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Table 5 Issues worthy of further study in c9FTD/ALS

From: Cognitive and behavioral features of c9FTD/ALS

Demographic and inheritance issues
•      Is there a slight male predominance in the dementia-predominant phenotype of c9FTD/ALS? If so, why?
•      Is the C9ORF72 mutation present across races and continents? If not, does the mutation represent a common founder?
•      Why are there such variable ages of onset and durations of disease across affected individuals?
•      Does genetic anticipation occur in c9FTD/ALS? If so, does the age of onset decrease as the expansion repeat number increases?
•      What explains incomplete penetrance in some families?
•      What is the mechanism for explaining sporadic cases?
Clinical phenotype
•      Why are the bvFTD or ALS phenotypes or both so consistently expressed?
•      Why are the syndromes of primary progressive aphasia, corticobasal syndrome, and primary parkinsonism so uncommon in the C9ORF72 mutation whereas the frequencies of these syndromes are higher in mutations associated with microtubule-associated protein tau (MAPT) and progranulin (PGRN)?
•      Does the hexanucleotide repeat length impact the topography of degeneration and therefore the phenotype?
Cognitive features
•      What is the underlying substrate for executive dysfunction and word retrieval impairment in those with no frontotemporal changes on neuroimaging studies? Does cerebellar dysfunction contribute to the 'frontal' cognitive features?
•      What are the qualitative features of memory impairment on neuropsychological assessment?
•      What is the underlying substrate for memory impairment in those with no frontotemporal changes on neuroimaging studies?
•      What is the underlying substrate for aphasia, particularly in those with no frontotemporal changes on neuroimaging studies?
•      How will c9FTD/ALS cases be viewed for experimental drug trial participation if they do not meet the neuropsychological profile criteria of bvFTD?
Behavioral features
•      Why are psychosis and other dramatic/bizarre behavior changes relatively common in c9FTD/ALS? What is the underlying substrate for these behavioral features?
•      What is the underlying substrate for the prominent behavioral features in those with minimal or no frontotemporal changes on neuroimaging studies? Does cerebellar dysfunction contribute to these prominent behavioral features?
  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.