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

Bradley F. Boeve, Kevin B. Boylan, Neill R. Graff-Radford, Mariely Dejesus-Hernandez, David S. Knopman, Otto Pedraza, Prashanthi Vemuri, David Jones, Val Lowe, Melissa E. Murray, Dennis W. Dickson, Keith A. Josephs, Beth K. Rush, Mary M. Machulda, Julie A. Fields, Tanis J. Ferman, Matthew Baker, Nicola J. Rutherford, Jennifer Adamson, Zbigniew K. WszolekAnahita Adeli, Rodolfo Savica, Brendon Boot, Karen M. Kuntz, Ralitza Gavrilova, Andrew Reeves, Jennifer Whitwell, Kejal Kantarci, Clifford R. Jack, Joseph E. Parisi, John A. Lucas, Ronald C. Petersen, Rosa Rademakers

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303 Scopus citations


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
Issue number3
StatePublished - Mar 2012

Bibliographical note

Funding Information:
The ‘Mayo Alzheimer’s Disease Research Centre’ (P50 AG016574); the ‘Mayo Alzheimer’s Disease Patient Registry’ (UO1 AG006786); ‘Identifying Mechanisms of Dementia: Role for MRI in the Era of Molecular Imaging’ (RO1 AG011378); the ALS Association (to R.R.); the ALS Therapy Alliance (to R.R.); the MCF ALS Centre donor funds (to K.B.B.); the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program of the Mayo Foundation, and the NIH/NINDS Morris K. Udall Centre of Excellence for Parkinson’s Disease Research at Mayo Clinic Florida (P50 NS072187 and P50 NS072187-01S2); NIH (grants R01 NS065782 and R01 AG026251, to R.R.).


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


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