Clinical and Metabolic Signature of UNC13A rs12608932 Variant in Amyotrophic Lateral Sclerosis

Background and ObjectivesTo characterize the clinical and cognitive behavioral phenotype and brain18F-2-fluoro-2-deoxy-d-glucose-PET (18F-FDG-PET) metabolism of patients with amyotrophic lateral sclerosis (ALS) carrying the rs12608932 variant of theUNC13Agene.MethodsThe study population included 1,409 patients with ALS withoutC9orf72, SOD1, TARDBP, andFUSmutations identified through a prospective epidemiologic ALS register. Control participants included 1,012 geographically matched, age-matched, and sex-matched participants. Clinical and cognitive differences between patients carrying the C/C rs12608932 genotype and those carrying the A/A + A/C genotype were assessed. A subset of patients underwent18F-FDG-PET.ResultsThe C/C genotype was associated with an increased risk of ALS (odds ratio: 1.54, 95% confidence interval 1.18–2.01,p= 0.001). Patients with the C/C genotype were older, had more frequent bulbar onset, and manifested a higher rate of weight loss. In addition, they showed significantly reduced performance in the letter fluency test, fluency domain of Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and story-based empathy task (reflecting social cognition). Patients with the C/C genotype had a shorter survival (median survival time, C/C 2.25 years, interquartile range [IQR] 1.33–3.92; A/A + C/C: 2.90 years, IQR 1.74–5.41;p= 0.0001). In Cox multivariable analysis, C/C genotype resulted to be an independent prognostic factor. Finally, patients with a C/C genotype had a specific pattern of hypometabolism on brain18F-FDG-PET extending to frontal and precentral areas of the right hemisphere.DiscussionC/C rs12608932 genotype ofUNC13Ais associated with a specific motor and cognitive/behavioral phenotype, which reflects on18F-FDG-PET findings. Our observations highlight the importance of adding the rs12608932 variant inUNC13Ato the ALS genetic panel to refine the individual prognostic prediction and reduce heterogeneity in clinical trials.