MULTICENTRIC REFERRAL-BASED STUDY OF ALS-RELATED GENES IN AN ARGENTINE ALS/FTD COHORT: PRELIMINARY RESULTS.

GARGIULO MONACHELLI GM; CLAIRE LEBLOND; MARIELA BETTINI; ALEJANDRA FIGUEREDO; IGNACIO MELE; MARIA LAURA GARAU; MARCELO RUGIERO; GONZALEZ DENISELLE M.C; PATRICK A DION; MIGUEL PAGANO; ROULEAU GUY

Dublin

Simposio; 27th International Symposium on ALS/MND; 2016

Multicentric referral-based study of ALS-related genes in an Argentine ALS/FTD cohort Gisella Gargiulo-Monachelli (1,7), Claire S. LeBlond (2), Mariela Bettini (3), Maria Alejandra Figueredo (4), Ignacio Mele (1), Maria Laura Garau (1), Marcelo Rugiero (3), Ma. Claudia Gonzalez Deniselle (7), Patrick A. Dion (2), Miguel A. Pagano (1), Guy A. Rouleau (2).1. Department of Neurology, Fernandez Hospital. 2. Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Qc, Canada. 3. Seccion Enfermedades Neuromusculares, Hospital Italiano de Buenos Aires. 4. Consultorio de enfermedades de motoneurona, Hospital San Roque y Hospital Español de La Plata. 7. Instituto de Biologia y Medicina Experimental (IBYME), UBA-CONICET.BackgroundGenetically, C9ORF72 repeat expansions are the most common cause of ALS and FTD [1]. We previously found in an Argentine ALS and FTD cohort that C9+ cases involved patients with a positive family history of disease. C9+ ALS was associated with a young onset, rapid progression, initial bulbar symptoms and the co-existence of non-motor phenotypes (FTD and psychiatric disease) [2].ObjectivesOur objective was to expand our previous work with whole-exome sequencing (WES) to screen for 28 ALS-related genes in a larger cohort of ALS and FTD patients in Argentina.MethodologyTo assess the mutation frequency of ALS-associated-genes in ALS cases from Argentina, we screened 28 genes (SOD1, FUS, TARDBP, C9ORF72, VAPB, VCP, UBQLN2, DAO, PFN1, hnRNPA2B1, hnRNPA1, ANG, FIG4, OPTN, DCTN1, CHMP2B, NEFH, PRPH, SQSTM1, TAF15, HFE, GRN, ARHGEF28, ERBB4, SPAST, P4HB, PDIA2 and PDIA3). Single nucleotide variations were studied using Molecular Inverted Probe (MIP) captures and Illumina sequencing (PMID=23160955) for the 28 genes. Hexanucleotide repeats of C9ORF72 were studied by repeat-primed-PCR (PMID= 21944779 & 21944778).ResultsA total of 108 patients were recruited between August 2012 and Nov 2015 of whom 52% were males. Twenty one percent were FALS cases, defined if a first or second degree relative had ALS or FTD. Mean age of onset was 53 years old. Clinical characteristics ranged from: classic ALS (n=47, 43.5%), bulbar onset ALS or progressive bulbar palsy (n=13, 12%), UMN dominant-ALS (n=9, 8.3%), ALS+FTD (n=9, 8.3%), Flail arm or flail leg (n=6, 5.5%), FALS with 1st or 2nd degree relative with ALS only (n=5, 4.6%), PLS (n=5, 4.6%), PMA (n=4, 3.7%), FTD only (n=3, 2.7%), slowly progressive ALS defined as >10 years from symptom onset (n=3, 2.7%), ALS+PD (n=2, 1.8%) and respiratory onset ALS (n=2, 1.8%). WES and repeat-primed-PCR results will be presented at the 27th International Symposium on ALS/MND to be held in Dublin, Ireland 7-9 December 2016.Discussions and conclusionsThis is the first prospective, multicentric, referral-based, ALS and FTD cohort to analyze mutation frequency of ALS-related genes in Argentina. We will present a full analysis of genotype-phenotype correlations at the ALS/MND Symposium. Patients in our country are not usually tested for ALS genes, neither sporadic nor familial cases. We encourage the implementation of a nationwide genetic screening of the most frequent ALS and FTD-associated genes in clinically selected cases. References[1] Majounie E, Renton AE, Mok K, et al. Lancet Neurol 2012; 11: 323?30.[2] Gargiulo-Monachelli G, LeBlond CS, Bettini M, et al. In: Annual Meeting of the American Academy of Neurology. Neurology April 6, 2015; vol 84, Suppl 14; Abstract P02.050