Abstract
BACKGROUND AND OBJECTIVES: SOD1 variants in patients with amyotrophic lateral sclerosis (ALS) have been associated with peculiar clinical features and disease progression but rarely with cognitive and behavioral impairment. This study aims at describing the features of frontotemporal syndromes in patients with ALS carrying SOD1 variants. METHODS: Italian patients with ALS were consecutively enrolled between 2012 and 2020 at our Motor Neuron Disease Center. All underwent clinical assessment, extensive neurophysiologic test battery for the evaluation of cognitive functions and behavior, and targeted next-generation sequencing of SOD1, FUS, TARDBP, VCP, PFN1, TUBA4A, OPTN, SQSTM1, UBQLN2, and C9orf72 genes. Neuropsychological profiles of SOD1+ patients (SOD1+) were compared with those with no gene variants (SOD1-). To this aim, the occurrence of cognitive and behavioral impairment defined according to the current guidelines, the number of pathologic test performances based on Italian normative values, and scores of the Frontal Behavioral Inventory were collected. RESULTS: Among 288 patients consecutively examined, we identified 8 known pathogenic SOD1 variants and one variant of uncertain significance (p.Ser26Asn) not previously described in 14 patients with ALS belonging to 11 families. The clinical phenotypes were mainly characterized by predominant lower motor neuron involvement with onset at the lower limbs, and one patient had bulbar onset. SOD1+ patients (n = 14) were compared with SOD1- patients (N = 274). SOD1+ patients were younger than SOD1-, and both groups had similar functional motor disabilities and disease duration. Based on the overall neuropsychological findings, the percentage of SOD1+ and SOD1- patients with altered profiles were approximately 60%. However, behavioral impairment defined by the Strong criteria, and most commonly featuring with irritability and mental rigidity, was more frequent in SOD1+ than SOD1- patients and mainly associated with variants in exon 5. Conversely, cognitive impairment was mainly found in SOD1- patients. DISCUSSION: Our findings from a large cohort of deeply phenotyped patients with ALS demonstrated that behavioral involvement is more common than previously thought among patients harboring SOD1 variants and that it is independent from patients' age and disease stage. These findings could be relevant for the assessment of clinical trial outcomes and disease management.