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Publications (5)36.03 Total impact

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    ABSTRACT: Progressive supranuclear palsy (PSP) is a disorder of unknown pathogenesis. Familial clusters of PSP have been reported related to mutations of protein tau. We report the linkage of a large Spanish family with typical autosomal dominant PSP to a new locus in chromosome 1. Four members of this family had typical PSP, confirmed by neuropathology in one case. At least five ancestors had similar disease. Other members of the family have incomplete phenotypes. The power of the linkage analysis was increased by detecting presymptomatic individuals with 18F-fluoro-dopa and 18F-deoxyglucose positron emission tomography. We screened the human genome with 340 polymorphic markers and we enriched the areas of interest with additional markers. The disease status was defined according to the clinical and positron emission tomography data. We excluded linkage to the tau gene in chromosome 17. PSP was linked, in this family, to one area of 3.4 cM in chromosome 1q31.1, with a maximal multipoint < OD score of +3.53. This area contains at least three genes, whose relevance in PSP is unknown. We expect to further define the gene responsible for PSP, which could help to understand the pathogenesis of this disease and to design effective treatment.
    Annals of Neurology 06/2005; 57(5):634-41. · 11.19 Impact Factor
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    ABSTRACT: Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships. We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity. The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to alpha-synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the alpha-synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis. The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls. The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function. Our data show that, in addition to the previously described hereditary alpha-synucleinopathies, dementia with Lewy bodies is related to mutation of alpha-synuclein.
    Annals of Neurology 03/2004; 55(2):164-73. · 11.19 Impact Factor
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    ABSTRACT: Steele-Richardson-Olszewski syndrome (SROS) is a neurodegenerative disorder of unknown aetiology, most frequently sporadic. Familial cases of SROS have been described. An intronic polymorphism of the tau gene is associated with sporadic SROS and mutations of the tau gene are present in atypical cases of SROS. The role of tau has been excluded in other families with pathology proven SROS, suggesting that this syndrome may have multiple causes. An 82-year-old patient, father of 3 children with autosomal recessive juvenile parkinsonism due to combined heterozygous mutations of the parkin gene, developed clinical features of SROS 2 years before death. The diagnosis was confirmed by pathology. He carried the C212Y mutation of the parkin gene and was homozygous for the A0 polymorphism and for the H1 haplotype. The role of parkin in the processing of tau is discussed.
    Movement Disorders 12/2002; 17(6):1374-80. · 4.56 Impact Factor
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    ABSTRACT: Several genetic errors in alpha-synuclein (Park1) and ubiquitin carboxyl-terminal-hydrolase L1(Park5) genes cause autosomal dominant familial Parkinson disease. Mutations in the parkin gene (Park2) are the major cause of autosomal recessive Parkinson disease. To analyze the clinical and molecular data of 19 Spanish kindreds (13 with recessive, 4 with dominant, and 2 with uncertain inheritance) who have familial Parkinson disease. We searched for the previously described mutations in Park1 and Park5 genes and for new or described mutations in Park2. We used single-strand conformation polymorphism, direct sequencing, and restriction digestion of polymerase chain reaction (PCR)-amplified genomic DNA for this study. None of these families have either Park1 or Park5 mutations. We found 5 different mutations in Park2 gene in 5 of the families with recessive inheritance. To our knowledge, 2 of these mutations, V56E and C212Y, have not been previously reported. The other mutations found (deletion of exons 3 and 5 and 225delA) have been described in other ethnic groups. Heterozygous carriers of a single Park2 mutation either were asymptomatic or developed clinical symptoms in late adulthood or after brief exposure to haloperidol therapy. Mutations in Park2 gene account for 38% of the families with recessive parkinsonism in Spain. We found 2 cases of simple heterozygous Park2 mutation carriers that developed clinical symptoms, either in late adulthood or after brief exposure to parkinsonizing agents. Thus, hereditary Parkinson disease has more variable clinical phenotype and molecular defects than previously thought since heterozygous mutations could be a risk factor for parkinsonism.
    JAMA Neurology 07/2002; 59(6):966-70. · 7.58 Impact Factor
  • European Neurology 02/2002; 48(4):232-4. · 1.50 Impact Factor