Multiple Sclerosis Families Research Articles

DigiTRAC: Qualitative insights from knowledge users to inform the development of a Digital Toolkit for enhancing resilience among multiple sclerosis caregivers

BackgroundResilience-promoting resources are critically needed to support positive caregiving experiences for multiple sclerosis (MS) caregivers. A digital toolkit offers a flexible way to access and use evidence-based resources that align with MS caregivers’ interests and needs over time. ObjectiveWe explored the perspectives of key knowledge users regarding content areas, features, and other considerations to inform an MS caregiver resilience digital toolkit. MethodsTwenty-two individuals completed a demographic survey as part of this study: 11 MS family caregivers, 7 representatives of organizations providing support services for people with MS and/or caregivers, and 4 clinicians. We conducted nine semi-structured individual interviews and two focus groups. Data were analyzed using content analysis. ResultsParticipants recommended that a digital toolkit should include content focused on promoting MS caregivers’ understanding of the disease, its trajectory and available management options, and enhancing caregiving skills and caregivers’ ability to initiate and maintain behaviours to promote their own well-being. Features that allow for tracking and documenting care recipients’ and caregivers’ experiences, customization of engagement, and connectivity with other sources of support were also recommended. Participants suggested a digital toolkit should be delivered through an app with web browser capabilities accessible on smartphones, tablets, or laptops. They also acknowledged the need to consider how users’ previous technology experiences and issues related to accessibility, usability, privacy and security could influence toolkit usage. ConclusionThese findings will guide future toolkit development and evaluation. More broadly, this study joins the chorus of voices calling for critical attention to the well-being of MS family caregivers.

Multiple Sclerosis Polygenic Risk Is Not Enriched in Three Multicase Families in Comparison to Population-Based Cases

Multiple sclerosis (MS) is a complex neurological and autoimmune disease with an established genetic component. Families with multiple cases of MS are rare but do occur. We hypothesised that multicase families may have a heightened polygenic risk for MS. In this work, we have determined whether polygenic risk for MS is enriched in multicase families in comparison to a case-control cohort. Using the findings from the largest MS genome-wide association study, we calculated a weighted polygenic risk score (wPRS) for MS. We applied this wPRS to study a population-based MS case-control cohort (3,252 people with MS and 5,725 controls) and three multicase MS families (9 individuals with MS, 10 unaffected family members). For both the population-based cohort and the three families, 167 of the 233 known genome-wide significant MS-associated variants were identified and used to calculate the wPRS. Within the population-based cohort, the wPRS was significantly higher in MS cases than controls (P=2.2×10−16). The wPRS of familial MS cases was not significantly different to population-based MS cases (P>0.05). Both affected and unaffected MS family members had higher wPRS than population controls. MS families have a higher polygenic risk for MS, but this did not differ to the polygenic risk of population-based MS cases. Only one family carried the established HLA-DRB1 15:01 MS risk allele, which was present in both affected and unaffected family members. Across families, unaffected family members had an elevated polygenic risk in comparison to population controls indicating that a higher polygenic risk does not fully explain the clustering of MS in families.

Challenged thriving: a qualitative study of resilience in multiple sclerosis family carers during the COVID-19 pandemic

This study investigates the lived experiences of multiple sclerosis family carers during the COVID-19 pandemic and explores the impact of the pandemic on psychological resilience processes using a socioecological framework. Following thematic analysis of interviews, two main findings emerged: first, behavioural vigilance intended to mitigate viral spread eclipsed carers’ needs and deprived them of support resources; and, second, multiple sclerosis carers harboured resilience via practices of gratitude and leveraging interpersonal relationships. Future action is needed to develop public crisis responses that integrate multiple sclerosis carers’ needs, including improved care-continuity models, the alleviation of social isolation and advancements in multifaceted wellness preservation.

Exploring COVID-19 experiences for persons with multiple sclerosis and carers: An Australian qualitative study.

