Novel evidence of phenotypical variability in the hexanucleotide repeat expansion in chromosome 9.

C9ORF72 repeat expansion is currently considered as a major genetic cause of amyotrophic lateral sclerosis (ALS) and, in particular, of combined frontotemporal dementia-motor neuron disorder (FTD-MND) pedigrees. Studies of large series of patients have indicated that various phenotypic presentations may be observed even in the same family. Here, we describe four patients carrying a C9ORF72 mutation with heterogeneous clinical presentation sharing a rapid disease course. Cases #1 and #2 presented with predominant semantic deficits, accompanied in one patient by clinical signs of ALS. Case #3 showed a phenotype compatible with a diagnosis of behavioral variant of FTD. Case #4 presented with memory impairments, apathy, and social withdrawal, and had negative cerebrospinal fluid markers for Alzheimer's disease. Two patients showed a positive familiar history of MND and dementia (at least one first-degree family member affected). The two other patients were apparently sporadic cases. Our data provide further evidence for the heterogeneity of phenotypes associated with the C9ORF72 mutation and indicate its association with a fluent progressive aphasia phenotype. The present findings confirm the importance of screening for the hexanucleotide repeat expansion in chromosome 9 in the case not only of familial, but also of sporadic FTD, and in the presence of atypical cognitive disorders.