Neuroimaging features of C9ORF72 expansion

Abstract

Hexanucleotide expansion intronic to chromosome 9 open reading frame 72 (C9ORF72) has recently been identified as the most common genetic cause of both familial and sporadic amyotrophic lateral sclerosis and of frontotemporal dementia with or without concomitant motor neuron disease. Given the common frequency of this genetic aberration, clinicians seek to identify neuroimaging hallmarks characteristic of C9ORF72-associated disease, both to provide a better understanding of the underlying degenerative patterns associated with this mutation and to enable better identification of patients for genetic screening and diagnosis. A survey of the literature describing C9ORF72 neuroimaging thus far suggests that patients with this mutation may demonstrate symmetric frontal and temporal lobe, insular, and posterior cortical atrophy, although temporal involvement may be less than that seen in other mutations. Some studies have also suggested cerebellar and thalamic involvement in C9ORF72-associated disease. Diffuse cortical atrophy that includes anterior as well as posterior structures and subcortical involvement thus may represent unique features of C9ORF72.

Figure 1

Representative magnetic resonance images for the three most common frontotemporal dementia (FTD)-causing gene mutations. T1-weighted magnetic resonance images are shown for three different patients, each harboring a single mutation in a different gene that causes FTD. The patient with MAPT demonstrates symmetrical atrophy in ventral frontotemporal regions, particularly in the anterior temporal poles, whereas the GRN mutation carrier demonstrates marked asymmetrical atrophy, most notable in dorsal, frontotemporal regions, with additional involvement in posterior areas. However, the patient with C9ORF72 expansion shows diffuse, symmetrical atrophy in frontal, temporal, and parietal cortical regions as well as cerebellum. C9ORF72, chromosome 9 open reading frame 72; GRN, granulin; MAPT, microtubule-associated protein tau.