The COVID-19 pandemic continues to impact communities around the world. In this study, we explored the COVID-19 experiences of persons with multiple sclerosis (MS) and carers. Using a qualitative approach, interviews were undertaken with 27 participants residing in Australia (10 persons with MS, 10 carersand 7 MS service providers). Demographic and background data were also collected. Interviews were analysed using an inductive iterative thematic analysis. Across all groups, participants consistently recognized pandemic challenges and impacts for persons with MS and carers, especially due to disruption to routines and services. Emotional and mental health impacts were also highlighted, as anxiety, fear of contracting COVID-19and stress, including relationship stress between persons with MS and carers and family members. Some persons with MS also mentioned physical health impacts, while for carers, the challenge of disruptions included increased demands and reduced resources. In addition to acknowledging challenges, persons with MS and carers also gave examples of resilience. This included coping and adapting by finding new routines and creating space through rest and breaksand through appreciating positives including the benefits of access to telehealth. Additional support is required for persons with MS and carers in navigating the impacts of COVID-19 as the pandemic progresses. In addition to addressing challenges and disruptions, such support should also acknowledge and support the resilience of people with MS and carers and enhance resilience through supporting strategies for coping and adaptation. Service user stakeholders were consulted at the beginning and end of the study. They provided feedback on interview questions and participant engagement, as well as service user perspectives on the themes identified in the current study. Participants were provided with summaries of key themes identified and invited to provide comments.

A continuum of languishing to flourishing: exploring experiences of psychological resilience in multiple sclerosis family caregivers

ABSTRACT Purpose Resilience research in family caregiving in chronic neurological conditions is growing, but multiple sclerosis (MS) caregivers are noticeably absent from this body of work. MS caregivers represent a unique population due to the disease’s early onset, prolonged life expectancy, and heterogeneity. As such, this study aimed to explore MS caregivers’ conceptualizations of resilience, examine MS caregivers’ experiences of resilience development, and determine which assets and resources influence resilience in this role. Methods Twenty-four Canadian MS caregivers were recruited. Semi-structured in-depth interviews were conducted with questions derived from an ecological resilience framework. Data were analysed using reflexive thematic analysis. Results Themes constructed a cyclical resilience model, beginning with encounters with hardship and extending to thriving adjustment. Subthemes included reports of additive challenges, impactful individual and community resources, and multi-level adaptive pathways. Within this cycle, the achievement of healthy adjustment exerted a positive feedback function and informed future responses to lifelong challenges. Conclusions Despite the salience of resilience processes within caregiver testimonies, inadequate resources at societal levels were evident. These findings afford researchers and decision-makers relevant information for designing and implementing resilience-building interventions for MS caregivers that attend to contextual factors and current systemic support deficiencies.

Investigating the role of common and rare variants in multiplex multiple sclerosis families reveals an increased burden of common risk variation

Many multiple sclerosis (MS)-associated common risk variants as well as candidate low-frequency and rare variants have been identified; however, approximately half of MS heritability remains unexplained. We studied seven multiplex MS families, six of which with parental consanguinity, to identify genetic factors that increase MS risk. Candidate genomic regions were identified through linkage analysis and homozygosity mapping, and fully penetrant, rare, and low-frequency variants were detected by exome sequencing. Weighted sum score and polygenic risk score (PRS) analyses were conducted in MS families (24 affected, 17 unaffected), 23 sporadic MS cases, 63 individuals in 19 non-MS control families, and 1272 independent, ancestry-matched controls. We found that familial MS cases had a significantly higher common risk variation burden compared with population controls and control families. Sporadic MS cases tended to have a higher PRS compared with familial MS cases, suggesting the presence of a higher rare risk variation burden in the families. In line with this, score distributions among affected and unaffected family members within individual families showed that known susceptibility alleles can explain disease development in some high-risk multiplex families, while in others, additional genetic contributors increase MS risk.

Profiles of resilience in multiple sclerosis family care-partners: A Canadian cross-sectional study.

