Cargando…
Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72
Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism....
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286335/ https://www.ncbi.nlm.nih.gov/pubmed/22366793 http://dx.doi.org/10.1093/brain/aws004 |
_version_ | 1782224539889958912 |
---|---|
author | Boeve, Bradley F. Boylan, Kevin B. Graff-Radford, Neill R. DeJesus-Hernandez, Mariely Knopman, David S. Pedraza, Otto Vemuri, Prashanthi Jones, David Lowe, Val Murray, Melissa E. Dickson, Dennis W. Josephs, Keith A. Rush, Beth K. Machulda, Mary M. Fields, Julie A. Ferman, Tanis J. Baker, Matthew Rutherford, Nicola J. Adamson, Jennifer Wszolek, Zbigniew K. Adeli, Anahita Savica, Rodolfo Boot, Brendon Kuntz, Karen M. Gavrilova, Ralitza Reeves, Andrew Whitwell, Jennifer Kantarci, Kejal Jack, Clifford R. Parisi, Joseph E. Lucas, John A. Petersen, Ronald C. Rademakers, Rosa |
author_facet | Boeve, Bradley F. Boylan, Kevin B. Graff-Radford, Neill R. DeJesus-Hernandez, Mariely Knopman, David S. Pedraza, Otto Vemuri, Prashanthi Jones, David Lowe, Val Murray, Melissa E. Dickson, Dennis W. Josephs, Keith A. Rush, Beth K. Machulda, Mary M. Fields, Julie A. Ferman, Tanis J. Baker, Matthew Rutherford, Nicola J. Adamson, Jennifer Wszolek, Zbigniew K. Adeli, Anahita Savica, Rodolfo Boot, Brendon Kuntz, Karen M. Gavrilova, Ralitza Reeves, Andrew Whitwell, Jennifer Kantarci, Kejal Jack, Clifford R. Parisi, Joseph E. Lucas, John A. Petersen, Ronald C. Rademakers, Rosa |
author_sort | Boeve, Bradley F. |
collection | PubMed |
description | Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings. |
format | Online Article Text |
id | pubmed-3286335 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-32863352012-02-27 Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 Boeve, Bradley F. Boylan, Kevin B. Graff-Radford, Neill R. DeJesus-Hernandez, Mariely Knopman, David S. Pedraza, Otto Vemuri, Prashanthi Jones, David Lowe, Val Murray, Melissa E. Dickson, Dennis W. Josephs, Keith A. Rush, Beth K. Machulda, Mary M. Fields, Julie A. Ferman, Tanis J. Baker, Matthew Rutherford, Nicola J. Adamson, Jennifer Wszolek, Zbigniew K. Adeli, Anahita Savica, Rodolfo Boot, Brendon Kuntz, Karen M. Gavrilova, Ralitza Reeves, Andrew Whitwell, Jennifer Kantarci, Kejal Jack, Clifford R. Parisi, Joseph E. Lucas, John A. Petersen, Ronald C. Rademakers, Rosa Brain Original Articles Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings. Oxford University Press 2012-03 2012-02-24 /pmc/articles/PMC3286335/ /pubmed/22366793 http://dx.doi.org/10.1093/brain/aws004 Text en © The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Boeve, Bradley F. Boylan, Kevin B. Graff-Radford, Neill R. DeJesus-Hernandez, Mariely Knopman, David S. Pedraza, Otto Vemuri, Prashanthi Jones, David Lowe, Val Murray, Melissa E. Dickson, Dennis W. Josephs, Keith A. Rush, Beth K. Machulda, Mary M. Fields, Julie A. Ferman, Tanis J. Baker, Matthew Rutherford, Nicola J. Adamson, Jennifer Wszolek, Zbigniew K. Adeli, Anahita Savica, Rodolfo Boot, Brendon Kuntz, Karen M. Gavrilova, Ralitza Reeves, Andrew Whitwell, Jennifer Kantarci, Kejal Jack, Clifford R. Parisi, Joseph E. Lucas, John A. Petersen, Ronald C. Rademakers, Rosa Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 |
title | Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 |
title_full | Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 |
title_fullStr | Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 |
title_full_unstemmed | Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 |
title_short | Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 |
title_sort | characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the ggggcc repeat expansion in c9orf72 |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286335/ https://www.ncbi.nlm.nih.gov/pubmed/22366793 http://dx.doi.org/10.1093/brain/aws004 |
work_keys_str_mv | AT boevebradleyf characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT boylankevinb characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT graffradfordneillr characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT dejesushernandezmariely characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT knopmandavids characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT pedrazaotto characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT vemuriprashanthi characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT jonesdavid characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT loweval characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT murraymelissae characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT dicksondennisw characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT josephskeitha characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT rushbethk characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT machuldamarym characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT fieldsjuliea characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT fermantanisj characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT bakermatthew characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT rutherfordnicolaj characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT adamsonjennifer characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT wszolekzbigniewk characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT adelianahita characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT savicarodolfo characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT bootbrendon characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT kuntzkarenm characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT gavrilovaralitza characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT reevesandrew characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT whitwelljennifer characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT kantarcikejal characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT jackcliffordr characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT parisijosephe characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT lucasjohna characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT petersenronaldc characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 AT rademakersrosa characterizationoffrontotemporaldementiaandoramyotrophiclateralsclerosisassociatedwiththeggggccrepeatexpansioninc9orf72 |