Clinical and molecular features of patients with amyotrophic lateral sclerosis and SOD1 mutations: a monocentric study

Delia Gagliardi; Paolo Ripellino; Megi Meneri; Roberto Del Bo; Sara Antognozzi; Giacomo Pietro Comi; Claudio Gobbi; Antonia Ratti; Nicola Ticozzi; Vincenzo Silani; Dario Ronchi; Stefania Corti

doi:10.3389/fneur.2023.1169689

Clinical and molecular features of patients with amyotrophic lateral sclerosis and SOD1 mutations: a monocentric study

Front Neurol. 2023 May 17:14:1169689. doi: 10.3389/fneur.2023.1169689. eCollection 2023.

Authors

Delia Gagliardi^{1

2}, Paolo Ripellino³, Megi Meneri^{1

2}, Roberto Del Bo¹, Sara Antognozzi¹, Giacomo Pietro Comi^{1

4}, Claudio Gobbi^{3

5}, Antonia Ratti^{6

7}, Nicola Ticozzi^{1

6}, Vincenzo Silani^{1

6}, Dario Ronchi¹, Stefania Corti^{1

2}

Affiliations

¹ Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), Dino Ferrari Centre, University of Milan, Milan, Italy.
² Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
³ Department of Neurology, Neurocenter of Southern Switzerland EOC, Lugano, Switzerland.
⁴ Neuromuscular and Rare Diseases Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁵ Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.
⁶ Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.
⁷ Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.

Abstract

Introduction: SOD1 was the first gene associated with both familial and sporadic forms of amyotrophic lateral sclerosis (ALS) and is the second most mutated gene in Caucasian ALS patients. Given their high clinical and molecular heterogeneity, a detailed characterization of SOD1-ALS patients could improve knowledge about the natural history of this disease. Here, the authors aimed to provide a clinical and molecular description of a monocentric cohort of SOD1-ALS patients.

Methods: Amyotrophic lateral sclerosis (ALS) patients referring to the neurology unit of our center between 2008 and 2021 were clinically assessed and underwent molecular testing for SOD1. Segregation studies in available family members and in silico analysis were performed to sustain the pathogenicity of the identified SOD1 variants.

Results: Among the 576 patients in our cohort, we identified 19 individuals harboring a mutation in SOD1 (3.3%), including 15 (78.9%) with a familial and four (21.1%) with a sporadic form. The spinal onset of the disease was observed in all patients, and survival was extremely variable, ranging from 8 months to over 30 years. Twelve different SOD1 missense variants were identified in our cohort, including one novel mutation (p.Pro67Leu).

Discussion: In the present series, we provided the first description of an Italian monocentric cohort of SOD1-ALS patients, and we expanded the repertoire of SOD1 mutations. Our cohort presents several remarkable features, including variable expressivity in the same family, atypical presentation (ataxia, cognitive impairment, and other extra-motor symptoms), and different modes of inheritance of a given mutation in the same family. Given the recent authorization of SOD1-directed antisense oligonucleotide for use in SOD1-ALS patients, we recommend prompt screening for SOD1 mutations in novel ALS patients with familiar or sporadic presentations.

Keywords: SOD1 variants; SOD1-ALS; amyotrophic lateral sclerosis; cohort; superoxide dismutase.