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      Attenuated variants of Lesch-Nyhan disease

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          Abstract

          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.

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          Most cited references88

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          A FAMILIAL DISORDER OF URIC ACID METABOLISM AND CENTRAL NERVOUS SYSTEM FUNCTION.

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            Validity and reliability of a rating scale for the primary torsion dystonias.

            For quantitative assessment of the primary torsion dystonias, a rating scale is proposed that has two sections--a Movement Scale, based on examination, and a Disability Scale, based on the patient's statements about seven activities of daily living. We assessed the validity of the Movement Scale by comparing scores with a ranking of patients according to dystonia severity and with ratings of the patients on the Disability Scale. In addition, we assessed the inter-and intra-rater reliability of the scale by comparing independent scorings of patients by four examiners and by comparing scorings by the same examiners performed at different times. We found that the Movement Scale was a valid and reliable indicator of the severity of primary torsion dystonia.
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              Delineation of the motor disorder of Lesch-Nyhan disease.

              Lesch-Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Affected individuals exhibit over-production of uric acid, along with a characteristic neurobehavioural syndrome that includes mental retardation, recurrent self-injurious behaviour and motor disability. Prior studies involving relatively small numbers of patients have provided different conclusions on the nature of the motor disorder. The current study includes the results of a multi-centre international prospective study of the motor disorder in the largest cohort of patients studied to date. A total of 44 patients ranging from 2 to 38 years presented a characteristic motor syndrome that involved severe action dystonia superimposed on baseline hypotonia. Although some patients also displayed other extrapyramidal or pyramidal signs, these were always less prominent than dystonia. These results are compared with a comprehensive review of 122 prior reports that included a total of 254 patients. Explanations for the differing observations available in the literature are provided, along with a summary of how the motor disorder of LND relates to current understanding of its pathophysiology involving the basal ganglia.
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                Author and article information

                Contributors
                On behalf of : for the Lesch-Nyhan Disease International Study Group
                Journal
                Brain
                brainj
                brain
                Brain
                Oxford University Press
                0006-8950
                1460-2156
                March 2010
                22 February 2010
                22 February 2010
                : 133
                : 3
                : 671-689
                Affiliations
                1 Department of Neurology and Department of Human Genetics, Emory University, Atlanta GA, USA
                2 Department of Metabolic Biochemistry, Hopital Necker-Enfants Malades, and Universite Paris Descartes, Paris, France
                3 Division of Clinical Biochemistry and Genetic Institute, Hospital Universitario La Paz, Universidad Autonoma de Madrid, Spain
                4 Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, and Amphia Hospital, Breda, The Netherlands
                5 Department of Psychiatry & Behavioural Sciences, and Department of Radiology, Johns Hopkins University, Baltimore MD, USA
                6 Division of Paediatric Neurology, Hospital Virgen de la Salud, Toledo, Spain
                7 Centro de Estudio de las Metabolopatias Congenitas; Universidad Nacional de Cordoba, Cordoba, Argentina
                8 Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
                9 Dipartimento Struttura Clinica Medica-Patologica Medica, Universita degli Studi di Sassari, Italy
                10 Wu Chien-Hui’s Clinic, San-Hwa, Tainan County, Taiwan
                11 Department of Public Health, Faculty of Medicine, Kaohsiung Medical University College of Medicine, Kaohsiung, Taiwan
                12 Department of Paediatrics; University of California San Diego, La Jolla CA
                13 Department of Psychiatry & Behavioural Sciences, and Department of Paediatrics, Johns Hopkins University, Baltimore, MD, USA
                14 Department of Neurology, University of Maryland, Baltimore MD, USA
                15 Division of Internal Medicine, Hospital Universtitario La Paz, Universidad Autonoma de Madrid, Spain
                Author notes
                Correspondence to: H. A. Jinnah, Department of Neurology and Department of Human Genetics, Emory University School of Medicine, Atlanta GA, 30322, USA E-mail: hjinnah@ 123456emory.edu
                Article
                awq013
                10.1093/brain/awq013
                2842514
                20176575
                0513a97e-9c89-4010-8152-001992d657c4
                © The Author(s) 2010. Published by Oxford University Press on behalf of Brain.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 August 2009
                : 14 December 2009
                : 4 January 2010
                Categories
                Original Articles

                Neurosciences
                metabolic disease,behaviour,dystonia,kelly–seegmiller syndrome,genotype–phenotype correlation,neurogenetics,uric acid

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