Behavioral and Cognitive Phenotypes of Patients With Amyotrophic Lateral Sclerosis Carrying SOD1 Variants

Abstract

Background and Objectives:SOD1 variants in patients with amyotrophic lateral sclerosis (ALS) have been associated to peculiar clinical features and disease progression but rarely to cognitive and behavioural impairment. This study aims at describing the features of frontotemporal syndromes in ALS patients 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 neurophysiological 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 to those with no gene variants (SOD1-). To this aim, the occurrence of cognitive and behavioral impairment defined according to current guidelines, the number of pathological test performances based on Italian normative values, and scores of the Frontal Behavioural 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 ALS patients 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 to 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 about 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 ALS patients 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.

High Frequency of Cognitive and Behavioral Impairment in Amyotrophic Lateral Sclerosis Patients with SOD1 Pathogenic Variants

“…A more recent paper on 14 ALS‐SOD1 patients reported that behavioral impairment, as defined by the Strong criteria, was more frequent in ALS‐SOD1 than in ALS patients without SOD1 pathogenic variants. It was also suggested that behavioral impairment was more frequent in subjects carrying SOD1 variants in exon 5 24 . In our series, while confirming that behavioral impairment was more frequent in ALS‐SOD1 than in WT‐ALS, we did not observe any difference in frequency based on the involved exon.…”

“…It was also suggested that behavioral impairment was more frequent in subjects carrying SOD1 variants in exon 5. 24 In our series, while confirming that behavioral impairment was more frequent in ALS-SOD1 than in WT-ALS, we did not observe any difference in frequency based on the involved exon. In all these studies, including ours, no SOD1-ALS patients with FTD was identified.…”

Differences in Cerebral Glucose Metabolism in ALS Patients with and without C9orf72 and SOD1 Mutations

“…Our findings are in line with several postmortem studies that described lesions of the (extrapyramidal) motor and nonmotor systems in SOD1 -positive cases, including subcortical structures as well as frontotemporal cortices [ 53 , 54 ]. A recent study also revealed that behavioral changes are more commonly found in patients carrying SOD1 variants than previously thought [ 18 ].…”

“…Cognitive involvement in SOD1 -ALS is seldomly reported. A recent study however suggested that behavioral changes may be more common than previously thought among patients harboring SOD1 variants [ 18 ].…”

Cognitive disorders in amyotrophic lateral sclerosis

“…К ним относится в первую очередь мутация в гене С9ORF72, в меньшей степени -мутации CHCHD10, SQSTM1, TBK1, CCNF и др. [32,33]. Высока частота когнитивно-поведенческих нарушений и при классических формах БАС.…”