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

Andrea Calvo; Antonio Canosa; Cristina Moglia; Umberto Manera; Maurizio Grassano; Rosario Vasta; Francesca Palumbo; Paolo Cugnasco; Salvatore Gallone; Maura Brunetti; Fabiola De Marchi; Vincenzo Arena; Marco Pagani; Clifton Dalgard; Sonja W Scholz; Ruth Chia; Lucia Corrado; Sandra Dalfonso; Letizia Mazzini; Bryan J Traynor; Adriano Chio

doi:10.1212/NXG.0000000000200033

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

Neurol Genet. 2022 Oct 26;8(6):e200033. doi: 10.1212/NXG.0000000000200033. eCollection 2022 Dec.

Authors

Andrea Calvo¹, Antonio Canosa¹, Cristina Moglia¹, Umberto Manera¹, Maurizio Grassano¹, Rosario Vasta¹, Francesca Palumbo¹, Paolo Cugnasco¹, Salvatore Gallone¹, Maura Brunetti¹, Fabiola De Marchi¹, Vincenzo Arena¹, Marco Pagani¹, Clifton Dalgard¹, Sonja W Scholz¹, Ruth Chia¹, Lucia Corrado¹, Sandra Dalfonso¹, Letizia Mazzini¹, Bryan J Traynor¹, Adriano Chio¹

Affiliation

¹ "Rita Levi Montalcini" Department of Neuroscience (A. Calvo, A. Canosa, C.M., U.M., M.G., R.V., F.P., P.C., M.B., A. Chio), University of Torino, Turin, Italy; Neurology 1 (A. Calvo, A. Canosa, C.M., U.M., S.G., A. Chio), Azienda Universitario-Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy; Neuroscience Institute of Turin (NIT) (A. Calvo, A. Chio), Turin, Italy; Institute of Cognitive Sciences and Technologies (A. Canosa, M.P., A. Chio), C.N.R., Rome, Italy; ALS Center (F.D.M., L.M.), Department of Neurology, Maggiore della Carità Hospital, University of Eastern Piedmont, Novara, Italy; Positron Emission Tomography Centre AFFIDEA-IRMET S.p.A. (V.A.), Turin, Italy; Department of Medical Radiation Physics and Nuclear Medicine (M.P.), Karolinska University Hospital, Stockholm, Sweden; Department of Anatomy (C.D.), Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD; The American Genome Center (C.D.), Uniformed Services University of the Health Sciences, Bethesda, MD; Neurodegenerative Diseases Research Unit (S.W.S.), Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD; Department of Neurology (S.W.S., B.J.T.), Johns Hopkins University Medical Center, Baltimore, MD; Neuromuscular Diseases Research Section (R.C., B.J.T.), Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD; and Department of Health Sciences (L.C., S.D.D.), University of Eastern Piedmont, Novara, Italy.

Abstract

Background and objectives: To characterize the clinical and cognitive behavioral phenotype and brain ¹⁸F-2-fluoro-2-deoxy-d-glucose-PET (¹⁸F-FDG-PET) metabolism of patients with amyotrophic lateral sclerosis (ALS) carrying the rs12608932 variant of the UNC13A gene.

Methods: The study population included 1,409 patients with ALS without C9orf72, SOD1, TARDBP, and FUS mutations 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 underwent ¹⁸F-FDG-PET.

Results: The 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 brain ¹⁸F-FDG-PET extending to frontal and precentral areas of the right hemisphere.

Discussion: 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 variant in UNC13A to the ALS genetic panel to refine the individual prognostic prediction and reduce heterogeneity in clinical trials.