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ObjectiveTo assess the burden of rare genetic variants and to estimate the contribution of known amyotrophic lateral sclerosis (ALS) genes in an Italian population-based cohort, we performed whole genome sequencing in 959 patients with ALS and 677 matched healthy controls.MethodsWe performed genome sequencing in a population-based cohort (Piemonte and Valle d'Aosta Registry for ALS [PARALS]). A panel of 40 ALS genes was analyzed to identify potential disease-causing genetic variants and to evaluate the gene-wide burden of rare variants among our population.ResultsA total of 959 patients with ALS were compared with 677 healthy controls from the same geographical area. Gene-wide association tests demonstrated a strong association with SOD1, whose rare variants are the second most common cause of disease after C9orf72 expansion. A lower signal was observed for TARDBP, proving that its effect on our cohort is driven by a few known causal variants. We detected rare variants in other known ALS genes that did not surpass statistical significance in gene-wise tests, thus highlighting that their contribution to disease risk in our cohort is limited.ConclusionsWe identified potential disease-causing variants in 11.9% of our patients. We identified the genes most frequently involved in our cohort and confirmed the contribution of rare variants in disease risk. Our results provide further insight into the pathologic mechanism of the disease and demonstrate the importance of genome-wide sequencing as a diagnostic tool.

ObjectiveTo assess the determinants of amyotrophic lateral sclerosis (ALS) phenotypes in a population-based cohort.MethodsThe study population included 2,839 patients with ALS diagnosed in Piemonte, Italy (1995–2015). Patients were classified according to motor (classic, bulbar, flail arm, flail leg, predominantly upper motor neuron [PUMN], respiratory) and cognitive phenotypes (normal, ALS with cognitive impairment [ALSci], ALS with behavioral impairment [ALSbi], ALSci and ALSbi combined [ALScbi], ALS–frontotemporal dementia [FTD]). Binary logistic regression analysis was adjusted for sex, age, and genetics.ResultsBulbar phenotype correlated with older age (p < 0.0001), women were more affected than men at increasing age (p < 0.0001), classic with younger age (p = 0.029), men were more affected than women at increasing age (p < 0.0001), PUMN with younger age (p < 0.0001), flail arm with male sex (p < 0.0001) and younger age (p = 0.04), flail leg with male sex with increasing age (p = 0.008), and respiratory with male sex (p < 0.0001). C9orf72 expansions correlated with bulbar phenotype (p < 0.0001), and were less frequent in PUMN (p = 0.041); SOD1 mutations correlated with flail leg phenotype (p < 0.0001), and were less frequent in bulbar (p < 0.0001). ALS-FTD correlated with C9orf72 (p < 0.0001) and bulbar phenotype (p = 0.008), ALScbi with PUMN (p = 0.014), and ALSci with older age (p = 0.008).ConclusionsOur data suggest that the spatial–temporal combination of motor and cognitive events leading to the onset and progression of ALS is characterized by a differential susceptibility to the pathologic process of motor and prefrontal cortices and lower motor neurons, and is influenced by age, sex, and gene variants. The identification of those factors that regulate ALS phenotype will allow us to reclassify patients into pathologically homogenous subgroups, responsive to targeted personalized therapies.

