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Updated: Aug 28, 2025
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Published on: July 16, 2021
Phenotype Analysis of Fused in Sarcoma Mutations in Amyotrophic Lateral Sclerosis
Maurizio Grassano1, Giorgia Brodini1, Giovanni De Marco1
1ALS 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.
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.
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