Delayed emergence from propofol anesthesia in a patient with Lesch-Nyhan syndrome: A case report.

RATIONALE: Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder presenting with uric acid overproduction, neurocognitive disability, and behavioral disturbances. Inhalational anesthesia has been frequently used in LNS patients undergoing surgery. Characteristic compulsive self-injurious behavior and high risk of emesis may hinder inhalational induction. Propofol may be beneficial for these patients because of its easy and rapid titration for anesthetic depth during induction, early recovery from anesthesia, and antiemetic effect as well as uricosuric effect. PATIENT CONCERNS: A 16-year-old male adolescent was scheduled for percutaneous nephrolithotomy. He exhibited poorly controlled muscle, self-injurious behaviors and intellectual disability. DIAGNOSIS: The patient presented with neurodevelopmental delay in the first year of life, and was diagnosed with LNS, with a substitution of phenylalanine to leucine in hypoxanthine-guanine phosphoribosyltransferase (HPRT) 1 gene on the X-chromosome at 3 years of age. INTERVENTIONS: Total intravenous anesthesia was used for induction and maintenance of anesthesia with propofol and remifentanil using target-controlled infusion. OUTCOMES: Time to recovery of consciousness was prolonged after uneventful surgery. Serum uric acid levels gradually increased during postoperative period. LESSONS: Propofol anesthesia using target-controlled infusion does not provide significant clinical advantages in rapid emergence from anesthesia and management of hyperuricemia in LNS patients undergoing urological surgery.

Oral self-mutilation in Lesch-Nyhan Syndrome. Case Report. / Síndrome de Lesch-Nyhan y automutilación oral. Reporte de un caso.

INTRODUCTION: Lesch-Nyhan syndrome (LNS) is an inherited recessive X-related disorder caused by the deficiency of the enzyme hypoxanthin-guanine phosphorribosyl transferase (HPRT). Compul sive self-mutilation and dystonia occurs before the first year of age and is expressed by persistent bites on the oral mucosa, lips, tongue, fingers, and shoulders. The dental intervention performed on most of these patients is multiple tooth extraction to prevent serious secondary lesions. OBJECTIVE: To present a clinical case of LNS and describe pediatric dentistry management in patients with self-mutilating behavior. CLINICAL CASE: Male patient, 7 years old, LNS carrier. He was referred to the Dental Unit from the Department of Pediatric Neurology for evaluation and management of self-inflicted wounds on fingers, lips and cheeks associated with weight loss and decreased food intake. The surgical procedure consisted of multiple extractions, surgical remodeling of the residual alveolar ridges under general anesthesia. In the second postoperative month, the patient was discharged definitively, with an adequate nutritional status and no signs of self-mutilation in hands or oral cavity. CONCLUSIONS: Although LNS is rare, it is essential to know how to proceed in order to provide the best quality of life for patients and their families. Early tooth extractions, as an initial phase in severe cases, seem to be the most useful alternative to minimize damage.

Síndrome de Lesch-Nyhan y automutilación oral. Reporte de un caso / Oral self-mutilation in Lesch-Nyhan Syndrome. Case Report

Resumen: Introducción: El síndrome de Lesch-Nyhan (SLN) es un trastorno hereditario recesivo relacionado con el cromosoma X, causado por la deficiencia de la enzima hipoxantina-guanina fosforribosil transferasa (HPRT). La automutilación compulsiva y distonía ocurre antes del año de edad y se expresa con mordeduras persistentes en la mucosa oral, labios, lengua, dedos y hombros. La intervención odontológica realizada en la mayoría de estos pacientes es la extracción dental múltiple para prevenir lesiones graves secundarias. Objetivo: presentar un caso clínico de SLN y describir el manejo odonto-pediátrico en pacientes con conducta automutilatoria. Caso clínico: Paciente varón, 7 años de edad, portador de SLN. Fue referido a la Unidad de Odontología desde el Departamento de Neurología Pediátrica para la evaluación y manejo de heridas autoinfligidas en dedos, labios y mejillas asociadas a una pérdida de peso y disminución de la ingesta de alimentos. El procedimiento quirúrgico consistió en extracciones dentales múltiples, y remodelación quirúrgica de las crestas alveolares residuales, bajo anestesia general. Al segundo mes posquirúrgico el paciente fue dado de alta definitivamente, con un adecuado estado nutricional y sin signos de automutilación en manos ni en cavidad oral. Conclusio nes: A pesar, que el SLN es infrecuente, es esencial saber cómo proceder para dar la mejor calidad de vida a los pacientes y sus familias. Las extracciones tempranas del diente, como fase inicial en casos severos, parecen ser la alternativa más útil para minimizar el daño y el dolor por la automutilación.

