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Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p

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Families with autosomal dominant frontotemporal dementia and amyotrophic lateral sclerosis (FTD/ALS) have previously been linked to a locus on chromosome 9p21. We describe the clinical phenotype and pathology of a large family with autosomal dominant FTD/ALS with nine affected members originating from Gwent in South Wales, UK. We also further refine the locus on chromosome 9p21 using a haplotype sharing approach and assess heterogeneity in 9p21 linked families. Within this family, affected individuals present with either FTD or ALS or both diseases simultaneously. In addition there was marked phenotypic variation including ataxia, Parkinsonism, psychosis and visuo-spatial cognitive deficits. The pathological features of the three cases described were consistent with type 2 FTD pathology, as previously reported in similar families. However, we also report distinctive cerebellar and glial pathology and a significant proportion of TDP-43 negative inclusions. No mutations in known genes for FTD or ALS were found. We identified a large 4.8-megabase haplotype on chromosome 9p21, which was shared by all affected family members. This haplotype overlaps and limits the previously reported FTD/ALS linkage region on chromosome 9p21. Sequencing of this region did not identify any evidence of a pathogenic exonic mutation. This suggests that the pathogenic change affects non-coding DNA and that the disease is caused by variation in gene or protein expression.

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  1. Ratnavalli E, Brayne C, Dawson K, Hodges JR (2002) The prevalence of frontotemporal dementia. Neurology 58(11):1615–1621

    PubMed  CAS  Google Scholar 

  2. Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM, Schulz PE (2005) Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology 65(4):586–590. doi:10.1212/01.wnl.0000172911.39167.b6

    Article  PubMed  CAS  Google Scholar 

  3. Rippon GA, Scarmeas N, Gordon PH, Murphy PL, Albert SM, Mitsumoto H, Marder K, Rowland LP, Stern Y (2006) An observational study of cognitive impairment in amyotrophic lateral sclerosis. Arch Neurol 63(3):345–352. doi:10.1001/archneur.63.3.345

    Article  PubMed  Google Scholar 

  4. Lomen-Hoerth C, Anderson T, Miller B (2002) The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 59(7):1077–1079

    PubMed  Google Scholar 

  5. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314(5796):130–133. doi:10.1126/science.1134108

    Article  PubMed  CAS  Google Scholar 

  6. Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, White CL 3rd, Schneider JA, Grinberg LT, Halliday G, Duyckaerts C, Lowe JS, Holm IE, Tolnay M, Okamoto K, Yokoo H, Murayama S, Woulfe J, Munoz DG, Dickson DW, Ince PG, Trojanowski JQ, Mann DM (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the consortium for frontotemporal lobar degeneration. Acta Neuropathol 114(1):5–22. doi:10.1007/s00401-007-0237-2

    Article  PubMed  Google Scholar 

  7. Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ, Foong C, White CL 3rd, Schneider JA, Kretzschmar HA, Carter D, Taylor-Reinwald L, Paulsmeyer K, Strider J, Gitcho M, Goate AM, Morris JC, Mishra M, Kwong LK, Stieber A, Xu Y, Forman MS, Trojanowski JQ, Lee VM, Mackenzie IR (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171(1):227–240

    Article  PubMed  CAS  Google Scholar 

  8. Polvikoski TM, Murray A, Harper PS, Neal JW (2003) Familial motor neurone disease with dementia: phenotypic variation and cerebellar pathology. J Neurol Neurosurg Psychiatry 74(11):1516–1520

    Article  PubMed  CAS  Google Scholar 

  9. Namimatsu S, Ghazizadeh M, Sugisaki Y (2005) Reversing the effects of formalin fixation with citraconic anhydride and heat: a universal antigen retrieval method. J Histochem Cytochem 53(1):3–11. doi:10.1369/jhc.4C6466.2005

    Article  PubMed  CAS  Google Scholar 

  10. Momeni P, Schymick J, Jain S, Cookson MR, Cairns NJ, Greggio E, Greenway MJ, Berger S, Pickering-Brown S, Chio A, Fung HC, Holtzman DM, Huey ED, Wassermann EM, Adamson J, Hutton ML, Rogaeva E, St George-Hyslop P, Rothstein JD, Hardiman O, Grafman J, Singleton A, Hardy J, Traynor BJ (2006) Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD. BMC Neurol 6:44. doi:10.1186/1471-2377-6-44

    Article  PubMed  Google Scholar 

  11. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575. doi:10.1086/519795

    Article  PubMed  CAS  Google Scholar 

  12. Le Ber I, Camuzat A, Berger E, Hannequin D, Laquerriere A, Golfier V, Seilhean D, Viennet G, Couratier P, Verpillat P, Heath S, Camu W, Martinaud O, Lacomblez L, Vercelletto M, Salachas F, Sellal F, Didic M, Thomas-Anterion C, Puel M, Michel BF, Besse C, Duyckaerts C, Meininger V, Campion D, Dubois B, Brice A (2009) Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease. Neurology 72(19):1669–1676. doi:10.1212/WNL.0b013e3181a55f1c

