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 Chio

doi:10.1212/NXG.0000000000200011

Phenotype Analysis of Fused in Sarcoma Mutations in Amyotrophic Lateral Sclerosis

Neurol Genet. 2022 Sep 12;8(5):e200011. doi: 10.1212/NXG.0000000000200011. eCollection 2022 Oct.

Authors

Maurizio Grassano¹, Giorgia Brodini¹, Giovanni De Marco¹, Federico Casale¹, Giuseppe Fuda¹, Paolina Salamone¹, Maura Brunetti¹, Luca Sbaiz¹, Salvatore Gallone¹, Paolo Cugnasco¹, Alessandro Bombaci¹, Rosario Vasta¹, Umberto Manera¹, Antonio Canosa¹, Cristina Moglia¹, Andrea Calvo¹, Bryan J Traynor¹, Adriano Chio¹

Affiliation

¹ ALS Center (M.G., G.B., G.D.M., F.C., G.F., P.S., P.C., A.B., R.V., U.M., Antonio Canosa, C.M., Andrea Calvo, Adriano Chio), ''Rita Levi Montalcini'' Department of Neuroscience, University of Turin, Italy; Neuromuscular Diseases Research Section (M.G., B.J.T.), Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD; Laboratory of Genetics (M.B., L.S.), Department of Clinical Pathology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino; S.C. Neurologia 1U (S.G., U.M., Antonio Canosa, C.M., Andrea Calvo, Adriano Chio), Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Reta Lila Weston Institute (B.J.T.), UCL Queen Square Institute of Neurology, University College London, United Kingdom; Department of Neurology (B.J.T.), Johns Hopkins University Medical Center, Baltimore; National Institute of Neurological Disorders and Stroke (B.J.T.), NIH, Bethesda; ASO Rapid Development Laboratory (B.J.T.), Therapeutics Development Branch, National Center for Advancing Translational Sciences, NIH, Rockville, MD; and Institute of Cognitive Sciences and Technologies (Adriano Chio), National Council of Research, Rome, Italy.

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.