Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion
Open accessAbstract
BACKGROUND: Some patients meeting behavioural variant frontotemporal dementia (bvFTD) diagnostic criteria progress slowly and plateau at mild symptom severity. Such patients have mild neuropsychological and functional impairments, lack characteristic bvFTD brain atrophy and have thus been referred to as bvFTD 'phenocopies' or slowly progressive (bvFTD-SP). The few patients with bvFTD-SP that have been studied at autopsy have demonstrated no evidence of FTD pathology, suggesting that bvFTD-SP is neuropathologically distinct from other forms of FTD. Here, two patients with bvFTD-SP with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansions are described. METHODS: 384 patients with an FTD clinical spectrum and Alzheimer's disease diagnoses were screened for C9ORF72 expansion. Two bvFTD-SP mutation carriers were identified. Neuropsychological and functional data, as well as brain atrophy patterns, assessed using voxel based morphometry (VBM), were compared with 44 patients with sporadic bvFTD and 85 healthy controls. RESULTS: Both patients were aged 48 years at baseline and met possible bvFTD criteria. In the first patient, VBM revealed thalamic and posterior insula atrophy. Over 7 years, his neuropsychological performance and brain atrophy remained stable. In the second patient, VBM revealed cortical atrophy with subtle frontal and insular volume loss. Over 2 years, her neuropsychological and functional scores as well as brain atrophy remained stable. CONCLUSIONS: C9ORF72 mutations can present with a bvFTD-SP phenotype. Some bvFTD-SP patients may have neurodegenerative pathology, and C9ORF72 mutations should be considered in patients with bvFTD-SP and a family history of dementia or motor neuron disease.
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C9orf72 repeat expansion carriers can present with psychiatric symptoms and form a diagnostic challenge given their slow progressive course and atypical findings in neuroimaging.
“C9orf72 repeat expansion carriers can present with psychiatric symptoms and form a diagnostic challenge given their slow progressive course and atypical findings in neuroimaging (see 'Genetic testing' section) (Khan et al. , 2012; Solje et al. , 2015; Ducharme et al. , 2017).”
From Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders (2020) · cites this paper as Khan et al., 2012
Family histories in C9orf72 mutation carriers can be negative or ambiguous due to the large variation in clinical phenotype, including psychiatric and other atypical presentations.
“It is well known, however, that family histories in C9orf72 mutation carriers can be negative or ambiguous due to the large variation in clinical phenotype, including psychiatric and other atypical presentations.61”
From Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations (2022) · cites this paper as [61]
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- Authors
- Khan, B. K., Yokoyama, J. S., Takada, L. T., Sha, S. J., Rutherford, N. J., Fong, J. C., Karydas, A. M., Wu, T., Ketelle, R. S., Baker, M. C., Hernandez, M.-D., Coppola, G., Geschwind, D. H., Rademakers, R., Lee, S. E., Rosen, H. J., Rabinovici, G. D., Seeley, W. W., Rankin, K. P., Boxer, A. L., & Miller, B. L.
- Affiliations
- University of California, San Francisco (US)
- Mayo Clinic in Florida (US)
- University of California, Los Angeles (US)
- Corresponding author
- Boxer, Adam L
- ORCID
- Venue
- Journal of Neurology, Neurosurgery & Psychiatry
- Publisher
- BMJ
- Published
- 2012-03-07
- Volume
- 83
- Issue
- 4
- Pages
- 358-364
- ISSN
- 0022-3050 (ISSN-L)
- 1468-330X
- PMC
- PMC3388906
- OpenAlex
- W2152018727
- Cited by
- 185
- References
- 33
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 7 · 2023: 5 · 2022: 11 · 2021: 20 · 2020: 14 · 2019: 14 · 2018: 15 · 2017: 14 · 2016: 20 · 2015: 18 · 2014: 17 · 2013: 14 · 2012: 11
- FWCI
- 12.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5m01rr000079-42)
- University of California, San Francisco
- National Institute on Aging (K23AG021606, R01AG029577, P01AG017586, RF1AG029577, K23AG039414, P50AG1657303, R01AG032306, R01AG031278, K23AG031861, R01AG026251, R01AG026938, R01AG038791, P01AG019724, P50AG023501)
- National Institute of Neurological Disorders and Stroke (R01NS065782)
- National Center for Research Resources (M01-RR000079, M01 RR-0079)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- behavioral variant frontotemporal dementia, C9orf72 repeat expansion, frontotemporal dementia, brain atrophy, thalamic atrophy, cortical atrophy, phenocopy, neurodegeneration
- MeSH terms
- C9orf72 Protein, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Brain Mapping, Female, Heterozygote, Humans, Male, Middle Aged, Mutation, Neuropsychological Tests, Proteins, DNA Repeat Expansion, Frontotemporal Dementia
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