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Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family

BackgroundFrontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) is a heritable form of FTD, but the gene(s) responsible for the majority of autosomal dominant FTD-ALS cases have yet to be found. Previous studies have identified a region on chromosome 9p that is associated with FTD and ALS.... Full description

Journal Title: Journal of neurology neurosurgery and psychiatry, 2011-02, Vol.82 (2), p.196-203
Main Author: Boxer, Adam L
Other Authors: Mackenzie, Ian R , Boeve, Bradley F , Baker, Matthew , Seeley, William W , Crook, Richard , Feldman, Howard , Hsiung, Ging-Yuek R , Rutherford, Nicola , Laluz, Victor , Whitwell, Jennifer , Foti, Dean , McDade, Eric , Molano, Jennifer , Karydas, Anna , Wojtas, Aleksandra , Goldman, Jill , Mirsky, Jacob , Sengdy, Pheth , DeArmond, Stephen , Miller, Bruce L , Rademakers, Rosa
Format: Electronic Article Electronic Article
Language: English
Subjects:
ALS
Publisher: London: BMJ Publishing Group Ltd
ID: ISSN: 0022-3050
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title: Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family
format: Article
creator:
  • Boxer, Adam L
  • Mackenzie, Ian R
  • Boeve, Bradley F
  • Baker, Matthew
  • Seeley, William W
  • Crook, Richard
  • Feldman, Howard
  • Hsiung, Ging-Yuek R
  • Rutherford, Nicola
  • Laluz, Victor
  • Whitwell, Jennifer
  • Foti, Dean
  • McDade, Eric
  • Molano, Jennifer
  • Karydas, Anna
  • Wojtas, Aleksandra
  • Goldman, Jill
  • Mirsky, Jacob
  • Sengdy, Pheth
  • DeArmond, Stephen
  • Miller, Bruce L
  • Rademakers, Rosa
subjects:
  • Adult
  • ALS
  • Amyotrophic lateral sclerosis
  • Amyotrophic Lateral Sclerosis - complications
  • Amyotrophic Lateral Sclerosis - genetics
  • Amyotrophic Lateral Sclerosis - pathology
  • Analysis
  • Article
  • Autopsy
  • Biological and medical sciences
  • Brain - pathology
  • chromosome 9p
  • Chromosomes, Human, Pair 9 - genetics
  • clinical neurology
  • Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
  • dementia
  • DNA Mutational Analysis
  • Family
  • Female
  • Frontotemporal dementia
  • Frontotemporal Dementia - complications
  • Frontotemporal Dementia - genetics
  • Frontotemporal Dementia - pathology
  • Genetic aspects
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • genetics
  • Genome-Wide Association Study
  • Haplotypes
  • Humans
  • Immunohistochemistry
  • Lod Score
  • Magnetic Resonance Imaging
  • Male
  • Medical sciences
  • Middle Aged
  • Neurology
  • Parkinson Disease - genetics
  • pathology
  • Pedigree
  • Risk factors
  • TAR-DNA binding protein 43
ispartof: Journal of neurology, neurosurgery and psychiatry, 2011-02, Vol.82 (2), p.196-203
description: BackgroundFrontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) is a heritable form of FTD, but the gene(s) responsible for the majority of autosomal dominant FTD-ALS cases have yet to be found. Previous studies have identified a region on chromosome 9p that is associated with FTD and ALS.MethodsThe authors report the clinical, volumetric MRI, neuropathological and genetic features of a new chromosome 9p-linked FTD-ALS family, VSM-20.ResultsTen members of family VSM-20 displayed heterogeneous clinical phenotypes of isolated behavioural-variant FTD (bvFTD), ALS or a combination of the two. Parkinsonism was common, with one individual presenting with a corticobasal syndrome. Analysis of structural MRI scans from five affected family members revealed grey- and white-matter loss that was most prominent in the frontal lobes, with mild parietal and occipital lobe atrophy, but less temporal lobe atrophy than in 10 severity-matched sporadic bvFTD cases. Autopsy in three family members showed a consistent and unique subtype of FTLD-TDP pathology. Genome-wide linkage analysis conclusively linked family VSM-20 to a 28.3 cM region between D9S1808 and D9S251 on chromosome 9p, reducing the published minimal linked region to a 3.7 Mb interval. Genomic sequencing and expression analysis failed to identify mutations in the 10 known and predicted genes within this candidate region, suggesting that next-generation sequencing may be needed to determine the mutational mechanism associated with chromosome 9p-linked FTD-ALS.ConclusionsFamily VSM-20 significantly reduces the region linked to FTD-ALS on chromosome 9p. A distinct pattern of brain atrophy and neuropathological findings may help to identify other families with FTD-ALS caused by this genetic abnormality.
