Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)765-783
Number of pages19
JournalBrain
Volume135
Issue number3
DOIs
StatePublished - Mar 2012

Fingerprint

Parkinsonian Disorders
Age of Onset
Frontotemporal Dementia
Chromosomes, Human, Pair 9
Neuroimaging
Primary Progressive Aphasia
Nerve Degeneration
Motor Neuron Disease
Mutation
Penetrance
Amyotrophic Lateral Sclerosis
DNA-Binding Proteins
Motor Neurons
Ubiquitin
Open Reading Frames
Dementia
Molecular Weight
Demography
Pathology
Phenotype

Keywords

  • amyotrophic lateral sclerosis
  • chromosome 9
  • frontotemporal dementia
  • motor neuron disease
  • neurogenetics
  • TDP-43

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

@article{e5e207b3e08f4dc684b3ed261d50c746,
title = "Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72",
abstract = "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.",
keywords = "amyotrophic lateral sclerosis, chromosome 9, frontotemporal dementia, motor neuron disease, neurogenetics, TDP-43",
author = "Boeve, {Bradley F} and Boylan, {Kevin B.} and {Graff Radford}, {Neill R} and Mariely Dejesus-Hernandez and Knopman, {David S} and Pedraza, {Otto D} and Vemuri, {Prashanthi D} and Jones, {David T} and Val Lowe and Murray, {Melissa E} and Dickson, {Dennis W} and Josephs, {Keith Anthony} and Rush, {Beth K} and Machulda, {Mary Margaret} and Fields, {Julie A} and Ferman, {Tanis Jill} and Matthew Baker and Rutherford, {Nicola J.} and Jennifer Adamson and Wszolek, {Zbigniew K} and Anahita Adeli and Rodolfo Savica and Brendon Boot and Kuntz, {Karen M.} and Gavrilova, {Ralitza M} and Andrew Reeves and Whitwell, {Jennifer Lynn} and Kantarci, {Kejal M} and Jack, {Clifford R Jr.} and Parisi, {Joseph E} and Lucas, {John A} and Petersen, {Ronald Carl} and Rademakers, {Rosa V}",
year = "2012",
month = "3",
doi = "10.1093/brain/aws004",
language = "English (US)",
volume = "135",
pages = "765--783",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "3",

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TY - JOUR

T1 - Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72

AU - Boeve, Bradley F

AU - Boylan, Kevin B.

AU - Graff Radford, Neill R

AU - Dejesus-Hernandez, Mariely

AU - Knopman, David S

AU - Pedraza, Otto D

AU - Vemuri, Prashanthi D

AU - Jones, David T

AU - Lowe, Val

AU - Murray, Melissa E

AU - Dickson, Dennis W

AU - Josephs, Keith Anthony

AU - Rush, Beth K

AU - Machulda, Mary Margaret

AU - Fields, Julie A

AU - Ferman, Tanis Jill

AU - Baker, Matthew

AU - Rutherford, Nicola J.

AU - Adamson, Jennifer

AU - Wszolek, Zbigniew K

AU - Adeli, Anahita

AU - Savica, Rodolfo

AU - Boot, Brendon

AU - Kuntz, Karen M.

AU - Gavrilova, Ralitza M

AU - Reeves, Andrew

AU - Whitwell, Jennifer Lynn

AU - Kantarci, Kejal M

AU - Jack, Clifford R Jr.

AU - Parisi, Joseph E

AU - Lucas, John A

AU - Petersen, Ronald Carl

AU - Rademakers, Rosa V

PY - 2012/3

Y1 - 2012/3

N2 - 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.

AB - 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.

KW - amyotrophic lateral sclerosis

KW - chromosome 9

KW - frontotemporal dementia

KW - motor neuron disease

KW - neurogenetics

KW - TDP-43

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U2 - 10.1093/brain/aws004

DO - 10.1093/brain/aws004

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