An expanded hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72), on chromosome 9p21, has recently been identified as a major cause of familial frontotemporal dementia (FTD). The neuropathology and clinical characteristics associated with C9ORF72 mutations are heterogeneous with the unknown pathomechanism. These cases were reported with a series of neuropathology, including TDP-43 pathology, ubiquilin (UBQLN) pathology, p62 pathology, microglial pathology, RNA-binding protein pathology and pathology associated with dipeptide-repeat (DPR) proteins. TDP-43 positive neuropathology was important in FTD patients with the mutations. Nevertheless, the majority of reports agree with a special pattern of neuropathology with p62 positive, TDP-43-negative inclusions being a consistent feature. Although subjects with the C9ORF72 mutations more frequently present with earlier onset age, earlier death, a shortened survival and a positive family history, most of the subjects present with typical clinical features of FTD. All these findings support that the C9ORF72 mutations become important newly recognized causes of FTD, providing a more detailed characterization of the associated clinical and pathological features. The following review summarizes the pathological development of FTD associated with C9ORF72, the clinical and pathological features of this cohort, some pathological mechanism hypotheses, and describes their phenotypic range and overlap with other neurodegenerative diseases.
Keywords: C9ORF92; Frontotemporal dementia; Genetics TDP-43; Mutation; Pathology; Phenotype.