title: Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data.
abstract: We have established that the frequency of LRRK2 mutations in a series of 118 cases of familial Parkinson's disease is 5.1%. In the largest family with autosomal dominant, late-onset Parkinson's disease where affected subjects share a Y1699C missense mutation we provide a detailed clinical, pathological and imaging report. The phenotype in this large British kindred included asymmetrical, levodopa-responsive parkinsonism where unilateral leg tremor at onset and foot dystonia were prominent features. There was no significant abnormality of cognition but there was prominent behavioural disorder. We observed a lower age of onset in successive generations. Histopathology in one patient showed substantia nigra cell loss and Lewy body formation, with small numbers of cortical Lewy bodies. 18F-dopa positron emission tomography (PET) in another patient showed a pattern of nigrostriatal dysfunction typical of idiopathic Parkinson's disease. 18F-dopa-PET scans in unaffected family members prior to identifying the disease locus did not detect subclinical nigrostriatal dysfunction. Olfaction was assessed in affected subjects and Lewy bodies were identified in the olfactory bulb as well as cortex and brainstem of one deceased patient. In order to assess the role of mutations in this gene in other familial cases we undertook a mutation screen of all 51 exons of LRRK2 in 117 other smaller British kindreds with familial Parkinson's disease. The commonest mutation was G2019S and we also identified two novel mutations, R1941H and T2356I, in the coding sequence. These data suggest that parkinsonism caused by mutations in LRRK2 is likely to represent the commonest locus for autosomal dominant Parkinson's disease with a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson's disease.
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, London, UK.
authors.forename: Naheed L
authors.initials: NL
authors.lastname: Khan
authors.forename: Shushant
authors.initials: S
authors.lastname: Jain
authors.forename: John M
authors.initials: JM
authors.lastname: Lynch
authors.forename: Nicola
authors.initials: N
authors.lastname: Pavese
authors.forename: Patrick
authors.initials: P
authors.lastname: Abou-Sleiman
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Healy
authors.forename: William P
authors.initials: WP
authors.lastname: Gilks
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.forename: Milan
authors.initials: M
authors.lastname: Ganguly
authors.forename: Vaneesha
authors.initials: V
authors.lastname: Gibbons
authors.forename: Sonia
authors.initials: S
authors.lastname: Gandhi
authors.forename: Jenny
authors.initials: J
authors.lastname: Vaughan
authors.forename: Louise H
authors.initials: LH
authors.lastname: Eunson
authors.forename: Regina
authors.initials: R
authors.lastname: Katzenschlager
authors.forename: Juliet
authors.initials: J
authors.lastname: Gayton
authors.forename: Graham
authors.initials: G
authors.lastname: Lennox
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.forename: David
authors.initials: D
authors.lastname: Nicholl
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Bhatia
authors.forename: Niall
authors.initials: N
authors.lastname: Quinn
authors.forename: David
authors.initials: D
authors.lastname: Brooks
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lees
authors.forename: Mary B
authors.initials: MB
authors.lastname: Davis
authors.forename: Paola
authors.initials: P
authors.lastname: Piccini
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D004252:DNA Mutational Analysis; D004739:England; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D009830:Olfactory Bulb / Q000473:pathology; D010300:Parkinson Disease / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D049268:Positron-Emission Tomography; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D019275:Radiopharmaceuticals
chemical_list: D019275:Radiopharmaceuticals; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases