Characterization of a Family With c9FTD/ALS Associated With the GGGGCC Repeat Expansion in C9ORF72

Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by significant abnormalities of frontal and/or temporal lobes that result clinically in personality/behavioral changes and/or progressive aphasia.1-3 Frontotemporal dementia may occur in a sporadic or familial form. The first major gene associated with frontotemporal dementia with or without parkinsonism was microtubule associated protein tau (MAPT), mutations of which lead to the cascade of hyperphosphorylated tau.4 Mutations in the gene encoding progranulin (PGRN) also cause FTD with or without parkinsonism, with ubiquitin-immunoreactive and TAR DNA-binding protein 43–immunoreactive inclusions being the pathologic hallmark.5,6 Many kindreds with FTD with or without amyotrophic lateral sclerosis (ALS) with TDP-43-immunoreactive inclusions were linked to chromosome 9,7-14 and the hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the underlying genetic cause.15,16 Such cases are now collectively termed under the c9FTD/ALS terminology.15,17,18 We report the clinical, neuropsychologic, and neuroimaging findings of a family with the C9ORF72 mutation and clinical diagnoses bridging the FTD, parkinsonism, and ALS spectrum.