    Article  PubMed  CAS  Google Scholar 

  13. Luty AA, Kwok JB, Thompson EM, Blumbergs P, Brooks WS, Loy CT, Dobson-Stone C, Panegyres PK, Hecker J, Nicholson GA, Halliday GM, Schofield PR (2008) Pedigree with frontotemporal lobar degeneration—motor neuron disease and tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9. BMC Neurol 8:32. doi:10.1186/1471-2377-8-32

    Article  PubMed  Google Scholar 

  14. Boxer AL, Mackenzie IR, Boeve BF, Baker M, Seeley WW, Crook R, Feldman H, Hsiung GY, Rutherford N, Laluz V, Whitwell J, Foti D, McDade E, Molano J, Karydas A, Wojtas A, Goldman J, Mirsky J, Sengdy P, Dearmond S, Miller BL, Rademakers R (2010) Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J Neurol Neurosurg Psychiatry. doi:10.1136/jnnp.2009.204081

  15. Gijselinck I, Engelborghs S, Maes G, Cuijt I, Peeters K, Mattheijssens M, Joris G, Cras P, Martin JJ, De Deyn PP, Kumar-Singh S, Van Broeckhoven C, Cruts M (2010) Identification of 2 loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol 67(5):606–616. doi:10.1001/archneurol.2010.82

    Article  PubMed  Google Scholar 

  16. Morita M, Al-Chalabi A, Andersen PM, Hosler B, Sapp P, Englund E, Mitchell JE, Habgood JJ, de Belleroche J, Xi J, Jongjaroenprasert W, Horvitz HR, Gunnarsson LG, Brown RH Jr (2006) A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66(6):839–844. doi:10.1212/01.wnl.0000200048.53766.b4

    Article  PubMed  CAS  Google Scholar 

  17. Valdmanis PN, Dupre N, Bouchard JP, Camu W, Salachas F, Meininger V, Strong M, Rouleau GA (2007) Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p. Arch Neurol 64(2):240–245. doi:10.1001/archneur.64.2.240

    Article  PubMed  Google Scholar 

  18. Vance C, Al-Chalabi A, Ruddy D, Smith BN, Hu X, Sreedharan J, Siddique T, Schelhaas HJ, Kusters B, Troost D, Baas F, de Jong V, Shaw CE (2006) Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2–21.3. Brain 129(4):868–876. doi:10.1093/brain/awl030

    Article  PubMed  Google Scholar 

  19. Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SF, Hakonarson H, Bucan M (2007) PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res 17(11):1665–1674. doi:10.1101/gr.6861907

    Article  PubMed  CAS  Google Scholar 

  20. Boxer RS, Kleppinger A, Brindisi J, Feinn R, Burleson JA, Kenny AM (2010) Effects of dehydroepiandrosterone (DHEA) on cardiovascular risk factors in older women with frailty characteristics. Age Ageing 39(4):451–458. doi:10.1093/ageing/afq043

    Article  PubMed  CAS  Google Scholar 

  21. Seelaar H, Schelhaas HJ, Azmani A, Kusters B, Rosso S, Majoor-Krakauer D, de Rijik MC, Rizzu P, ten Brummelhuis M, van Doorn PA, Kamphorst W, Willemsen R, van Swieten JC (2007) TDP-43 pathology in familial frontotemporal dementia and motor neuron disease without progranulin mutations. Brain 130(Pt 5):1375–1385. doi:10.1093/brain/awm024

    Article  PubMed  Google Scholar 

  22. Rosen DR (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 364(6435):362. doi:10.1038/364362c0

    PubMed  CAS  Google Scholar 

  23. Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323(5918):1208–1211. doi:10.1126/science.1165942

    Article  PubMed  CAS  Google Scholar 

  24. Lagier-Tourenne C, Cleveland DW (2009) Rethinking ALS: the FUS about TDP-43. Cell 136(6):1001–1004. doi:10.1016/j.cell.2009.03.006

    Article  PubMed  CAS  Google Scholar 

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We are grateful to members of this family for participating in this research. We are grateful for the opportunity to review clinical notes made by Prof. P. Harper, Prof. A. Compston and Dr. T. Pickersgill and to Dr A. Liu (Consultant Neuroradiologist, University Hospital of Wales) for reviewing the radiology. This work was supported by the Motor Neuron Disease Assocaition (UK), the Medical Research Council (UK) Grant G0700943 and the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project Z01 AG000951-06.

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Correspondence to Huw R. Morris.

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Online Resource 1: Radiological features, coronal and axial T2 MRI showing parieto-occipital atrophy in case 6 (A–D), frontotemporal atrophy in case 8 (E–H) and normal imaging in case 9 (I–L). (PDF 148 kb)

Online Resource 2: Case histories (PDF 50 kb)

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Pearson, J.P., Williams, N.M., Majounie, E. et al. Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p. J Neurol 258, 647–655 (2011).

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