TY - JOUR
T1 - Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p
AU - Hsiung, Ging Yuek R.
AU - Dejesus-Hernandez, Mariely
AU - Feldman, Howard H.
AU - Sengdy, Pheth
AU - Bouchard-Kerr, Phoenix
AU - Dwosh, Emily
AU - Butler, Rachel
AU - Leung, Bonnie
AU - Fok, Alice
AU - Rutherford, Nicola J.
AU - Baker, Matt
AU - Rademakers, Rosa
AU - Mackenzie, Ian R.A.
N1 - Funding Information:
Canadian Institutes of Health Research (operating grants no. 179009, no. 74580 to I.R.A.M. and H.H.F.); Pacific Alzheimer’s Research Foundation (centre grant C06-01 to I.R.A.M. and H.H.F.); ALS Association (to R.R.); National Institutes of Health (grants no. R01 NS065782, R01 AG026251 to R.R.) and Clinical Genetics Investigatorship award from the Canadian Institutes of Health Research (to G.-Y.R.H.).
PY - 2012/3
Y1 - 2012/3
N2 - Frontotemporal dementia and amyotrophic lateral sclerosis are closely related clinical syndromes with overlapping molecular pathogenesis. Several families have been reported with members affected by frontotemporal dementia, amyotrophic lateral sclerosis or both, which show genetic linkage to a region on chromosome 9p21. Recently, two studies identified the FTD/ALS gene defect on chromosome 9p as an expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). In the present study, we provide detailed analysis of the clinical features and neuropathology for 16 unrelated families with frontotemporal dementia caused by the C9ORF72 mutation. All had an autosomal dominant pattern of inheritance. Eight families had a combination of frontotemporal dementia and amyotrophic lateral sclerosis while the other eight had a pure frontotemporal dementia phenotype. Clinical information was available for 30 affected members of the 16 families. There was wide variation in age of onset (mean=54.3, range=34-74 years) and disease duration (mean=5.3, range=1-16 years). Early diagnoses included behavioural variant frontotemporal dementia (n=15), progressive non-fluent aphasia (n=5), amyotrophic lateral sclerosis (n=9) and progressive non-fluent aphasia-amyotrophic lateral sclerosis (n=1). Heterogeneity in clinical presentation was also common within families. However, there was a tendency for the phenotypes to converge with disease progression; seven subjects had final clinical diagnoses of both frontotemporal dementia and amyotrophic lateral sclerosis and all of those with an initial progressive non-fluent aphasia diagnosis subsequently developed significant behavioural abnormalities. Twenty-one affected family members came to autopsy and all were found to have transactive response DNA binding protein with Mr 43 kD (TDP-43) pathology in a wide neuroanatomical distribution. All had involvement of the extramotor neocortex and hippocampus (frontotemporal lobar degeneration-TDP) and all but one case (clinically pure frontotemporal dementia) had involvement of lower motor neurons, characteristic of amyotrophic lateral sclerosis. In addition, a consistent and relatively specific pathological finding was the presence of neuronal inclusions in the cerebellar cortex that were ubiquitin/p62-positive but TDP-43-negative. Our findings indicate that the C9ORF72 mutation is a major cause of familial frontotemporal dementia with TDP-43 pathology, that likely accounts for the majority of families with combined frontotemporal dementia/amyotrophic lateral sclerosis presentation, and further support the concept that frontotemporal dementia and amyotrophic lateral sclerosis represent a clinicopathological spectrum of disease with overlapping molecular pathogenesis.
AB - Frontotemporal dementia and amyotrophic lateral sclerosis are closely related clinical syndromes with overlapping molecular pathogenesis. Several families have been reported with members affected by frontotemporal dementia, amyotrophic lateral sclerosis or both, which show genetic linkage to a region on chromosome 9p21. Recently, two studies identified the FTD/ALS gene defect on chromosome 9p as an expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). In the present study, we provide detailed analysis of the clinical features and neuropathology for 16 unrelated families with frontotemporal dementia caused by the C9ORF72 mutation. All had an autosomal dominant pattern of inheritance. Eight families had a combination of frontotemporal dementia and amyotrophic lateral sclerosis while the other eight had a pure frontotemporal dementia phenotype. Clinical information was available for 30 affected members of the 16 families. There was wide variation in age of onset (mean=54.3, range=34-74 years) and disease duration (mean=5.3, range=1-16 years). Early diagnoses included behavioural variant frontotemporal dementia (n=15), progressive non-fluent aphasia (n=5), amyotrophic lateral sclerosis (n=9) and progressive non-fluent aphasia-amyotrophic lateral sclerosis (n=1). Heterogeneity in clinical presentation was also common within families. However, there was a tendency for the phenotypes to converge with disease progression; seven subjects had final clinical diagnoses of both frontotemporal dementia and amyotrophic lateral sclerosis and all of those with an initial progressive non-fluent aphasia diagnosis subsequently developed significant behavioural abnormalities. Twenty-one affected family members came to autopsy and all were found to have transactive response DNA binding protein with Mr 43 kD (TDP-43) pathology in a wide neuroanatomical distribution. All had involvement of the extramotor neocortex and hippocampus (frontotemporal lobar degeneration-TDP) and all but one case (clinically pure frontotemporal dementia) had involvement of lower motor neurons, characteristic of amyotrophic lateral sclerosis. In addition, a consistent and relatively specific pathological finding was the presence of neuronal inclusions in the cerebellar cortex that were ubiquitin/p62-positive but TDP-43-negative. Our findings indicate that the C9ORF72 mutation is a major cause of familial frontotemporal dementia with TDP-43 pathology, that likely accounts for the majority of families with combined frontotemporal dementia/amyotrophic lateral sclerosis presentation, and further support the concept that frontotemporal dementia and amyotrophic lateral sclerosis represent a clinicopathological spectrum of disease with overlapping molecular pathogenesis.
KW - C9ORF72, TDP-43
KW - amyotrophic lateral sclerosis
KW - frontotemporal dementia
KW - frontotemporal lobar degeneration
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U2 - 10.1093/brain/awr354
DO - 10.1093/brain/awr354
M3 - Article
C2 - 22344582
AN - SCOPUS:84857587514
SN - 0006-8950
VL - 135
SP - 709
EP - 722
JO - Brain
JF - Brain
IS - 3
ER -