Psychological resilience may play an important role in protecting multiple sclerosis care-partners from the negative effects of their support role. However, predictors of resilience in this population have yet to be identified. To identify characteristics predictive of psychological resilience in multiple sclerosis care-partners as informed by the Ecological Model of Resilience. Informal multiple sclerosis care-partners (n = 540) completed an online survey. Psychological resilience was measured using the 25-item Connor-Davidson Resilience Scale. Sociodemographic and care-context predictors of resilience were analyzed using hierarchical regression. The mean resilience score was 59.0 (SD = 7.6) out of a possible 100. Sociodemographic variables accounted for 31% of the variance in resilience scores in multiple sclerosis care-partners. When care-context variables were incorporated into the model, 55% of variance was explained (F[7,320] = 26.824, p < 0.001). Each group of variables remained significant in both low disability and high disability models. Social support was the only individual variable that remained significant across all models (p < 0.05). Multiple sclerosis care-partners differ strikingly from other caregiving populations. Both sociodemographic and care-context variables were found to promote or hinder resilience in multiple sclerosis care-partners. Social support, in particular, may be an important target for promoting resilience in multiple sclerosis care-partners and could be leveraged in future initiatives.

Combination of Genomic and Transcriptomic Approaches Highlights Vascular and Circadian Clock Components in Multiple Sclerosis.

Aiming at exploring vascular components in multiple sclerosis (MS) with brain outflow disturbance, we combined transcriptome analysis in MS internal jugular vein (IJV) wall with WES in MS families with vertical transmission of disease. Main results were the differential expression in IJV wall of 16 MS-GWAS genes and of seven genes (GRIN2A, GRIN2B, IL20RB, IL26, PER3, PITX2, and PPARGC1A) not previously indicated by GWAS but encoding for proteins functionally interacting with MS candidate gene products. Strikingly, 22/23 genes have been previously associated with vascular or neuronal traits/diseases, nine encoded for transcriptional factors/regulators and six (CAMK2G, GRIN2A, GRIN2B, N1RD1, PER3, PPARGC1A) for circadian entrainment/rhythm components. Among the WES low-frequency (MAF ≤ 0.04) SNPs (n = 7) filtered in the 16 genes, the NR1D1 rs17616365 showed significantly different MAF in the Network for Italian Genomes affected cohort than in the 1000 Genome Project Tuscany samples. This pattern was also detected in five nonintronic variants (GRIN2B rs1805482, PER3 rs2640909, PPARGC1A rs2970847, rs8192678, and rs3755863) in genes coding for functional partners. Overall, the study proposes specific markers and low-frequency variants that might help (i) to understand perturbed biological processes in vascular tissues contributing to MS disease, and (ii) to characterize MS susceptibility genes for functional association with disease-pathways.

Age and sex adjusted prevalence and annual incidence of multiple sclerosis in East-Azerbaijan, Iran

BackgroundIncidence and prevalence of multiple sclerosis (MS) is postulated to be rising in recent decades. Therefore, updating and completing the information of patients is essential, especially in high population areas. East-Azerbaijan is the largest and most populous province in the northwest of Iran. This study aimed to determine the prevalence and annual incidence of MS from 2008 to 2017 in East-Azerbaijan. MethodsWe evaluated the data of all patients who had registered at the MS center in the university hospital. The data include nearly all MS patients in the East-Azerbaijan region, because it is the only referral site in the area. All of the reported rates were calculated in 100,000 of the total population. ResultsBy the end of 2017, the number of MS patients was 2995 (residing in the, with 769 (25.67%) men and 2226 (74.32%) women. The prevalence rate was 75.72/100,000 (95 % CI: 73.06-78.48), 38.2 in men (95% CI: 35.5-41.0), and 114.61 for women (95% CI: 109.9-119.4), with a female to male (F/M) ratio of 3:1. The mean annual incidence rate was 7.63/100,000 (95% CI: 5.6-9.3), and this rate was higher in women than men. During the nine years, the incidence rate increased. The patients' mean age was 32.33 ± 8.92, with a peak prevalence in 25-29 years for both genders. In this study, 13.9% of patients had a positive MS family history. ConclusionsThis study showed a high prevalence of MS in the region. There is a significant increase in the incidence of MS during the nine years in East-Azerbaijan. The increment of incidence was more prominent in women. Also, considering the increasing incidence rate, it is concluded that the risk of MS is increasing in this region.