language: eng
source:
identifier: ISSN: 0022-3050
fulltext: no_fulltext
issn:
  • 0022-3050
  • 1468-330X
url: Link


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titleClinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family
creatorBoxer, Adam L ; Mackenzie, Ian R ; Boeve, Bradley F ; Baker, Matthew ; Seeley, William W ; Crook, Richard ; Feldman, Howard ; Hsiung, Ging-Yuek R ; Rutherford, Nicola ; Laluz, Victor ; Whitwell, Jennifer ; Foti, Dean ; McDade, Eric ; Molano, Jennifer ; Karydas, Anna ; Wojtas, Aleksandra ; Goldman, Jill ; Mirsky, Jacob ; Sengdy, Pheth ; DeArmond, Stephen ; Miller, Bruce L ; Rademakers, Rosa
creatorcontribBoxer, Adam L ; Mackenzie, Ian R ; Boeve, Bradley F ; Baker, Matthew ; Seeley, William W ; Crook, Richard ; Feldman, Howard ; Hsiung, Ging-Yuek R ; Rutherford, Nicola ; Laluz, Victor ; Whitwell, Jennifer ; Foti, Dean ; McDade, Eric ; Molano, Jennifer ; Karydas, Anna ; Wojtas, Aleksandra ; Goldman, Jill ; Mirsky, Jacob ; Sengdy, Pheth ; DeArmond, Stephen ; Miller, Bruce L ; Rademakers, Rosa
descriptionBackgroundFrontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) is a heritable form of FTD, but the gene(s) responsible for the majority of autosomal dominant FTD-ALS cases have yet to be found. Previous studies have identified a region on chromosome 9p that is associated with FTD and ALS.MethodsThe authors report the clinical, volumetric MRI, neuropathological and genetic features of a new chromosome 9p-linked FTD-ALS family, VSM-20.ResultsTen members of family VSM-20 displayed heterogeneous clinical phenotypes of isolated behavioural-variant FTD (bvFTD), ALS or a combination of the two. Parkinsonism was common, with one individual presenting with a corticobasal syndrome. Analysis of structural MRI scans from five affected family members revealed grey- and white-matter loss that was most prominent in the frontal lobes, with mild parietal and occipital lobe atrophy, but less temporal lobe atrophy than in 10 severity-matched sporadic bvFTD cases. Autopsy in three family members showed a consistent and unique subtype of FTLD-TDP pathology. Genome-wide linkage analysis conclusively linked family VSM-20 to a 28.3 cM region between D9S1808 and D9S251 on chromosome 9p, reducing the published minimal linked region to a 3.7 Mb interval. Genomic sequencing and expression analysis failed to identify mutations in the 10 known and predicted genes within this candidate region, suggesting that next-generation sequencing may be needed to determine the mutational mechanism associated with chromosome 9p-linked FTD-ALS.ConclusionsFamily VSM-20 significantly reduces the region linked to FTD-ALS on chromosome 9p. A distinct pattern of brain atrophy and neuropathological findings may help to identify other families with FTD-ALS caused by this genetic abnormality.
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languageeng
publisherLondon: BMJ Publishing Group Ltd
subjectAdult ; ALS ; Amyotrophic lateral sclerosis ; Amyotrophic Lateral Sclerosis - complications ; Amyotrophic Lateral Sclerosis - genetics ; Amyotrophic Lateral Sclerosis - pathology ; Analysis ; Article ; Autopsy ; Biological and medical sciences ; Brain - pathology ; chromosome 9p ; Chromosomes, Human, Pair 9 - genetics ; clinical neurology ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; dementia ; DNA Mutational Analysis ; Family ; Female ; Frontotemporal dementia ; Frontotemporal Dementia - complications ; Frontotemporal Dementia - genetics ; Frontotemporal Dementia - pathology ; Genetic aspects ; Genetic Linkage ; Genetic Predisposition to Disease ; genetics ; Genome-Wide Association Study ; Haplotypes ; Humans ; Immunohistochemistry ; Lod Score ; Magnetic Resonance Imaging ; Male ; Medical sciences ; Middle Aged ; Neurology ; Parkinson Disease - genetics ; pathology ; Pedigree ; Risk factors ; TAR-DNA binding protein 43
ispartofJournal of neurology, neurosurgery and psychiatry, 2011-02, Vol.82 (2), p.196-203
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2Boeve, Bradley F
3Baker, Matthew
4Seeley, William W
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6Feldman, Howard
7Hsiung, Ging-Yuek R
8Rutherford, Nicola
9Laluz, Victor
10Whitwell, Jennifer
11Foti, Dean
12McDade, Eric
13Molano, Jennifer
14Karydas, Anna
15Wojtas, Aleksandra
16Goldman, Jill
17Mirsky, Jacob
18Sengdy, Pheth
19DeArmond, Stephen
20Miller, Bruce L
21Rademakers, Rosa
title
0Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family
1Journal of neurology, neurosurgery and psychiatry
addtitleJ Neurol Neurosurg Psychiatry
descriptionBackgroundFrontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) is a heritable form of FTD, but the gene(s) responsible for the majority of autosomal dominant FTD-ALS cases have yet to be found. Previous studies have identified a region on chromosome 9p that is associated with FTD and ALS.MethodsThe authors report the clinical, volumetric MRI, neuropathological and genetic features of a new chromosome 9p-linked FTD-ALS family, VSM-20.ResultsTen members of family VSM-20 displayed heterogeneous clinical phenotypes of isolated behavioural-variant FTD (bvFTD), ALS or a combination of the two. Parkinsonism was common, with one individual presenting with a corticobasal syndrome. Analysis of structural MRI scans from five affected family members revealed grey- and white-matter loss that was most prominent in the frontal lobes, with mild parietal and occipital lobe atrophy, but less temporal lobe atrophy than in 10 severity-matched sporadic bvFTD cases. Autopsy in three family members showed a consistent and unique subtype of FTLD-TDP pathology. Genome-wide linkage analysis conclusively linked family VSM-20 to a 28.3 cM region between D9S1808 and D9S251 on chromosome 9p, reducing the published minimal linked region to a 3.7 Mb interval. Genomic sequencing and expression analysis failed to identify mutations in the 10 known and predicted genes within this candidate region, suggesting that next-generation sequencing may be needed to determine the mutational mechanism associated with chromosome 9p-linked FTD-ALS.ConclusionsFamily VSM-20 significantly reduces the region linked to FTD-ALS on chromosome 9p. A distinct pattern of brain atrophy and neuropathological findings may help to identify other families with FTD-ALS caused by this genetic abnormality.
