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Abstract Details

Role of hnRNPA1 in an Italian ALS Population-Based Cohort
Neuromuscular and Clinical Neurophysiology (EMG)
P9 - Poster Session 9 (12:00 PM-1:00 PM)
1-010
To assess the role of heterogeneous nuclear ribonucleoproteins (hnRNP) in amyotrophic lateral sclerosis (ALS), we examined hnRNPA1 rare variants in an ALS cohort from Italy. We sought to determine the prevalence of HNRNPA1 mutations and their associated clinical phenotype.
Mutations in the prion-like domain of the gene encoding the hnRNPA1 protein have been implied in ALS pathogenesis and previously reported in ALS patients. However, evidence for their role in ALS is still inconclusive.
We identified variants in hnRNPA1 gene through whole-genome sequencing of 957 individuals with sporadic and familial ALS, of the Piemonte ALS Register (PARALS) and 677 control subjects. We performed a gene-based rare variants analysis and then assessed the clinical characteristics of the patients who carry the candidate disease-associated variants.
We detect an enrichment of hnRNPA1 rare variants in ALS patients (p-value 0.034). We found 5 (0.5%) individuals carrying 5 distinct nonsynonymous SNV that were absent in the control population. Four of these variants are located in the prion-like domain of the gene: the variant c.C666G (p.F222L) in exon 6 and the variants c.G824T (p.G275V), c.C876G (p.N292K) and G883A (p.G295R) in exon 8. All cases were apparently sporadic. Limb onset occurred in all five patents and none of them showed cognitive impairment. Mean age of onset was 58.0 years. The mean rate of decline for ALS-FRS was 0.37 points/months; two patients showed a late involvement of bulbar (29.0 months) and respiratory functions (39.5 months). hnRNPA1 variants were associated with a longer survival (HR 13.7, 95% C.I. 4.78-39.5, p < 0.001) than non-mutated ALS patients from the PARALS.
Our data demonstrate that hnRNPA1 is a low frequency cause of disease in our cohort. Mutations in hnRNPA1 define a relatively uniform slow-progressive subset of ALS.
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 Â鶹´«Ã½Ó³»­.
Andrea Calvo, MD, PhD, FÂ鶹´«Ã½Ó³»­ (Dept. of Neuroscience, University of Turin) Dr. Calvo has nothing to disclose.
Sonja W. Scholz, MD, FÂ鶹´«Ã½Ó³»­ (National Institute of Neurological Disorders and Stroke) Dr. Scholz has received personal compensation for serving as an employee of National Institutes of Health. An immediate family member of Dr. Scholz has received personal compensation for serving as an employee of National Institutes of Health. The institution of Dr. Scholz has received research support from National Institutes of Health. The institution of an immediate family member of Dr. Scholz has received research support from National Institutes of Health. An immediate family member of Dr. Scholz has received intellectual property interests from a discovery or technology relating to health care. Dr. Scholz has a non-compensated relationship as a Scientific Advisory Council Member with Lewy Body Dementia Association that is relevant to Â鶹´«Ã½Ó³»­ interests or activities. Dr. Scholz has a non-compensated relationship as a Editorial Board Member with JAMA Neurology that is relevant to Â鶹´«Ã½Ó³»­ interests or activities. Dr. Scholz has a non-compensated relationship as a Editorial Board Member with Journal of Parkinson's Disease that is relevant to Â鶹´«Ã½Ó³»­ interests or activities. Dr. Scholz has a non-compensated relationship as a Scientific Advisory Board Member with Mission MSA that is relevant to Â鶹´«Ã½Ó³»­ interests or activities. Dr. Scholz has a non-compensated relationship as a Scientific Advisory Board Member with The GBA1 Canada Initiative (G-Can) that is relevant to Â鶹´«Ã½Ó³»­ interests or activities.
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.
Rosario Vasta, MD (University of Turin, Department of Neurosciences) Dr. Vasta has nothing to disclose.
Cristina Moglia (University of Torino) Cristina Moglia has nothing to disclose.
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.
No disclosure on file