phosphoribosyltransferase (HPRT) activity were examined behaviorally and neurochemically for phenotypic similarity to the human Lesch-Nyhan syndrome. In this syndrome, male children markedly deficient in the enzyme HPRT develop self-mutilation and severe motoric difficulties, and exhibit a pronounced deficiency of dopamine in the basal ganglia. The HPRT-deficient mice showed no evidence of self-mutilation, no detectable motor impairments on tests selected for sensitivity to basal ganglia dysfunction, and no differences in response to apomorphine. Biochemical analyses revealed significantly lower levels of striatal dopamine in the HPRT-deficient mice than in HPRT normal littermates, but the depletion was only of the order of 19%. The results suggest that mice lacking HPRT activity do not phenotypically resemble children born with the same enzymatic deficiency in part because mutant mouse striatal dopamine levels are not as low as those seen in clinical cases with Lesch-Nyhan disease. In contrast to Lesch-Nyhan children, mice may be able to utilize alternative pathways more effectively to maintain purine and neurotransmitter levels within the ranges required for normal brain development and function.     

A review of behavioral treatments used for Lesch-Nyhan syndrome

Lesch-Nyhan syndrome is a genetic disorder resulting in hyperuricemia, choreoathetosis, mental retardation, and self-mutilation. The most salient feature of this disorder is the self-injurious behavior (SIB). Although the utility of behavioral interventions with SIB has been well documented, behavioral interventions with Lesch-Nyhan syndrome have been limited in number and long-term success. This article reviews the behavioral treatments that have been used in treating individuals with Lesch-Nyhan syndrome and discusses the strengths and weaknesses of these methods. Suggestions for future directions in the use of behavioral interventions for controlling SIB in Lesch-Nyhan syndrome are provided.     

New mutations of the HPRT gene in Lesch-Nyhan syndrome

Lesch-Nyhan syndrome is an X-linked recessive disorder involving the purine metabolism, with resultant hyperuricemia, choreoathetosis, self-mutilation, and profound neurologic dysfunction. A deficiency of the enzyme hypoxanthine guanine phosphoribosyl-transferase is responsible for the disease. The human HPRT gene is located at Xq26-27 and consists of 57 base pairs. At least 2,000 mutations throughout the HPRT gene coding region from exon 1-9 have been reported. Four patients from three Chinese families were diagnosed with Lesch-Nyhan syndrome according to the clinical and laboratory findings. DNA studies revealed the first family (Patients 1 and 2) had a missense mutation in exon 3 of the HPRT encoding region. This novel mutation occurs in the hot spot of the HPRT gene. The second family (Patient 3) was found to have a missense mutation in exon 8 of the HPRT gene. The third family (Patient 4) carried a mutation in the splicing region of intron 4 of the HPRT gene. All three mutations were de novo.     

Animal models of Lesch-Nyhan syndrome

In humans, deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) is associated with a disorder known as Lesch-Nyhan syndrome which includes severe neurobehavioral abnormalities. Several animal models which have been developed to examine the neurobiologic substrates of this disorder have suggested a role for abnormal function in purine/dopamine neurotransmission, but the relationship between HPRT-deficiency and these abnormalities remains unknown. Recently, HPRT-deficient mice have been produced which appear to have similar, though more subtle changes in brain dopamine function. These mice will be useful in elucidating the relationship between HPRT-deficiency and the neurological deficits observed in patients with this disorder.     

Elevated UTP and CTP content in cultured neurons from HPRT-deficient transgenic mice

Hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8.; HPRT) catalyzes the salvage synthesis of inosine-5′-monophosphate (IMP) and guanosine-5′-monophosphate (GMP) from the purine bases hypoxanthine and guanine, respectively. Complete deficiency of HPRT activity is associated with the Lesch-Nyhan syndrome (LNS), characterized by excessive purine production and severe neurological manifestations. The etiology of the metabolic consequences of HPRT deficiency is clarified, but that of the neurological manifestations is not yet understood. HPRT-deficient mice represent an experimental animal model of LNS. In search for a possible metabolic abnormality in LNS brains, connecting the neurological deficit to HPRT deficiency, the purine and pyrimidine nucleotide content of cultured neurons, prepared from HPRT-deficient transgenic mice, was now determined. The HPRT-deficient neuronal cultures exhibited a significantly elevated content of the pyrimidine nucleotides UTP (1.33-fold the normal level, p=0.0002) and CTP (1.28-fold the normal level, p=0.02), but normal content of the purine nucleotides ATP and GTP. This abnormality in neuronal pyrimidine nucleotide content may be associated with the pathophysiology of the neurological deficit in LNS.     

