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Table 3 Salient features of the FTD-predominant phenotype of c9FTD/ALS due to the GGGGCC hexanucleotide repeat expansion in C9ORF72

From: Cognitive and behavioral features of c9FTD/ALS

•      The mutation is as frequent as or more frequent than microtubule-associated protein tau (MAPT) or progranulin (PGRN) in most clinical cohorts with FTD ± parkinsonism ± ALS.
•      There is a slight male predominance.
•      Age of onset is between 33 and 78, and most patients present in the 40- to 70-year age range.
•      Survival is variable but typically is in the 5- to 9-year range.
•      Survival is shorter when the ALS phenotype is present.
•      Inheritance is autosomal dominant.
•      Many examples of incomplete penetrance exist.
•      Sporadic cases clearly exist.
•      Some kindreds appear to exhibit an anticipation-like phenomenon.
Clinical phenotype
•      The characteristic phenotype is bvFTD ± parkinsonism ± ALS.
•      The primary progressive aphasia and Alzheimer's disease-dementia phenotypes are uncommon but do exist.
•      The primary parkinsonism and corticobasal syndrome phenotypes are rare to nonexistent.
Cognitive features
•      Executive dysfunction is very common, as would be expected in an FTD-spectrum disorder, but the underlying substrate for this cognitive feature is not fully understood in those with no frontotemporal changes on neuroimaging studies.
•      Memory impairment is frequent, but the underlying substrate for this is not fully understood.
•      Aphasia is frequent but is typically a manifestation as the disease evolves after the predominant bvFTD phenotype. The underlying substrate for aphasia in not fully understood.
•      Visuospatial dysfunction in uncommon, but in view of the known parietal atrophy and hypometabolism in such cases, this feature is adequately explained.
•      Because memory dysfunction or visuospatial dysfunction or both are present in many cases with c9FTD/ALS, such cases will not fulfill the neuropsychological criterion for bvFTD.
Behavioral features
•      Almost all cases with a dementia phenotype have early behavioral disinhibition, early apathy or inertia, early loss of sympathy or empathy, and hyperorality and dietary changes and thus fulfill the bvFTD behavioral criteria.
•      Psychosis and other dramatic/bizarre behavior changes can occur.
•      The underlying substrate for the bvFTD features in those with minimal or no frontotemporal changes on neuroimaging studies is poorly understood.
Other clinical features
•      Many with the bvFTD-predominant phenotype have evidence of parkinsonism or upper or lower motor neuron involvement or a combination of the three.
  1. ALS, amyotrophic lateral sclerosis; bvFTD, behavioral variant frontotemporal dementia; c9FTD/ALS, frontotemporal dementia or amyotrophic lateral sclerosis (or both) linked to chromosome 9; C9ORF72, (gene encoding the mutation in) chromosome 9 open reading frame 72; FTD, frontotemporal dementia; GGGGCC, (the hexanucleotide expansion of) guanine-guanine-guanine-guanine-cytosine-cytosine.