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Individual Oligogenic Background in p.D91A-SOD1 Amyotrophic Lateral Sclerosis Patients.

ABSTRACT: The p.D91A is one of the most common ALS-causing SOD1 mutations and is known to be either recessive or dominant. The homozygous phenotype is characterized by prolonged survival and slow progression of disease, whereas the affected heterozygous phenotypes can vary. To date, no genetic protective factors located close to SOD1 have been associated with the mild progressive homozygous phenotype. Using Next Generation Sequencing (NGS), we characterized a small cohort of sporadic and familial p.D91A-SOD1 heterozygous (n = 2) or homozygous (n = 5) ALS patients, to reveal any additional contributing variant in 39 ALS-related genes. We detected unique sets of non-synonymous variants, four of which were of uncertain significance and several in untranslated regions of ALS-related genes. Our results supported an individual oligogenic background underlying both sporadic and familial p.D91A cases irrespective of their p.D91A mutant alleles. We suggest that a comprehensive genomic view of p.D91A-SOD1 ALS patients may be useful in identifying emerging variants and improving disease diagnosis as well as guiding precision medicine.

SUBMITTER: Gentile G

PROVIDER: S-EPMC8701978 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Individual Oligogenic Background in p.D91A-SOD1 Amyotrophic Lateral Sclerosis Patients.

Gentile Giulia G Perrone Benedetta B Morello Giovanna G Simone Isabella Laura IL Andò Sebastiano S Cavallaro Sebastiano S Conforti Francesca Luisa FL

Genes 20211123 12

The p.D91A is one of the most common ALS-causing SOD1 mutations and is known to be either recessive or dominant. The homozygous phenotype is characterized by prolonged survival and slow progression of disease, whereas the affected heterozygous phenotypes can vary. To date, no genetic protective factors located close to SOD1 have been associated with the mild progressive homozygous phenotype. Using Next Generation Sequencing (NGS), we characterized a small cohort of sporadic and fam ...[more]

PMID: 34946792

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Project description:Background and objectivesSOD1 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.MethodsItalian 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.ResultsAmong 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.DiscussionOur 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.

Project description:BackgroundInnate neuroimmune dysfunction is a pathobiological feature of amyotrophic lateral sclerosis (ALS). However, links, if any, between disease and adaptive immunity are poorly understood. Thus, the role of T cell immunity in disease was investigated in human G93A superoxide dismutase 1 (SOD1) transgenic (Tg) mice and subsequently in ALS patients.Methods and findingsQuantitative and qualitative immune deficits in lymphoid cell and T cell function were seen in G93A-SOD1 Tg mice. Spleens of Tg animals showed reductions in size, weight, lymphocyte numbers, and morphological deficits at terminal stages of disease compared to their wild-type (Wt) littermates. Spleen sizes and weights of pre-symptomatic Tg mice were unchanged, but deficits were readily seen in T cell proliferation coincident with increased annexin-V associated apoptosis and necrosis of lymphocytes. These lymphoid deficits paralleled failure of Copolymer-1 (COP-1) immunization to affect longevity. In addition, among CD4(+) T cells in ALS patients, levels of CD45RA(+) (naïve) T cells were diminished, while CD45RO(+) (memory) T cells were increased compared to age-matched caregivers. In attempts to correct mutant SOD1 associated immune deficits, we reconstituted SOD1 Tg mice with unfractionated naïve lymphocytes or anti-CD3 activated CD4(+)CD25(+) T regulatory cells (Treg) or CD4(+)CD25(-) T effector cells (Teff) from Wt donor mice. While naive lymphocytes failed to enhance survival, both polyclonal-activated Treg and Teff subsets delayed loss of motor function and extended survival; however, only Treg delayed neurological symptom onset, whereas Teff increased latency between disease onset and entry into late stage.ConclusionsA profound and progressive immunodeficiency is operative in G93A-SOD1 mice and is linked to T cell dysfunction and the failure to elicit COP-1 neuroprotective immune responses. In preliminary studies T cell deficits were also observed in human ALS. These findings, taken together, suggest caution in ascribing vaccination outcomes when these animal models of human ALS are used for study. Nonetheless, the abilities to improve neurological function and life expectancy in G93A-SOD1 Tg mice by reconstitution with activated T cells do provide opportunities for therapeutic intervention.

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Individual Oligogenic Background in p.D91A-SOD1 Amyotrophic Lateral Sclerosis Patients.

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Individual Oligogenic Background in p.D91A-<i>SOD1</i> Amyotrophic Lateral Sclerosis Patients.

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