title: Attenuated variants of Lesch-Nyhan disease.
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.
authors.affiliation: Department of Neurology and Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. hjinnah@emory.edu
authors.forename: H A
authors.initials: HA
authors.lastname: Jinnah
authors.forename: Irene
authors.initials: I
authors.lastname: Ceballos-Picot
authors.forename: Rosa J
authors.initials: RJ
authors.lastname: Torres
authors.forename: Jasper E
authors.initials: JE
authors.lastname: Visser
authors.forename: David J
authors.initials: DJ
authors.lastname: Schretlen
authors.forename: Alfonso
authors.initials: A
authors.lastname: Verdu
authors.forename: Laura E
authors.initials: LE
authors.lastname: Laróvere
authors.forename: Chung-Jen
authors.initials: CJ
authors.lastname: Chen
authors.forename: Antonello
authors.initials: A
authors.lastname: Cossu
authors.forename: Chien-Hui
authors.initials: CH
authors.lastname: Wu
authors.forename: Radhika
authors.initials: R
authors.lastname: Sampat
authors.forename: Shun-Jen
authors.initials: SJ
authors.lastname: Chang
authors.forename: Raquel Dodelson
authors.initials: RD
authors.lastname: de Kremer
authors.forename: William
authors.initials: W
authors.lastname: Nyhan
authors.forename: James C
authors.initials: JC
authors.lastname: Harris
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Reich
authors.forename: Juan G
authors.initials: JG
authors.lastname: Puig
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000378:metabolism / Q000503:physiopathology; D015331:Cohort Studies; D020820:Dyskinesias / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007926:Lesch-Nyhan Syndrome / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D001523:Mental Disorders / Q000378:metabolism / Q000503:physiopathology; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D014527:Uric Acid / Q000378:metabolism; D055815:Young Adult
chemical_list: D014527:Uric Acid