Abstract: Introduction: Lesch-Nyhan syndrome (LNS) is an inherited recessive X-related disorder caused by the deficiency of the enzyme hypoxanthin-guanine phosphorribosyl transferase (HPRT). Compul sive self-mutilation and dystonia occurs before the first year of age and is expressed by persistent bites on the oral mucosa, lips, tongue, fingers, and shoulders. The dental intervention performed on most of these patients is multiple tooth extraction to prevent serious secondary lesions. Objective: To present a clinical case of LNS and describe pediatric dentistry management in patients with self-mutilating behavior. Clinical case: Male patient, 7 years old, LNS carrier. He was referred to the Dental Unit from the Department of Pediatric Neurology for evaluation and management of self-inflicted wounds on fingers, lips and cheeks associated with weight loss and decreased food intake. The surgical procedure consisted of multiple extractions, surgical remodeling of the residual alveolar ridges under general anesthesia. In the second postoperative month, the patient was discharged definitively, with an adequate nutritional status and no signs of self-mutilation in hands or oral cavity. Conclusions: Although LNS is rare, it is essential to know how to proceed in order to provide the best quality of life for patients and their families. Early tooth extractions, as an initial phase in severe cases, seem to be the most useful alternative to minimize damage.

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

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Development of new forms of self-injurious behavior following total dental extraction in Lesch-Nyhan disease.

We report two Lesch-Nyhan Disease (LND) patients who developed new forms of self-injurious behavior following total dental extraction. Patients 1 and 2 were submitted to total teeth extraction at the age of 13 and 8 years, respectively, due to continuous self-biting, not prevented by mouth guards. Severity of dystonia was markedly reduced and quality of life improved. After 12 and 17 months, respectively, patient 1 started rubbing one foot against other and scratching toenails with his hands, and patient 2 stuck his legs and feet against hard objects. These forms of self-injury behavior could be easily prevented with protective materials, according to the mothers.

A review of the implication of hypoxanthine excess in the physiopathology of Lesch-Nyhan disease.

Lesch-Nyhan disease is caused by HGprt deficiency, however, the mechanism by which enzyme deficiency leads to the severe neurological manifestations is still unknown. We hypothesized that hypoxanthine excess leads, directly or indirectly, through its action in adenosine transport, to aberrations in neuronal development. We found that hypoxanthine diminishes adenosine transport and enhances stimulation of adenosine receptors. These effects cause an imbalance between adenosine, dopamine, and serotonin receptors in HGprt deficient cells, and cells differentiated with hypoxanthine showed an increase in dopamine, adenosine and serotonin receptors expression. Hypoxanthine deregulates early neuronal differentiation increasing WNT4 and EN1 gene expression.

Successful unrelated umbilical cord blood transplantation in Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome (LNS) is a chronic, progressive neurodevelopmental disorder causing motor and behavioral dysfunction due to decreased synthesis of the enzyme hypoxantine-guanine phosphoribosyltransferase (HPRT). Affected boys have mental retardation, delayed development, extrapyramidal motor disturbances and self-injuring behavior. As hematopoietic stem cell transplantation (HSCT) has been shown to be effective in several neurodevelopmental inborn errors, we hypothesized that it could be favorable in LNS as well. Following a myeloablative conditioning regimen (busulphan 3.2 mg/kg/day for 4 days, cyclophosphamide 60 mg/kg/day for 2 days with ATG Thymoglobin 2.5 mg/kg/day for 4 days) an unrelated umbilical cord blood unit was transfused at the age of 2 years. The graft was a 6/6 HLA-matched at HLA-A, B loci by antigen level, and at DRB1 by allelic level typing. Infused total nucleated cell dose was 3.6 × 10e7 per kilogram body weight. Serum HPRT levels reached normal values by the end of the sixth month post transplant. Slow neurodevelopmental improvement seen during the three-year follow-up and the missing self-injuring behavior can be considered as a proof for the presence of enzyme-competent cells behind the blood-brain barrier.

Animal models of self-injurious behaviour: an overview.

Self-injurious behaviour is highly prevalent in neurodevelopmental disorders. Interestingly, it is not restricted to any individual diagnostic group. Rather, it is exhibited in various forms across patient groups with distinct genetic defects and classifications of disorders. This suggests that there may be shared neuropathology that confers vulnerability. Convergent evidence from clinical pharmacotherapy, brain imaging studies, postmortem neurochemical analyses, and animal models indicates that dopaminergic insufficiency is a key culprit. This chapter provides an overview of studies in which animal models have been used to investigate the biochemical basis of self-injury, and highlights the convergence in findings between these models and expression of self-injury in humans.

