Disease progression in C9orf72 mutation carriers

• Published in: Neurology Vol. 89; no. 3; p. 234
• Main Authors: Floeter, Mary K, Traynor, Bryan J, Farren, Jennifer, Braun, Laura E, Tierney, Michael, Wiggs, Edythe A, Wu, Tianxia
• Format: Journal Article
• Language: English
• Published: United States 18.07.2017
• Subjects: Adult; Amyotrophic Lateral Sclerosis - diagnosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - physiopathology; Amyotrophic Lateral Sclerosis - psychology; C9orf72 Protein; Diagnosis, Differential; Disease Progression; DNA Repeat Expansion; Female; Follow-Up Studies; Frontotemporal Dementia - diagnosis; Frontotemporal Dementia - genetics; Frontotemporal Dementia - physiopathology; Frontotemporal Dementia - psychology; Heterozygote; Humans; Longitudinal Studies; Male; Middle Aged; Motor Activity; Neuropsychological Tests; Phenotype; Prospective Studies; Proteins - genetics; Severity of Illness Index; Survival Analysis
• ISSN: 1526-632X
• DOI: 10.1212/WNL.0000000000004115

To assess changes in 3 clinical measures, the Revised ALS Functional Rating Scale (ALSFRS-R), letter fluency, and Frontal Behavioral Inventory (FBI), over time in mutation carriers (C9+) with varied clinical phenotypes. Thirty-four unrelated participants with mutations in were enrolled in a prospective natural history study. Participants were classified as asymptomatic, amyotrophic lateral sclerosis (ALS), ALS-familial frontotemporal dementia (FTD), or behavioral-variant FTD by clinical diagnostic criteria. Diagnostic cognitive and motor tests were repeated at 6 and 18 months. The ALSFRS-R, letter fluency, and FBI were administered at baseline and follow-up visits at 6, 12, and 18 months. The clinical diagnosis of most patients did not change over the follow-up. ALSFRS-R scores correlated with measures of motor function. Letter fluency correlated with FBI and cognitive tests. ALSFRS-R, letter fluency, and FBI differed among the C9+ diagnostic subgroups at enrollment and worsened over follow-up in symptomatic patients, with different slopes among the subgroups. Most patients survived to the 6-month time point after enrollment. Survival of C9+ patients with ALS and C9+ patients with ALS-FTD declined over the 12- and 18-month follow-up. The pattern of scores of the ALSFRS-R, letter fluency, and FBI distinguished between ALS, ALS-FTD, and FTD presentations of mutation carriers and asymptomatic carriers. Longitudinal changes in these measures occurred with disease progression in a manner consistent with presenting phenotype.