A patient with Lesch-Nyhan syndrome complicated by tracheobronchomalacia and fatal bleeding from tracheobrachiocephalic artery fistula

A 19-year-old man with Lesch-Nyhan syndrome (LNS), had dyspnea and an inspiratory wheeze, and underwent assisted mechanical ventilation and tracheostomy. Bronchoscopy revealed tracheomalacia of the cresent moon type. He lost his weight, and his general condition gradually worsened. Four months post-tracheostomy, he died of massive hemoptysis from a tracheobrachicephalic artery fistula. Many patients with LNS have renal failure and pneumonitis, whereas occasional cases are complicated by convulsions, recurrent coma, abnormalities of respiration, and sudden death. The etiology of sudden death is not clear. Although tracheomalacia, to our knowledge, has not been described in the literature, it may be a clinical feature of LNS associated with abnormal respiration and sudden death. Tracheobrachiocephalic artery fistula is common in patients with neuromuscular disorders and a chronic tracheostomy tube. Caution is required in LNS patients with opisthotonic extensor spasms of the neck and trunk, chronic bronchitis, and malnutrition.     

Impaired differentiation of HPRT-deficient dopaminergic neurons: A possible mechanism underlying neuronal dysfunction in Lesch-Nyhan syndrome

Lesch-Nyhan syndrome is a hereditary disorder of purine metabolism causing overproduction of uric acid and neurological problems including spasticity, choreoathetosis, mental retardation, and compulsive self-mutilation. The syndrome is caused by a defect in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), which converts guanine and hypoxanthine to the nucleotides GMP and IMP. There is evidence that the neurological problems are due to an adverse effect of the HPRT deficiency on the survival and/or development of dopaminergic neurons, specifically. Here we report that HPRT-deficient PC12 mutants that have a normal or near normal dopamine content (55–97% of that of wild-type cells) fail to undergo neuronal differentiation induced by nerve growth factor (NGF) when the de novo pathway of purine synthesis is partially inhibited. However, nerve growth factor-induced differentiation is near normal under these conditions in PC12 HPRT-deficient mutants containing much lower dopamine levels (<8% of that of wild type cells), indicating a neurotoxic effect of the endogenous dopamine in the mutants. The degree of inhibition of the de novo pathway of purine synthesis was the same in both classes of HPRT-deficient mutants. Expression of BCl-2 in a PC12 mutant that has a normal dopamine content allowed partial NGF-induced differentiation suggesting that the apoptotic pathway might be involved in the failure of differentiation when the de novo pathway of purine synthesis is partially inhibited. J. Neurosci. Res. 53:78–85, 1998. Published 1998 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Botulinum toxin: treatment of self-mutilation in patients with Lesch-Nyhan syndrome

Lesch-Nyhan syndrome (LNS) is a rare X-linked recessive disorder involving purine metabolism caused by the congenital absence of hypoxanthine guanine phosphoribosyl transferase. A characteristic feature of LNS is the appearance of intractable self-injurious behavior, usually in the form of severe lip and finger biting. The mechanism behind this severe self-mutilating behavior is unknown, and is one of the main challenges in the management of this condition. We here report the case of a 30-year-old man with a confirmed diagnosis of LNS who was successfully treated for self-mutilation of his lips with repeated botulinum toxin A (BTX-A) injections in the facial perioral muscles. Our findings suggest that treatment with BTX-A helped reduce self-abusive behavior in this patient. Our case illustrates that BTX-A injections can be a useful therapeutic approach in patients with self-abusive behavior.     

Monoamine deficiency in a transgenic (Hprt) mouse model of Lesch-Nyhan syndrome

The integrity of forebrain monoamine systems has been assessed both biochemically and immunohistochemically in transgenic mice carrying the mutant hprt-b^m2 gene, an animal model of Lesch-Nyhan syndrome. The mutant mice manifested 20–30% depletions of forebrain dopamine, and corresponding increase in dopamine turnover. By contrast, the mutant mice manifested normal tyrosine hydroxylase immunostaining of catecholamine cell bodies and terminals throughout the forebrain, and cell counts revealed no detectable loss of ventral mesencephalic dopamine neurones. Serotonin concentrations were also depleted, whereas no significant changes were found in noradrenaline or adrenaline, methylhydroxyphenylglycol (MHPG) or 5-hydroxyindoleacetic acid. The results indicate that a primary genetic deficiency in purine salvage pathways is associated with additional changes in forebrain monoamine metabolism in mouse as in man, although these changes are less pronounced in the animal model than in the human syndrome. The biochemical changes were not associated with explicit degeneration of the associated populations of neurones.     