Attenuated variants of Lesch-Nyhan disease.

Lesch-Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch-Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch-Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine-guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch-Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine-guanine phosphoribosyltransferase deficiency.

[Behavioral phenotypes and cognitive characteristics in mental retardation]. / Magatartási fenotípusok és kognitív sajátságok mentális retardációban.

The authors in a review article deal with characteristic cognitive and behavioral features appearing in mental retardations, which later are referred as behavioral phenotypes. Nyhan (1972) introduced the term "behavioral phenotype" to describe outwardly observable behavior so characteristic of children with genetic disorders that its presence suggests the underlying genetic condition. The behavioral phenotype is a characteristic pattern of motor, cognitive, linguistic and social abnormalities that is consistently associated with a biological/neurodevelopmental disorder. This does not mean that the behavior is present in all instances but that the probability of its occurrence is increased. In the future, more may be learned about brain mechanisms and gene-brain interactions by comparing those with behavioral involvement with others with the same syndrome but without the behavioral features.

Decreased GTP-stimulated adenylyl cyclase activity in HPRT-deficient human and mouse fibroblast and rat B103 neuroblastoma cell membranes.

Defect of the purine salvage enzyme, hypoxanthine phosphoribosyl transferase (HPRT), results in Lesch-Nyhan disease (LND). It is unknown how the metabolic defect translates into the severe neuropsychiatric phenotype characterized by self-injurious behavior, dystonia and mental retardation. There are abnormalities in GTP, UTP and CTP concentrations in HPRT-deficient cells. Moreover, GTP, ITP, XTP, UTP and CTP differentially support Gs-protein-mediated adenylyl cyclase (AC) activation. Based on these findings we hypothesized that abnormal AC regulation may constitute the missing link between HPRT deficiency and the neuropsychiatric symptoms in LND. To test this hypothesis, we studied AC activity in membranes from primary human skin and immortalized mouse skin fibroblasts, mouse Neuro-2a neuroblastoma cells and rat B103 neuroblastoma cells. In B103 control membranes, GTP, ITP, XTP and UTP exhibited profound stimulatory effects on basal AC activity that approached the effects of hydrolysis-resistant nucleotide analogs. In HPRT- membranes, the stimulatory effects of GTP, ITP, XTP and UTP were strongly reduced. Similarly, in human and mouse skin fibroblast membranes we also observed a decrease in GTP-stimulated AC activity in HPRT-deficient cells compared with the respective controls. In mouse Neuro-2a neuroblastoma membranes, AC activity in the presence of GTP was below the detection limit of the assay. We discuss several possibilities to explain the abnormalities in AC regulation in HPRT deficiency that encompass various species and cell types.

Behavioral aspects of Lesch-Nyhan disease and its variants.

Self-injury is a defining feature of lesch-nyhan disease (LND) but does not occur in the less severely affected Lesch-Nyhan variants (LNV). The aim of this study was to quantify behavioral and emotional abnormalities in LND and LNV. Thirty-nine informants rated 22 patients with LND (21 males, 1 female), 11 males with LNV, and 11 healthy controls (HC; 10 males, 1 female) using two well-validated rating scales. The age of patients with LND ranged from 12 years 7 months to 38 years 3 months (mean 22 y 11 mo; sd 7 y 8 mo), whereas the age range of those with LNV was 12 years 9 months to 65 years (mean 30 y 7 mo; sd 15 y 2 mo), and the healthy controls were aged 12 years 4 months to 31 years 3 months (mean 17 y 10 mo; sd 5 y 7 mo). Behavioral ratings were based on the Child Behavior Checklist and the American Association On Mental Retardation's Adaptive Behavior Scale--Residential And Community, 2nd edition. Statistical analyses revealed that patients with LND showed severe self-injury together with problematic aggression, anxious-depressed symptoms, distractibility, motor stereotypes, and disturbing interpersonal behaviors. Patients with LNV were rated as being intermediate between the HC and LND groups on all behavior scales. Although the LNV group did not differ from hcs on most scales, their reported attention problems were as severe as those found in LND. We conclude that self-injurious and aggressive behaviors are nearly universal and that other behavioral abnormalities are common in LND. Although patients with LNV typically do not self-injure or display severe aggression, attention problems are common and a few patients demonstrate other behavioral anomalies.

Case report: the Lesch-Nyhan syndrome.

