Journal
NEUROLOGY
Volume 73, Issue 18, Pages 1451-1456Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0b013e3181bf997a
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Funding
- Department of Health's NIHR Biomedical Research Centres
- Wellcome Trust
- Medical Research Council Prion Unit
- Alzheimer's Research Trust
- UCL Hospitals Clinical Research and Development Committee
- Elan Corporation
- Wyeth
- Lundbeck Inc.
- Sanofi-Aventis
- IXICO Ltd.
- Pfizer Inc.
- Neurochem Inc.
- MRC [G0801306, G0601846]
- NIH [U01 AG024904 (Co-I)]
- Alzheimer Research Trust [ART/RF/2007/1]
- Canadian Institutes of Health Research
- Pacific Alzheimer Research Foundation
- Michael Smith Foundation for Health Research
- The Sarah Matheson Trust
- Action Medical Research
- BrainNet Europe
- Myositis Support Group
- Orion Pharma
- European Commission
- BrainNet Europe II
- Network of Excellence
- Sarah Matheson Trust
- Parkinson's Disease Society, UK
- Department of Health
- MRC [G0501560, G0601846, G0401247, G0701075, G0801306, MC_U123160651, MC_U123182015] Funding Source: UKRI
- Alzheimers Research UK [ART-PhD2007-2] Funding Source: researchfish
- Medical Research Council [G0701075, G0601846, MC_U123160651, G0501560, G0401247, G0801306, MC_U123182015] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10123] Funding Source: researchfish
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Background: Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder. Methods: We collected blood samples from a cohort of 225 patients with a diagnosis within the FTLD spectrum and examined the heritability of FTLD by giving each patient a family history score, from 1 (a clear autosomal dominant history of FTLD) through to 4 (no family history of dementia). We also looked for mutations in each of the 5 disease-causing genes (MAPT, GRN, VCP, CHMP2B, and TARDP) and the FUS gene, known to cause motor neuron disease. Results: A total of 41.8% of patients had some family history (score of 1, 2, 3, or 3.5), although only 10.2% had a clear autosomal dominant history (score of 1). Heritability varied across the different clinical subtypes of FTLD with the behavioral variant being the most heritable and frontotemporal dementia-motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable. Mutations were found in MAPT (8.9% of the cohort) and GRN (8.4%) but not in any of the other genes. Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without GRN mutations (6) and FTLD-UPS (1). Conclusion: These findings show that frontotemporal lobar degeneration (FTLD) is a highly heritable disorder but heritability varies between the different syndromes. Furthermore, while MAPT and GRN mutations account for a substantial proportion of familial cases, there are other genes yet to be discovered, particularly in patients with type 3 FTLD-TDP without a GRN mutation. Neurology (R) 2009; 73:1451-1456
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