Objective: To describe a patient with a double pathogenetic mutation of C9ORF72 and TARDBP genes. Background Several genes have been found to be related to ALS; however, patients carrying two different pathogenetic genetic mutations have never been described. Design/Methods: We are performing a study of genetic determinants of familial ALS in Italy. All patients undergo mutational analysis for SOD1, FUS and TARDBP and OPTN . Repeat primer PCR to screen the presence of the hexanucleotide expansion in the first intron of C9ORF72 is performed. Results: The index case was a year-old man who at 43 developed bulbar-onset ALS with behavioural frontemporal dementia (FTD) occurring one year later. He deceased 34 months after the onset of ALS. He carried both a A382T missense mutation of the TARDBP gene and a hexanucleotide repeat expansion of C9ORF72 gene. His father, who also had a hexanucleotide repeat expansion of C9ORF72 gene, developed spinal onset ALS at 64, and behavioural FTD two years later. He deceased 78 months after the onset of ALS. His mother developed spinal onset ALS at 69 and a mild FTD six months later. She deceased at 73. She carried a A382T missense mutation of the TARDBP gene. The proband9s brother developed ALS at 33 and deceased 75 months after the onset of ALS, without cognitive impairment. No DNA is available of this patients. Conclusions: The proband had two mutations pathogenetic for ALS and FTD, one ( TARDBP ) transmitted from the maternal line, and the other ( C9ORF72 ) from the paternal line. He developed ALS with FTD at 43 years, much earlier than his parents, and had a more severe clinical course. The presence of two pathogenetic mutations in this patients indicates that multiple genetic factors should be considered in pathogenesis of ALS and are likely to modify the clinical course of the disease. Disclosure: Dr. Calvo has nothing to disclose. Dr. Borghero has nothing to disclose. Dr. Cannas has nothing to disclose. Dr. Marrosu has received personal compensation for activities with Biogen Idec and Merck Serono. Dr. Marrosu has received personal compensation in an editorial capacity for Neurological Sciences. Dr. Marrosu has received research support from Serono Foundation, Biogen Idec, Schering Italy, and Sanofi Aventis. Dr. Murru has nothing to disclose. Dr. Floris has nothing to disclose. Dr. Traynor has received personal compensation in an editorial capacity for the journal Neurology. Dr. Renton has nothing to disclose. Dr. Moglia has nothing to disclose. Dr. Canosa has nothing to disclose. Dr. Ilardi has nothing to disclose. Dr. Cammarosano has nothing to disclose. Dr. Brunetti has nothing to disclose. Dr. Ossola has nothing to disclose. Dr. Restagno has nothing to disclose. Dr. Chio has nothing to disclose.

Objective: To assess the recognition of facial expression of primary and social emotions and to correlate it with depressive and behavioural symptoms. Background Facial expressions play an important role in communication processes. Previous studies have indicated that ALS patients have disturbances in emotional perception and memory. Understanding social abilities in ALS patients is therefore a focus for further consideration and concern about the disease and patients management. Design/Methods: A group of 43 consecutive ALS patients and 54 controls were tested to evaluate their ability to recognize facial expressions of basic and social emotions. Further questionnaires were administered to the patients group in order to assess behavioural changes, mood and quality of life. Results: In recognizing facial expressions ALS patients made significantly more errors than healthy controls. Considering the 6 basic emotions, 12 patients and only 2 controls showed performances above the cut-off score. Similarly, patients made more errors than controls in the social emotion test. Bulbar onset or the presence of bulbar signs at the time of the evaluation was not correlated to the error recognition rate of basic and social facial expression. The error rate was not correlated to the patients physical status. We also found a statistically significant correlation between the facial recognition of basic emotions and neurobehavioral symptoms with a higher number of errors corresponding to a higher FrSBe score. Conclusions: Our findings suggest that patients with ALS show a different pattern of recognition in facial expression when compared to healthy adults. Emotional recognition deficits may occur in ALS, particularly with emotional facial expressions, and can arise independently from depressive symptoms. In our series the recognition of facial basic emotions seems to be correlated with the presence of behavioural changes of the frontotemporal type supporting the presence of a diminished social competence. Disclosure: Dr. Moglia has nothing to disclose. Dr. Calvo has nothing to disclose. Dr. Ilardi has nothing to disclose. Dr. Canosa has nothing to disclose. Dr. Cammarosano has nothing to disclose. Dr. Bersano has nothing to disclose. Dr. Bertuzzo has nothing to disclose. Dr. Manera has nothing to disclose. Dr. Moglia has nothing to disclose. Dr. Casale has nothing to disclose. Dr. Montuschi has nothing to disclose. Dr. Chio has nothing to disclose.