Lesch-Nyhan syndrome: CSF neurotransmitter abnormalities

Serial determinations of spinal fluid homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were made in four patients with the Lesch-Nyhan syndrome over a 5-year period. Control spinal fluids for age-matched comparison were obtained from 194 neurologic and nonneurologic pediatric patients. A rapid decline in control spinal fluid HVA and 5-HIAA occurs over the first 3 years of life (50 and 60%, respectively), and a more gradual decline persists throughout adolescence. The Lesch-Nyhan subjects have similar age-related changes in their spinal fluid neurotransmitter levels. Sequential 5-HIAA determinations from the four Lesch-Nyhan boys fall within the control range. The Lesch-Nyhan HVA levels are lower than the mean value for the age-matched control group in 18 of 19 samples. Ten of 19 determinations fell below the control range. Our findings provide evidence for altered CNS dopamine metabolism in the Lesch-Nyhan syndrome.     

Elevated fibrinopeptide A (FPA) in patients with Lesch-Nyhan syndrome.

The detection of elevated fibrinopeptide A (FPA) level in a patient with the Lesch-Nyhan syndrome complicated with cerebral infarction prompted us to examine FPA level in 3 other patients with the syndrome. FPA level significantly increased in all patients. Fibrinopeptide B beta 15-42 (FPB beta 15-42) level was increased in two, and both beta-thromboglobulin (beta TG) and platelet factor 4 (PF4) levels were elevated in one patient. These results suggest coagulation abnormalities in patients with Lesch-Nyhan syndrome.     

Monkeys with unilateral ventromedial tegmental lesions of the brain stem: models for Parkinson's disease and Lesch-Nyhan syndrome

1. Monkeys with surgical unilateral ventromedial tegmental lesions of the brain stem served as models for investigating abnormalities in Parkinson's disease and Lesch-Nyhan syndrome. 2. The animals exhibited some neurological deficits which are similar to those observed in Parkinson's disease or Lesch-Nyhan syndrome. 3. In monkeys with unilateral ventrolateral tegmental lesions, the levels of dopamine and the activities of catecholamine-synthesizing enzymes were reduced on the lesion side of the striatum, and hypokinesia and tremor developed on the contralateral extremities. 4. Dopa or dopamine agonists relieve tremor and evoke abnormal involuntary movements which are similar to the responses observed in patients with Parkinson's disease. 5. The antitremor effect of Dopa is potentiated by catechol-O-methyltransferase inhibition, suggesting a therapeutic potential for these types of agents. 6. Evidence was obtained that stimulation of D2 dopamine receptors by selective dopamine agonists exerts antitremor activity and evokes abnormal involuntary movements. 7. Combined administration of D1 and D2 dopamine agonists seems to enhance the antitremor activity. 8. Partial dopamine agonists exert antitremor activity and produce less severe abnormal involuntary movements than full dopamine agonists. 9. In a group of monkeys with unilateral ventromedial tegmental lesions of the brain stem the administration of mixed D1/D2 dopamine agonists results in the occurrence of self-biting behavior of the forelimb digits and spasticity of the hindlimbs and these symptoms are similar to those observed in patients with Lesch-Nyhan syndrome. 10. The self-biting behavior seems to be associated with the stimulation of central D1 dopamine receptors and therefore the possible involvement of dopamine neuronal abnormalities in Lesch-Nyhan syndrome deserves further investigation.     

Identification of a new Lesch-Nyhan syndrome mutation (HPRTBrasil) and analysis of potentially heterozygous females

The mutation in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene has been determined in two brothers affected with Lesch-Nyhan syndrome. Female members of the family who are at risk for being heterozygous carriers of the HPRT mutation were also studied to determine whether they carry the mutation. DNA sequencing revealed that the boys' mother is heterozygous for the mutation in her somatic cells, but that three maternal aunts are not heterozygous. Such carrier information is important for the future pregnancy plans of at-risk females. The mutation, an A-->T transversion at cDNA base 590 (590A-->T), results in an amino acid change of glutamic acid to valine at codon 197, and has not been reported previously in a Lesch-Nyhan syndrome male. This mutation is designated HPRTBrasil.