Patients and Partners in Research: Patient and Caregiver Perceptions of Research Engagement and the Role of Their Psychosocial States in Participation.

Multiple sclerosis (MS) is one of the most common, nontraumatic, disabling diseases diagnosed in adults. Self-empowered patients and families are valued members of the MS research team. The objective of this study was to explore patient and family perceptions of the influence of psychosocial state on their willingness to be research partners. Researchers conducted 5 focus groups with MS patients and family from the Upper Midwest Chapter of the National Multiple Sclerosis Society. The researchers asked questions addressing psychosocial factors influencing ability and willingness to work with MS researchers as partners. Relevant themes were identified including comfort level of individuals in formulating research questions, comfort level engaging in research, understanding of the meaning of research and self-perception about skills, research training, and knowledge needs. The findings of this study support the role of MS patients’ perspectives about MS, their understanding of the science of MS, and role of their psychosocial states as all these factors were patient identified as being key to their ability to be active, engaged and willing research participants.

Exome-Sequence Analyses of Four Multi-Incident Multiple Sclerosis Families.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the Central Nervous System (CNS). Currently, it is estimated that 30–40% of the phenotypic variability of MS can be explained by genetic factors. However, low susceptibility variants identified through Genome Wide Association Study (GWAS) were calculated to explain about 50% of the heritability. Whether familial high-risk variants also contribute to heritability is a subject of controversy. In the last few years, several familial variants have been nominated, but none of them have been unequivocally confirmed. One reason for this may be that genetic heterogeneity and reduced penetrance are hindering detection. Sequencing a large number of MS families is needed to answer this question. In this study, we performed whole exome sequencing in four multi-case families, of which at least three affected individuals per family were analyzed. We identified a total of 138 rare variants segregating with disease in each of the families. Although no single variant showed convincing evidence for disease causation, some genes seemed particularly interesting based on their biological function. The main aim of this study was to provide a complete list of all rare segregating variants to provide the possibility for other researchers to cross-check familial candidate genes in an unbiased manner.

Genetic analysis of nucleotide-binding leucine-rich repeat (NLR) receptors in multiple sclerosis.

Genetic and functional analyses of the inflammasome suggest a role for this multiprotein complex in the biological mechanisms leading to the onset and progression of multiple sclerosis (MS). Nucleotide-binding, leucine-rich repeat (NLR) receptors trigger the activation and assembly of specific inflammasomes in response to danger signals. Mining exome sequencing data from 326 MS patients identified 17 rare missense or nonsense variants in NLR family pyrin domain containing 1 (NLRP1), NLRP3, NLRP6, NLRP7 and NLR family CARD domain containing 4 (NLRC4). Genotyping these variants in 2503 MS cases and 1076 healthy controls did not result in statistically significant differences between groups, and segregation analysis within MS families was largely unsupportive of co-segregation of these variants with disease. However, the identification of MS patients harboring rare homozygote variants in NLRP1 (p.Ile601Phe and p.Ser1387Ile), a variant in NLRP3 (p.Leu832Ile) resulting in the substitution of a critical amino acid for the formation of its leucine-rich repeat domain, and several MS patients with NLRC4 variants (p.Arg310Ter and p.Glu600Ter) causing protein truncations suggest that rare protein-altering variants in inflammasome-activating NLR receptors may contribute to MS risk.

Fatigue and Suicidal Ideation in People With Multiple Sclerosis: The Role of Social Support.