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16DNA Mutational Analysis
17Family
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20Frontotemporal Dementia - complications
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25Genetic Predisposition to Disease
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27Genome-Wide Association Study
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31Lod Score
32Magnetic Resonance Imaging
33Male
34Medical sciences
35Middle Aged
36Neurology
37Parkinson Disease - genetics
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39Pedigree
40Risk factors
41TAR-DNA binding protein 43
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10Whitwell, Jennifer
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12McDade, Eric
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titleClinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family
authorBoxer, Adam L ; Mackenzie, Ian R ; Boeve, Bradley F ; Baker, Matthew ; Seeley, William W ; Crook, Richard ; Feldman, Howard ; Hsiung, Ging-Yuek R ; Rutherford, Nicola ; Laluz, Victor ; Whitwell, Jennifer ; Foti, Dean ; McDade, Eric ; Molano, Jennifer ; Karydas, Anna ; Wojtas, Aleksandra ; Goldman, Jill ; Mirsky, Jacob ; Sengdy, Pheth ; DeArmond, Stephen ; Miller, Bruce L ; Rademakers, Rosa
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2Amyotrophic lateral sclerosis
3Amyotrophic Lateral Sclerosis - complications
4Amyotrophic Lateral Sclerosis - genetics
5Amyotrophic Lateral Sclerosis - pathology
6Analysis
7Article
8Autopsy
9Biological and medical sciences
10Brain - pathology
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12Chromosomes, Human, Pair 9 - genetics
13clinical neurology
14Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
15dementia
16DNA Mutational Analysis
17Family
18Female
19Frontotemporal dementia
20Frontotemporal Dementia - complications
21Frontotemporal Dementia - genetics
22Frontotemporal Dementia - pathology
23Genetic aspects
24Genetic Linkage
25Genetic Predisposition to Disease
26genetics
27Genome-Wide Association Study
28Haplotypes
29Humans
30Immunohistochemistry
31Lod Score
32Magnetic Resonance Imaging
33Male
34Medical sciences
35Middle Aged
36Neurology
37Parkinson Disease - genetics
38pathology
39Pedigree
40Risk factors
41TAR-DNA binding protein 43
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8Rutherford, Nicola
9Laluz, Victor
10Whitwell, Jennifer
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12McDade, Eric
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14Karydas, Anna
15Wojtas, Aleksandra
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abstractBackgroundFrontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) is a heritable form of FTD, but the gene(s) responsible for the majority of autosomal dominant FTD-ALS cases have yet to be found. Previous studies have identified a region on chromosome 9p that is associated with FTD and ALS.MethodsThe authors report the clinical, volumetric MRI, neuropathological and genetic features of a new chromosome 9p-linked FTD-ALS family, VSM-20.ResultsTen members of family VSM-20 displayed heterogeneous clinical phenotypes of isolated behavioural-variant FTD (bvFTD), ALS or a combination of the two. Parkinsonism was common, with one individual presenting with a corticobasal syndrome. Analysis of structural MRI scans from five affected family members revealed grey- and white-matter loss that was most prominent in the frontal lobes, with mild parietal and occipital lobe atrophy, but less temporal lobe atrophy than in 10 severity-matched sporadic bvFTD cases. Autopsy in three family members showed a consistent and unique subtype of FTLD-TDP pathology. Genome-wide linkage analysis conclusively linked family VSM-20 to a 28.3 cM region between D9S1808 and D9S251 on chromosome 9p, reducing the published minimal linked region to a 3.7 Mb interval. Genomic sequencing and expression analysis failed to identify mutations in the 10 known and predicted genes within this candidate region, suggesting that next-generation sequencing may be needed to determine the mutational mechanism associated with chromosome 9p-linked FTD-ALS.ConclusionsFamily VSM-20 significantly reduces the region linked to FTD-ALS on chromosome 9p. A distinct pattern of brain atrophy and neuropathological findings may help to identify other families with FTD-ALS caused by this genetic abnormality.
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