Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data

• Published in: Brain (London, England : 1878) England : 1878), 2005-12, Vol.128 (12), p.2786-2796
• Main Authors: Khan, Naheed L., Jain, Shushant, Lynch, John M., Pavese, Nicola, Abou-Sleiman, Patrick, Holton, Janice L., Healy, Daniel G., Gilks, William P., Sweeney, Mary G., Ganguly, Milan, Gibbons, Vaneesha, Gandhi, Sonia, Vaughan, Jenny, Eunson, Louise H., Katzenschlager, Regina, Gayton, Juliet, Lennox, Graham, Revesz, Tamas, Nicholl, David, Bhatia, Kailash P., Quinn, Niall, Brooks, David, Lees, Andrew J., Davis, Mary B., Piccini, Paola, Singleton, Andrew B., Wood, Nicholas W.
• Format: Article
• Language: English
• Subjects: Adult; Age of Onset; Aged; ARSAC = Administration of Radioactive Substances Advisory Committee; Biological and medical sciences; Brain - diagnostic imaging; Brain - pathology; cM = centimorgan; dardarin; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diseases of striated muscles. Neuromuscular diseases; DNA Mutational Analysis; England; F-dopa PET = 18F-dopa positron emission tomography; Female; Genes, Dominant; Genetic Linkage; Genetic Testing; Haplotypes; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy bodies; LOD = logarithm of the odds; Lod Score; LRRK2; LRRK2 = leucine-rich; Male; Medical sciences; Middle Aged; Mutation, Missense - genetics; Neurology; NFTs = neurofibrillary tangles; NHNN = National Hospital for Neurology and Neurosurgery; Olfactory Bulb - pathology; Parkinson Disease - diagnosis; Parkinson Disease - genetics; Parkinson Disease - pathology; Pedigree; Positron-Emission Tomography; Protein Serine-Threonine Kinases - genetics; Radiopharmaceuticals; repeat kinase 2; UPSIT = University of Pennsylvania Smell Identification Test
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awh667

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.