Phenotype Analysis of Fused in Sarcoma Mutations in Amyotrophic Lateral Sclerosis

Abstract

Background and objectives: Pathogenic variations in fused in sarcoma (FUS) are among the most common genetic causes of amyotrophic lateral sclerosis (ALS) worldwide. They are supposedly characterized by a homogeneous pure motor phenotype with early-onset and short disease duration. However, a few FUS-mutated cases with a very late disease onset and slow progression have been reported. To analyze genotype-phenotype correlations and identify the prognostic factors in FUS-ALS cases.

Methods: We identified and cross-sectionally analyzed 22 FUS-ALS patient histories from a single-center cohort of 2,615 genetically tested patients and reviewed 289 previously published FUS-ALS cases. Survival analysis was performed by Kaplan-Meier survival curves, followed by the log-rank test and multivariate Cox analysis.

Results: Survival of FUS-ALS is age-dependent: In our cohort, early-onset cases had a rapid disease progression and short survival (p = 0.000003) while the outcome of FUS-mutated patients with mid-to-late onset did not differ from non-FUS-ALS patients (p = 0.437). Meta-analysis of literature data confirmed this trend (p = 0.00003). This survival pattern is not observed in other ALS-related genes in our series. We clustered FUS-ALS patients in 3 phenotypes: (1) axial ALS, with upper cervical and dropped-head onset in mid-to-late adulthood; (2) benign ALS, usually with a late-onset and slow disease progression; and (3) juvenile ALS, often with bulbar onset and preceded by learning disability or mild mental retardation. Those phenotypes arise from different mutations.

Discussion: We observed specific genotype-phenotype correlations of FUS-ALS and identified age at onset as the most critical prognostic factor. Our results demonstrated that FUS mutations underlie a specific subtype of ALS and enable a careful stratification of newly diagnosed FUS-ALS cases for clinical course and potential therapeutic windows. This will be crucial in the light of incoming gene-specific therapy.

Figure 1. Cumulative Distribution Plot of Age at Onset in Our Cohort

Wild type (WT) median age at onset 68.8 years (IQR 61.7–74.8), C9orf72 median age at onset 62.9 years (IQR 54.0–67.8), SOD1 median age at onset 66.6 years (IQR 46.8–77.23), TARDBP median age at onset 66.6 years (58.8–72.9), and FUS median age at onset 48.00 years (IQR 31.0–62.0). FUS = fused in sarcoma.

Figure 2. Survival Analyses of FUS Carriers

(A) Survival analysis of early-onset FUS carriers (age at onset younger than 46 years, left) and mid-to-late onset FUS (older than 46 years, right) vs nonmutated ALS cases. Early-onset FUS median survival 82.7 weeks (IQR 47.9–95.9) and non-FUS early-onset ALS median survival 204.7 weeks (IQR 126.1–274.0); log-rank p-value = 0.000006. Mid-to-late onset FUS median survival 126.1 (IQR 86.7–195.6) and non-FUS mid-to-late onset ALS median survival 121.9 (78.1–195.6); log-rank p-value = 0.2 (B) Survival analysis of early-onset FUS carriers (age at onset <46 years) vs mid-to-late onset FUS (>46 years). ALS = amyotrophic lateral sclerosis; FUS = fused in sarcoma.

Figure 3. Patterns of Motor and Nonmotor Involvement in FUS-ALS and Genotype-Phenotype Correlation of FUS Mutations

FUS = fused in sarcoma; NLS = nuclear localization signal.