Fatigue and poor sleep quality are among the most common patient-reported problems associated with multiple sclerosis (MS). Social support, on the other hand, is often found to be positively associated with quality of life in patients with neurological diseases. Studies also show that suicidal ideation (SI) levels in MS are elevated compared to the general population. Thus, the aim of this study is to assess the associations between fatigue, social support, and SI in patients with MS. Out of 184 MS patients asked to participate in this cross-sectional study, 156 agreed (RR 69.8%; 75% female; mean age: 39.95 ± 9.97 years). Patients filled-in the Multidimensional Fatigue Inventory-20, the Pittsburgh Sleep Quality Index, the Multidimensional Scale of Perceived Social Support and the subscale of the General Health Questionnaire-28 focused on assessing SI. Models were controlled for age, gender, disease duration, functional disability, and sleep quality. Data were analyzed using multiple linear regressions. SI was positively associated with lower sleep quality and four types of fatigue: general, mental, reduced activity, and reduced motivation (p < 0.05). Physical fatigue was not significantly associated with SI. Social support was negatively associated with SI in all models. The final models under study explained from 24.3 to 29.7% of the total variance in SI. SI yielded associations with both sleep quality and fatigue, with the exception of physical fatigue. Information provided by physicians on sleep management, and a psychosocial intervention focused on people who provide support for patients with MS (family, friends, and significant others) may reduce levels of SI.

Economic Burden of the Out-of-Pocket Expenses for People with Multiple Sclerosis in France.

BackgroundPeople with chronic diseases in France frequently incur out-of-pocket expenses (OOPE) related to their medical care.ObjectiveThe objective of this study was to evaluate OOPE incurred by people with multiple sclerosis (MS) with respect to direct non-medical and medical expenditure.MethodsData were collected through a web-based survey using an online patient community platform (Carenity). The survey questionnaire contained 87 questions (numerical response or Likert scale) and took less than 30 min to complete. Participants rated their disability on a ten-point scale.ResultsIn total, 376 patients, with a mean age of 48.3 years (95% confidence interval [CI] 47.2–49.5), participated in the survey. Participants estimated that they spent an average of €127 each month on OOPE for their MS, principally on physician consultations (mean annual expenditure of €75 by 183 participants), non-physician consultations (€358 by 135 participants) and non-prescription medication (mean expense of €67 per pharmacy visit by 234 patients). In total, 77% of participants who needed adaptations to their home or vehicle because of their MS contributed to the cost. No obvious relationship between OOPE and self-rated disability was observed. A total of 61.4% of participants reported that they had to choose between spending money on MS care or on their family and social life.ConclusionsMost patients with MS incurred significant OOPE linked to consultations, non-prescription medications or home equipment and medical equipment. These outlays could lead to dilemmas when choosing between spending on MS care or family or social life.

Expression of Concern: Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.

Expression of Concern: Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.

Psoriasis in family members of patients with multiple sclerosis

BackgroundIt has been noted both anecdotally and in a selection of studies that the incidence of multiple sclerosis (MS) and psoriasis may be related, however the nature of that association is unclear. Clustering among families of multiple autoimmune diseases may be linked to genetic factors. Whether family members of those with MS are at increased risk of psoriasis is not well established. MethodsA systematic review and meta-analysis was performed according to recommended PRISMA guidelines. Data from studies assessing the proportion or effect size of psoriasis cases reported for families or relatives of MS cases versus families or relatives of control cases without MS were extracted and meta-analysed. ResultsFrom a pooled unadjusted meta-analysis of 5 studies that met criteria, we found that family members of MS patients were at increased risk of psoriasis (OR 1.45 95% CI 1.07, 1.97). ConclusionFamily members of those with MS may be at greater risk of developing psoriasis.

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.

Clinical and Demographic Features in Iranian Multiple Sclerosis Patients: a Systematic Review and Meta-Analysis

Aim: This study was conducted to determine the clinical and demographic features in Iranian multiple sclerosis (MS) patients including clinical courses, positive MS family history, disability and age of disease onset. Materials &amp; methods: All stages of the study were reported according to the PRISMA guidelines. A systematic review of published literature in Persian and English journals with a comprehensive search was conducted on English international databases including Scopus, PubMed/Medline, Cochrane Library, Science Direct, Web of Science, Embase, PsycINFO, as well as the Google Scholar search engine and national databases. Results: The prevalence of clinical courses of relapsing remitting, primary progressive, secondary progressive and relapsing progressive in Iranian patients with MS was 77.1% (95% CI: 72.2–81.3), 6.2% (95% CI: 4.1–9.2), 9.5% (95% CI: 6.8–13.1) and 0.4% (95% CI: 0.2–0.8), respectively. Positive family history of MS in Iranian MS patients was 8.9% (95% CI: 6.9–11.4). The mean age of disease onset was 28.9 years (95% CI: 27.8–30.1). Conclusion: The results of this meta-analysis in an Iranian population can provide useful information for neurologists and healthcare.

