The clinical and metabolic signature of UNC13A rs12608932 polymorphism in ALS

Objective. To characterize the clinical and cognitive-behavioral phenotype and brain 18F-2-fluoro- 2-deoxy-D-glucose-PET (18F-FDG-PET) metabolism of ALS patients carrying the rs12608932 variant of the UNC13A gene. Methods. The study population included 1,409 ALS patients without C9orf72, SOD1, TARDBP and FUS mutations identified through a prospective epidemiological ALS register. Control subjects included 1012 geographically-, age- and sex-matched subjects. 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 underwent 18F-FDG-PET. Results. The C/C genotype was associated with an increased risk of ALS (odds ratio: 1.54, 95% c.i. 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, in the Fluency domain of ECAS, and in 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, 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 brain 18F-FDG-PET extending to frontal and precentral areas of the right hemisphere. Conclusions. C/C rs12608932 genotype of UNC13A is associated with a specific motor and cognitive/behavioral phenotype, which reflects on 18F-FDG-PET findings. Our observations highlight the importance of adding the rs12608932 polymorphism in UNC13A to the ALS genetic panel to refine the individual prognostic prediction and reduce heterogeneity in clinical trials.