Investigating the prevalence of mutations in amyotrophic lateral sclerosis: insights from an Italian cohort.

The gene encodes mitofusin 2, a key protein for mitochondrial fusion, transport, maintenance and cell communication. mutations are primarily linked to Charcot-Marie-Tooth disease type 2A. However, a few cases of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis/frontotemporal dementia phenotypes with concomitant mutations have been previously reported. This study examines the clinical and genetic characteristics of an Italian cohort of amyotrophic lateral sclerosis patients with rare, non-synonymous mutations. A group of patients ( = 385) diagnosed with amyotrophic lateral sclerosis at our Neurology Units between 2008 and 2023 underwent comprehensive molecular testing, including . After excluding pathogenic mutations in the main amyotrophic lateral sclerosis-related genes (i.e. , , and ), variants were classified based on the American College of Medical Genetics and Genomics guidelines, and demographic and clinical data of -mutated patients were retrieved. We identified 12 rare, heterozygous, non-synonymous variants in 19 individuals (4.9%). Eight of these variants, carried by nine patients (2.3%), were either pathogenic, likely pathogenic or variants of unknown significance according to the American College of Medical Genetics and Genomics guidelines. Among these patients, four exhibited a familial pattern of inheritance. The observed phenotypes included classic and bulbar amyotrophic lateral sclerosis, amyotrophic lateral sclerosis/frontotemporal dementia, flail arm, flail leg and progressive muscular atrophy. Median survival after disease onset was extremely variable, ranging from less than 1 to 13 years. This study investigates the prevalence of rare, non-synonymous variants within an Italian cohort of amyotrophic lateral sclerosis patients, who have been extensively investigated, enhancing our knowledge of the underlying phenotypic spectrum. Further research is needed to understand whether mutations contribute to motor neuron disease and to what extent. Improving our knowledge regarding the genetic basis of amyotrophic lateral sclerosis is crucial both in a diagnostic and therapeutic perspective.