Familial multiple sclerosis patients have a shorter delay in diagnosis than sporadic cases

BackgroundThe diagnosis of multiple sclerosis (MS) is still complicated despite improvement in diagnostic guidelines. This means that time from first symptom to diagnosis in some cases is prolonged. Many aspects of MS aetiology are unknown, but the involvement of a genetic component is well established. This is also highlighted by the occurrence of familial MS cases, which represent 10–20% of all MS cases. We hypothesize that subsequent family members in a MS family, have a shorter time from onset of disease to diagnosis compared to sporadic MS cases. To investigate this, we have conducted a register study comparing time from onset to diagnosis in familial and sporadic MS cases. MethodsThis is a nationwide register study based on information from the Danish Multiple Sclerosis Registry and the Danish Civil Registration System. We included familial (first-degree relatives) and sporadic MS cases and calculated time lag between onset and diagnosis of MS for sporadic MS cases and for1st, 2nd and 3rd family members within the MS families. Median test and Cox regression were the statistical methods used to compare the familial and sporadic groups. ResultsWe found that 2nd and 3rd affected family member had a significant shorter time from first symptom to diagnosis compared to sporadic MS cases (2nd family member: Hazard Ratio (HR): 1.12, CI: 1.03–1.21, p = 0.007 adjusted: HR: 0.95 p = 0.22, CI 0.89-1-03 and 3rd family member HR: 1.64 CI: 1.22–2.20, p = 0.001 adjusted model: HR: 1.70, p-value: 0.000, CI: 1.32–2.18). The same difference was not seen between 1st family members and sporadic cases (HR: 1.05, CI: 0.98–1.13, p = 0.15, adjusted: 0.98, p-value: 0.53, CI: 0.91–1.05). Estimated marginal mean delay in the four groups were 4.60 years (95% CI: 4.11–5.01) in1st family members, 4.23 years (3.71–4.75) in 2nd family members, 2.11 years (0.95–3.26) in 3rd family members and 4.99 years (4.99–4.99) in sporadic MS cases. ConclusionThe 2nd and 3rd family members in MS families tend do get diagnosed faster than sporadic cases. This has implications in the diagnostic process of familial MS cases.

Genetic Association and Altered Gene Expression of CYBB in Multiple Sclerosis Patients.

Multiple sclerosis (MS) is a chronic neurological disorder characterized by inflammation, demyelination, and axonal damage. Increased levels of reactive oxygen species (ROS), produced by macrophages and leading to oxidative stress, have been implicated as mediators of demyelination and axonal injury in both MS and experimental autoimmune encephalomyelitis, the murine model of the disease. On the other hand, reduced ROS levels can increase susceptibility to autoimmunity. In this work, we screened for association with MS 11 single nucleotide polymorphisms (SNPs) and two microsatellite markers in the five genes (NCF1, NCF2, NCF4, CYBA, and CYBB) of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) system, the enzymatic pathway producing ROS in the brain and neural tissues, in 347 Finnish patients with MS and 714 unaffected family members. This analysis showed suggestive association signals for NCF1 and CYBB (lowest p = 0.038 and p = 0.013, respectively). Functional relevance for disease predisposition was further supported for the CYBB gene, by microarray analysis in CD4+/− mononuclear cells of 21 individuals from five Finnish multiplex MS families, as well as by real-time RT-PCRs performed on RNA extracted from peripheral blood mononuclear cells of an Italian replication cohort of 21 MS cases and 21 controls. Our results showed a sex-specific differential expression of CYBB, suggesting that this gene, and more in general the NOX2 system, deserve to be further investigated for their possible role in MS.