Abstract Details

Title Unraveling the clinical and genetic spectrum of FUS-ALS

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S11 - ALS and Motor Neuron Disorders (2:00 PM-2:12 PM)

Poster/Presentation
Number 006

Background Mutations in Fused in Sarcoma (FUS) are among the most prevalent genetic causes of ALS worldwide, and they are supposedly characterized by a homogeneous pure motor phenotype with early-onset and short disease duration. However, FUS cases with a very late disease onset and slow progression have been reported

Objective To analyze genotype-phenotype correlations and identify the prognostic factors in FUS-ALS cases

Design/Methods We identified and cross-sectionally analyzed 22 FUS-ALS patient histories from a single-center cohort of 2615 genetically tested patients and reviewed 289 previously published FUS-ALS cases. Survival analysis was performed by Kaplan–Meier survival curves followed by log-rank test and multivariate Cox-analysis. Cluster analysis was applied using continuous and discrete variables to identify FUS-related phenotypes

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. Based on the results of cluster analysis, we divided FUS-ALS patients into three phenotypes: (a) axial ALS, with upper cervical and dropped-head onset in mid-to-late adulthood; (b) aggressive juvenile ALS, often with a bulbar onset and preceded by learning disability or mild mental retardation, (c) benign ALS, usually with a late-onset and slow disease progression. Those phenotypes arise from different mutations

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

Authors/Disclosures
Maurizio Grassano, MD (Dept. of Neuroscience, University of Turin) PRESENTER	Dr. Grassano has received research support from American Brain Foundation, ALS Association and American Academy of Neurology.
Andrea Calvo, MD, PhD, FAAN (Dept. of Neuroscience, University of Turin)	Dr. Calvo has nothing to disclose.
Cristina Moglia (University of Torino)	Cristina Moglia has nothing to disclose.
Antonio Canosa	Antonio Canosa has nothing to disclose.
Umberto Manera, MD (Department of Neuroscience "Rita Levi Montalcini" - University of Torino)	Dr. Manera has nothing to disclose.
Alessandro Bombaci, MD (Rita Levi Montalcini Department of Neuroscience, University of Turin)	Dr. Bombaci has nothing to disclose.
Giorgia Brodini	Ms. Brodini has nothing to disclose.
	No disclosure on file
Bryan Traynor, MD (National Institute on Aging)	The institution of Dr. Traynor has received research support from ALS Association. The institution of Dr. Traynor has received research support from Merck. The institution of Dr. Traynor has received research support from Myasthenia Gravis Foundation. The institution of Dr. Traynor has received research support from Cerevel Therapeutics. Dr. Traynor has received intellectual property interests from a discovery or technology relating to health care.
Adriano Chio, MD, FAAN (Dept. of Neuroscience, University of Turin)	Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cytokinetics. Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi. Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen.