Phenotype Analysis of Fused in Sarcoma Mutations in Amyotrophic Lateral Sclerosis
Maurizio Grassano, Giorgia Brodini, Giovanni De Marco, Federico Casale, Giuseppe Fuda, Paolina Salamone, Maura Brunetti, Luca Sbaiz, Salvatore Gallone, Paolo Cugnasco, Alessandro Bombaci, Rosario Vasta, Umberto Manera, Antonio Canosa, Cristina Moglia, Andrea Calvo, Bryan J. Traynor, Adriano Chiò
Abstract
<h3>Background and Objectives</h3> Pathogenic variations in fused in sarcoma <i>(FUS)</i> 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 <i>FUS-</i>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 <i>FUS</i>-ALS cases. <h3>Methods</h3> We identified and cross-sectionally analyzed 22 <i>FUS</i>-ALS patient histories from a single-center cohort of 2,615 genetically tested patients and reviewed 289 previously published <i>FUS</i>-ALS cases. Survival analysis was performed by Kaplan-Meier survival curves, followed by the log-rank test and multivariate Cox analysis. <h3>Results</h3> Survival of <i>FUS</i>-ALS is age-dependent: In our cohort, early-onset cases had a rapid disease progression and short survival (<i>p</i> = 0.000003) while the outcome of <i>FUS</i>-mutated patients with mid-to-late onset did not differ from non–<i>FUS</i>-ALS patients (<i>p</i> = 0.437). Meta-analysis of literature data confirmed this trend (<i>p</i> = 0.00003). This survival pattern is not observed in other ALS-related genes in our series. We clustered <i>FUS</i>-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. <h3>Discussion</h3> We observed specific genotype-phenotype correlations of <i>FUS</i>-ALS and identified age at onset as the most critical prognostic factor. Our results demonstrated that <i>FUS</i> mutations underlie a specific subtype of ALS and enable a careful stratification of newly diagnosed <i>FUS</i>-ALS cases for clinical course and potential therapeutic windows. This will be crucial in the light of incoming gene-specific therapy.