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

•      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.

Demographics

•      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

•      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.