ObjectiveTo assess the association of the degree of severity of motor impairment to that of cognitive impairment in a large cohort of patients with amyotrophic lateral sclerosis (ALS).MethodsThis is a population-based cross-sectional study on patients with ALS incident in Piemonte, Italy, between 2007 and 2015. Cognitive status was classified according to the revised ALS–FTD Consensus Criteria. The King system and the Milano Torino Staging system (MiToS) were used for defining the severity of motor impairment.ResultsOf the 797 patients included in the study, 163 (20.5%) had ALS–frontotemporal dementia (FTD), 38 (4.8%) cognitive and behavioral impairment (ALScbi), 132 (16.6%) cognitive impairment (ALSci), 63 (7.9%) behavioral impairment (ALSbi), 16 (2.0%) nonexecutive impairment, and 385 (48.2%) were cognitively normal. According to King staging, the frequency of cases with ALS-FTD progressively increased from 16.5% in stage 1–44.4% in stage 4; conversely, the frequency of ALSci, ALSbi, and ALScbi increased from King stage 1 to King stage 3 and decreased thereafter. A similar pattern was observed with the MiToS staging. ALS-FTD was more frequent in patients with bulbar involvement at time of cognitive testing. Patients with C9ORF72 expansion (n = 61) showed more severe cognitive impairment with increasing King and MiToS stages.ConclusionOur findings suggest that ALS motor and cognitive components may worsen in parallel, and that cognitive impairment becomes more pronounced when bulbar function is involved. Our data support the hypothesis that ALS pathology disseminates in a regional ordered sequence, through a cortico-efferent spreading model.

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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.

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IMPORTANCE Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.OBJECTIVE To identify the genetic variants associated with juvenile ALS. DESIGN, SETTING, AND PARTICIPANTSIn this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. MAIN OUTCOMES AND MEASURESDe novo variants present only in the index case and not in unaffected family members. RESULTSTrio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.CONCLUSIONS AND RELEVANCE These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

ObjectiveTo assess the burden of rare genetic variants and to estimate the contribution of known ALS genes in an Italian population-based cohort we performed whole genome sequencing in 959 ALS patients 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 ALS patients 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 utility.

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