Attenuated variants of Lesch-Nyhan disease

• Type of Material: Article
• Authors: Hyder A Jinnah, Emory University; Irene Ceballos-Picot, Hopital Necker-Enfants Malades; Rosa J. Torres, Hospital Universitario La Paz; Jasper E. Visser, Radboud University Nijmegen Medical Centre; David J. Schretlen, Johns Hopkins University; Alfonso Verdu, Hospital Virgen de la Salud; Laura E. Laróvere, Universidad Nacional de Cordoba; Chung-Jen Chen, Chang Gung Memorial Hospital Kaohsiung Medical Center; Antonello Cossu, Universita degli Studi di Sassari; Chien-Hui Wu, Wu Chien-Hui’s Clinic; Radhika Sampat, Emory University; Shun-Jen Chang, Kaohsiung Medical University College of Medicine; Raquel Dodelson de Kremer, Universidad Nacional de Cordoba; William Nyhan, University of California San Diego; James C. Harris, Johns Hopkins University; Stephen G. Reich, University of Maryland; Juan G. Puig, Hospital Universtitario La Paz
• Language: English
• Date: 2010
• Publisher: Oxford University Press (OUP)
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2010. Published by Oxford University Press on behalf of Brain.
• License: Creative Commons Attribution-NonCommercial 2.5 Generic
• Final Published Version (URL): http://brain.oxfordjournals.org/content/133/3/671
• Title of Journal or Parent Work: Brain
• ISSN: 0006-8950
• Volume: 133
• Issue: 3
• Start Page: 671
• End Page: 689
• Grant/Funding Information: Association Lesch-Nyhan Action; Centro de Investigaciones Biomedicas en Red para el Estudio de las Enfermedades Raras (CIBERER); Fondo de Investigaciones Sanitarias (FIS 06/0019 and FIS 08/0009); Lesch-Nyhan Syndrome Children’s Research Foundation; the National Institutes of Health (HD53312 and DK82840).
• Keywords: genotype–phenotype correlation; Kelly–Seegmiller syndrome; metabolic disease; dystonia; uric acid; neurogenetics; behaviour
• Research Categories: Biology, Neuroscience; Biology, Genetics

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.