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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Funding This work was supported by National Institutes of Health (grants R01AG031278, R01 AG038791, R01NS065782, R01 AG026251, R01 AG026938, R01 AG029577, K23 AG031861, K23 AG021606, P01 AG19724, M01-RR0079, P50 AG023501 and P50 AG1657303); the Hellman Foundation, the Tau Research Consortium, the ALS Association (ALSA), the State of California, Alzheimer's Disease Research Center of California (ARCC) (grant 03-7527) and the Larry Hillblom Foundation grants 2002/2J and 2007/2I.
Competing interests RR has a patent pending for the C9ORF72 non-coding expansion.
Ethics approval Ethics approval was provided by UCSF institutional review board.
Provenance and peer review Not commissioned; externally peer reviewed.