Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

Abstract

Objective: We investigated whether the C9orf72 expansion mutation in patients with amyotrophic lateral sclerosis (ALS) is associated with unique demographic and clinical features.

Methods: Between 2001 and 2015, approximately half of all patients attending the Emory ALS Clinic agreed to donate DNA for research. This research cohort of 781 patients was screened for the C9orf72 expansion, and demographic and clinical data were compared between those with and without the C9orf72 mutation. For mutation carriers without a family history of ALS, we sought further family history of dementia and other non-ALS neurodegenerative diseases in first-degree relatives.

Results: The C9orf72 expansion was identified in 61 patients (7.8%). Compared to those without the expansion mutation, these patients did not differ in race, age, or site of onset. As expected, C9orf72 patients were more likely to have a family history of ALS (59% vs 7.9%) and to present with comorbid frontotemporal dementia (FTD) (14.8% vs 1.7%). Survival was shorter in patients with the expansion (log-rank χ(2)[1] = 45.323, p < 0.001). Further investigation in 28 patients initially categorized as having no known family history of ALS identified a family history of dementia in 16 cases; 6 of these had characteristics suggestive of FTD.

Conclusions: Comparing the C9orf72 ALS population to the general ALS population, there were no differences in race, age at onset, or proportion of patients with bulbar onset disease. Differences identified in patients with the C9orf72 mutation included shortened survival and an equal proportion of men and women. In addition, we found that assessing family history for dementia may identify other family members likely to be carrying the C9orf72 expansion, reduce the number of sporadic cases, and thus increase our understanding of disease penetrance.

Figure 1. Flowchart of family history of amyotrophic lateral sclerosis (ALS) in screened cohort

A total of 781 cases were screened for the C9orf72 expansion. Of those 781, 90 cases had a known family history of ALS, while 691 had no known family history of ALS. C9orf72 hexanucleotide repeat expansion (C9Pos) cases with a known family history of ALS made up 36.7% of the cases with a known family history of ALS. In the remaining cases with known family history of ALS who did not have the C9orf72 hexanucleotide repeat expansion (C9Neg), there were 13 patients with SOD1 mutations, 2 patients with VCP mutations, and 2 patients with UBQLN2 mutations. This chart represents information prior to follow-up interviews and reanalysis of clinical charts to obtain information on family history of dementia and other neurodegenerative diseases.

Figure 2. Survival analysis

Kaplan-Meier curve analysis of survival of patients with amyotrophic lateral sclerosis with (C9Pos, red line) and without (C9Neg, green line) the pathogenic C9orf72 expansion (log-rank χ² = 45.323, p < 0.001). Hash marks indicate censored cases in each group. Overall, 781 cases (61 C9Pos, 720 C9Neg) were included in analysis. Median survival time for C9Pos = 2.4 years, 95% confidence interval (CI) 1.9–2.9, for C9Neg = 4.3 years, 95% CI 3.8–4.7.