BACKGROUND: Frontotemporal dementia associated with motor neuron disease (FTD-MND) is a rare neurodegenerative disorder that may be inherited by autosomal dominant trait. No major gene has been identified but a locus was mapped on chromosome 9 (9p21.3-p13.3). METHODS: Ten French families with FTD-MND were tested for linkage to the 9p21.3-p13.3 region. We report extensive mutation screening in 9p-linked families and their clinical characteristics. RESULTS: We identified six new families with evidence for linkage to the chromosome 9p. Cumulative multipoint LOD score values were positive between markers D9S1121 and D9S301, reaching a peak of 8.0 at marker D9S248. Haplotype reconstruction defined the telomeric boundary at marker AFM218xg11, slightly narrowing the candidate interval. We found no disease-causing mutations by sequencing 29 candidate genes including IFT74 and no copy number variations in the 9p region. The mean age at onset was 57.9 +/- 10.3 years (range, 41-84), with wide heterogeneity within and among families suggesting age-dependant penetrance. The patients presented isolated FTD (32%), isolated MND (29%), or both disorders (39%). The general characteristics of the disease did not differ, except for an older age at onset and shorter disease duration in the 9p-linked compared to nonlinked families. TDP-43-positive neuronal cytoplasmic inclusions were found in cortex and spinal cord in 3 patients. CONCLUSIONS: This study increases the number of 9p-linked families now reported and shows that this locus may have a major effect on frontotemporal dementia (FTD) and motor neuron disease (MND). Considering our results, the causative gene might be implicated in at least 60% of the families with FTD-MND disorder.
BACKGROUND: Frontotemporal dementia associated with motor neuron disease (FTD-MND) is a rare neurodegenerative disorder that may be inherited by autosomal dominant trait. No major gene has been identified but a locus was mapped on chromosome 9 (9p21.3-p13.3). METHODS: Ten French families with FTD-MND were tested for linkage to the 9p21.3-p13.3 region. We report extensive mutation screening in 9p-linked families and their clinical characteristics. RESULTS: We identified six new families with evidence for linkage to the chromosome 9p. Cumulative multipoint LOD score values were positive between markers D9S1121 and D9S301, reaching a peak of 8.0 at marker D9S248. Haplotype reconstruction defined the telomeric boundary at marker AFM218xg11, slightly narrowing the candidate interval. We found no disease-causing mutations by sequencing 29 candidate genes including IFT74 and no copy number variations in the 9p region. The mean age at onset was 57.9 +/- 10.3 years (range, 41-84), with wide heterogeneity within and among families suggesting age-dependant penetrance. The patients presented isolated FTD (32%), isolated MND (29%), or both disorders (39%). The general characteristics of the disease did not differ, except for an older age at onset and shorter disease duration in the 9p-linked compared to nonlinked families. TDP-43-positive neuronal cytoplasmic inclusions were found in cortex and spinal cord in 3 patients. CONCLUSIONS: This study increases the number of 9p-linked families now reported and shows that this locus may have a major effect on frontotemporal dementia (FTD) and motor neuron disease (MND). Considering our results, the causative gene might be implicated in at least 60% of the families with FTD-MND disorder.
