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Table 4 Clues that should alert clinicians to suspect the hexanucleotide repeat expansion in C9ORF72 in individual patients

From: Cognitive and behavioral features of c9FTD/ALS

Demographics
•      Age of onset in the 30- to 70-year age range
Inheritance
•      Apparent autosomal dominant pattern of inheritance of dementia or ALS or botha
Clinical phenotype
•      Presence of the phenotype of bvFTD ± parkinsonism ± ALS in the patient and his or her relativesa
•      Absence of any of the focal/asymmetric focal cortical degenerative syndromes (for example, primary progressive aphasia and corticobasal syndrome) in the patient and his or her relativesa
Cognitive/Neuropsychological features
•      Presence of executive dysfunction and word retrieval deficitsa
•      The presence of memory impairment or visuospatial impairment or both should not dissuade the suspicion of the mutation if many other clues are present.
•      Normal or minimally abnormal performance on neuropsychological tests early in the course of behavioral changes should not dissuade the suspicion of the mutation if many other clues are present.
Behavioral features
•      Presence of the 'classic bvFTD features' in the patient, including behavioral disinhibition, early apathy or inertia, early loss of sympathy or empathy, and hyperorality and dietary changesa
•      Presence of psychosis and other dramatic/bizarre behavior changes in the patient ± his or her relatives
Neuroimaging features
•      Presence of symmetric bilateral frontal (often mesial more so than dorsolateral) ± temporal ± parietal atrophy or hypometabolisma
•      Normal or minimally abnormal neuroimaging findings early in the course of behavioral changes should not dissuade the suspicion of the mutation if many other clues are present.
Neuropathologic features
•      Presence of TDP-43-, ubiquitin-, ubiquilin-, and p62-positive inclusions in the cerebellum in the patient or any of his or her relativesa
  1. aThis feature is a primary clue for considering the C9ORF72 mutation. ALS, amyotrophic lateral sclerosis; bvFTD, behavioral variant frontotemporal dementia; C9ORF72, (gene encoding the mutation in) chromosome 9 open reading frame 72.