Publications (4)50.16 Total impact
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Article: Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration.
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ABSTRACT: To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD). A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)-positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN- FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLD-TDP cases and all of the GRN- FTLD-TDP cases. Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN- FTLD-TDP (median, 58.0 vs 61.0 years; P < .001), as was age at death (median, 65.5 vs 69.0 years; P < .001). Concomitant motor neuron disease was much less common in GRN+ FTLD-TDP vs GRN- FTLD-TDP (5.4% vs 26.3%; P < .001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations. GRN+ FTLD-TDP differs in key features from GRN- FTLD-TDP.Archives of neurology 04/2011; 68(4):488-97. · 6.31 Impact Factor -
Article: Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions.
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ABSTRACT: Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.Nature Genetics 02/2010; 42(3):234-9. · 35.53 Impact Factor -
Article: Monoamine oxidase A and B inhibitors in Parkinson's disease.
Handbook of Clinical Neurology 02/2007; 84:93-120. -
Article: A review of the mechanisms and role of monoamine oxidase inhibitors in Parkinson's disease.
Neurology 11/2004; 63(7 Suppl 2):S32-5. · 8.31 Impact Factor
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- Handbook of Clinical Neurology (1)
- Neurology (1)
- Archives of neurology (1)
- Nature Genetics (1)
Institutions
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2004
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Technion - Israel Institute of Technology
- Department of Pharmacology
Haifa, Haifa District, Israel
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