Authors: Mariely DeJesus-Hernandez; Ian R Mackenzie; Bradley F Boeve; Adam L Boxer; Matt Baker; Nicola J Rutherford; Alexandra M Nicholson; NiCole A Finch; Heather Flynn; Jennifer Adamson; Naomi Kouri; Aleksandra Wojtas; Pheth Sengdy; Ging-Yuek R Hsiung; Anna Karydas; William W Seeley; Keith A Josephs; Giovanni Coppola; Daniel H Geschwind; Zbigniew K Wszolek; Howard Feldman; David S Knopman; Ronald C Petersen; Bruce L Miller; Dennis W Dickson; Kevin B Boylan; Neill R Graff-Radford; Rosa Rademakers Journal: Neuron Date: 2011-09-21 Impact factor: 17.173
Authors: Mariely DeJesus-Hernandez; Jannet Kocerha; NiCole Finch; Richard Crook; Matt Baker; Pamela Desaro; Amelia Johnston; Nicola Rutherford; Aleksandra Wojtas; Kathleen Kennelly; Zbigniew K Wszolek; Neill Graff-Radford; Kevin Boylan; Rosa Rademakers Journal: Hum Mutat Date: 2010-05 Impact factor: 4.878
Authors: Justin P Pearson; Nigel M Williams; Elisa Majounie; Adrian Waite; Jennifer Stott; Victoria Newsway; Alex Murray; Dena Hernandez; Rita Guerreiro; Andrew B Singleton; James Neal; Huw R Morris Journal: J Neurol Date: 2010-11-12 Impact factor: 4.849
Authors: Nicola J Rutherford; Michael G Heckman; Mariely Dejesus-Hernandez; Matt C Baker; Alexandra I Soto-Ortolaza; Sruti Rayaprolu; Heather Stewart; Elizabeth Finger; Kathryn Volkening; William W Seeley; Kimmo J Hatanpaa; Catherine Lomen-Hoerth; Andrew Kertesz; Eileen H Bigio; Carol Lippa; David S Knopman; Hans A Kretzschmar; Manuela Neumann; Richard J Caselli; Charles L White; Ian R Mackenzie; Ronald C Petersen; Michael J Strong; Bruce L Miller; Bradley F Boeve; Ryan J Uitti; Kevin B Boylan; Zbigniew K Wszolek; Neill R Graff-Radford; Dennis W Dickson; Owen A Ross; Rosa Rademakers Journal: Neurobiol Aging Date: 2012-07-26 Impact factor: 4.673
Authors: Vivianna M Van Deerlin; Patrick M A Sleiman; Maria Martinez-Lage; Alice Chen-Plotkin; Li-San Wang; Neill R Graff-Radford; Dennis W Dickson; Rosa Rademakers; Bradley F Boeve; Murray Grossman; Steven E Arnold; David M A Mann; Stuart M Pickering-Brown; Harro Seelaar; Peter Heutink; John C van Swieten; Jill R Murrell; Bernardino Ghetti; Salvatore Spina; Jordan Grafman; John Hodges; Maria Grazia Spillantini; Sid Gilman; Andrew P Lieberman; Jeffrey A Kaye; Randall L Woltjer; Eileen H Bigio; Marsel Mesulam; Safa Al-Sarraj; Claire Troakes; Roger N Rosenberg; Charles L White; Isidro Ferrer; Albert Lladó; Manuela Neumann; Hans A Kretzschmar; Christine Marie Hulette; Kathleen A Welsh-Bohmer; Bruce L Miller; Ainhoa Alzualde; Adolfo Lopez de Munain; Ann C McKee; Marla Gearing; Allan I Levey; James J Lah; John Hardy; Jonathan D Rohrer; Tammaryn Lashley; Ian R A Mackenzie; Howard H Feldman; Ronald L Hamilton; Steven T Dekosky; Julie van der Zee; Samir Kumar-Singh; Christine Van Broeckhoven; Richard Mayeux; Jean Paul G Vonsattel; Juan C Troncoso; Jillian J Kril; John B J Kwok; Glenda M Halliday; Thomas D Bird; Paul G Ince; Pamela J Shaw; Nigel J Cairns; John C Morris; Catriona Ann McLean; Charles DeCarli; William G Ellis; Stefanie H Freeman; Matthew P Frosch; John H Growdon; Daniel P Perl; Mary Sano; David A Bennett; Julie A Schneider; Thomas G Beach; Eric M Reiman; Bryan K Woodruff; Jeffrey Cummings; Harry V Vinters; Carol A Miller; Helena C Chui; Irina Alafuzoff; Päivi Hartikainen; Danielle Seilhean; Douglas Galasko; Eliezer Masliah; Carl W Cotman; M Teresa Tuñón; M Cristina Caballero Martínez; David G Munoz; Steven L Carroll; Daniel Marson; Peter F Riederer; Nenad Bogdanovic; Gerard D Schellenberg; Hakon Hakonarson; John Q Trojanowski; Virginia M-Y Lee Journal: Nat Genet Date: 2010-02-14 Impact factor: 38.330
Authors: J D Rohrer; R Guerreiro; J Vandrovcova; J Uphill; D Reiman; J Beck; A M Isaacs; A Authier; R Ferrari; N C Fox; I R A Mackenzie; J D Warren; R de Silva; J Holton; T Revesz; J Hardy; S Mead; M N Rossor Journal: Neurology Date: 2009-11-03 Impact factor: 9.910