BACKGROUND: The Lesch-Nyhan syndrome (LNS) is a rare x-linked excessive disorder of purine metabolism, caused by the congenital absence of hypoxanthine guanine phosphoribosyl transferase (HGPRT). CASE REPORT: In January 2000 a 2 year old boy was referred to a paediatric dental office in Landshut, Germany, because of severe and repeated lip chewing and aggressive tongue biting. A medical history revealed a normal pregnancy with no complications but a diagnosis of muscular hypotonia was made at four months of age. At 18 months a diagnosis of LNS was established through biochemical analysis and molecular examinations. The child displayed self-destructive behaviour, typical in children with LNS. Shortly thereafter the patient was supplied with arm cuffs for self-protection which were not tolerated and the self-mutilation continued. Eventually the extraction of all primary teeth was deemed necessary to prevent additional medical problems for this child. FOLLOW-UP: One year after the dental extractions the patient presented with no bite injuries but was now using his fingers to injure himself.

Pharmacologic thresholds for self-injurious behavior in a genetic mouse model of Lesch-Nyhan disease.

Congenital deficiency of hypoxanthine-guanine phosphoribosyl transferase (HPRT) causes Lesch-Nyhan disease in humans, which is associated with severe and recurrent self-injurious behavior (SIB). The HPRT-deficient knockout mouse model, however, does not display this unusual behavior. The present studies tested whether these mice might be more vulnerable to pharmacologic agents known to cause SIB in normal rodents, including clonidine, Bay K 8644, GBR 12909, methamphetamine, pemoline and caffeine. The results provided three conclusions. First, normal mice did not display SIB using some drugs known to provoke the behavior in rats (GBR 12909, caffeine), indicating important species differences in the expression of the behavior. Second, the C57BL/6J mice did not display SIB using drugs effective for other strains of mice (methamphetamine, pemoline), indicating important strain differences in expression of the behavior. Finally, there was no evidence that the HPRT-deficient mice were more susceptible to SIB when it occurred (clonidine, Bay K 8644).

Functional analysis of self-injurious behavior in an adult with Lesch-Nyhan syndrome.

A three-phase functional analysis was conducted to discover controlling variables of self-injury in a 28-year-old individual with Lesch-Nyhan syndrome. Experimental verification followed information-gathering and interpretive phases. Self-injurious responses were blocked to prevent harm to the participant; therefore, responses measured were precursors to self-injury. A multielement experimental design included four assessment conditions: social attention contingent on precursory behavior, attention contingent on behavior incompatible with precursory behavior, continuous attention and minimal attention. Highest rates of precursory behavior occurred during continuous attention and when incompatible behavior was reinforced. Social attention appeared to act as a discriminative stimulus for self-injurious behavior in this participant.

Neurocognitive functioning in Lesch-Nyhan disease and partial hypoxanthine-guanine phosphoribosyltransferase deficiency.

Lesch-Nyhan disease (LND) is a rare, X-linked genetic disorder that involves the nearly complete absence of an enzyme (hypoxanthine-guanine phosphoribosyltransferase, or HPRT) that is essential for purine salvage. In addition to hyperuricemia, all patients with classic LND suffer from movement disorder and compulsive self-injury, and most have mental retardation. Patients with partial HPRT deficiency (variants) always have hyperuricemia and often have neurologic abnormalities, but do not self-injure and usually are described as having normal intelligence. Here we compare 15 patients with LND to 9 variants and 13 normal adolescents and adults. Testing revealed unambiguous and qualitatively similar cognitive deficits in both patient groups. The variants produced scores that were intermediate between those of patients with LND and normal participants on nearly every cognitive measure. We discuss these findings in terms of what is known about the neuropathology of LND.

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.

Lesch-Nyhan disease and the basal ganglia.

The purpose of this review is to summarize emerging evidence that the neurobehavioral features of Lesch-Nyhan disease (LND), a developmental disorder caused by congenital deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), may be attributable to dysfunction of the basal ganglia. Affected individuals have severe motor disability described by prominent extrapyramidal features that are characteristic of dysfunction of the motor circuits of the basal ganglia. They also display disturbances of ocular motility, cognition, and behavioral control that may reflect disruption of other circuits of the basal ganglia. Though neuropathologic studies of autopsy specimens have revealed no obvious neuroanatomical abnormalities in LND, neurochemical studies have demonstrated 60-90% reductions in the dopamine content of the basal ganglia. In addition, recent PET studies have documented significant reductions in dopamine transporters and [18F]fluorodopa uptake in the basal ganglia. These findings support the proposal that many of the neurobehavioral features of LND might be related to dysfunction of the basal ganglia.