Familial Multiple Sclerosis Research Articles

The role of parental consanguinity and familial aggregation in development of multiple sclerosis: a case–control study

BackgroundSeveral studies pointed out the importance of genetic risk factors such as parental consanguinity (PC) and familial multiple sclerosis (FMS) in the risk of MS. This study aimed to investigate the PC and FMS among people with MS (pwMS) in Isfahan, Iran.MethodsThis case–control study was conducted on pwMS from the MS clinic of Kashani Hospital, Isfahan, Iran, in October 2023. A group of healthy controls (HC) were also recruited. Data on demographic and clinical characteristics and history of PC and FMS were collected from participants. The relationships between PC, FMS, and developing MS were assessed using multinomial logistic regression analysis. The odds ratio (OR) with a 95% confidence interval (CI) was computed.ResultsA total number of 4264 pwMS and 400 HCs were included. The prevalence of PC and FMS among pwMS were 29.3% and 24%, respectively. Multinomial logistic regression adjusted for age and sex indicated that the odds of developing MS were significantly associated with a history of PC (OR = 3.03, 95% CI 2.23 to 4.13, p < 0.001) and FMS (OR = 5.42, 95% CI 3.51 to 8.38, p < 0.001).ConclusionPC and FMS can increase the risk of developing MS. They should be considered along with other risk factors for developing MS. A comprehensive conclusion requires further research.

Consanguineous marriage among familial multiple sclerosis subjects: A national registry-based study

BackgroundThe rising prevalence of familial multiple sclerosis (MS) in Iran has spurred interest in the potential impact of parental consanguinity on the risk of developing the disease. This study aims to aggregate current knowledge on parental consanguinity and its possible effect on MS risk, particularly among familial MS patients from various regions and ethnicities in Iran. The objective is to enhance the understanding of MS genetics and encourage further research in this field. Materials and methodsA cross-sectional study was conducted on clinically definite familial MS (FMS) patients registered in the nationwide MS registry of Iran (NMSRI). Data were extracted and supplemented with structured telephone follow-ups to gather detailed histories of MS in relatives and the familial relationships of the patients' parents. A family penetration score was proposed. Descriptive statistics and inferential statistical tests were used to analyze the data at a significance level of 0.05, adhering to ethical guidelines. ResultsOut of 19,911 individuals registered in the NMSRI, 2307 FMS patients across 13 provinces were included in the final analysis. Among these, 385 (19.3 %) reported parental consanguinity, with 283 (14.2 %) having parents who were cousins and 102 (5.1 %) having parents who were distant relatives. The data showed no significant association between parental kinship and variables such as MS phenotype, number of affected relatives with MS, hospitalization rates, and expanded disability status scale score. Similarly, MS severity did not differ based on parental consanguinity (P-value >0.05). While the rate of consanguineous marriage was higher among patients with an onset age less than 18 years, there was no statistically significant difference in disease onset age based on parental consanguinity status. ConclusionOur study highlights the complexity of factors influencing MS development, including genetic and environmental components. These results highlight the need for further research to achieve a more comprehensive understanding of MS etiology.

Investigation of Novel Variants in Familial Multiple Sclerosis Through Family-based Association Tests and Segregation Analyses (S17.007)

Investigation of Novel Variants in Familial Multiple Sclerosis Through Family-based Association Tests and Segregation Analyses (S17.007)

Familial vs sporadic multiple sclerosis in the Israeli population: Differences in ethnicity distribution and disease progression, with anticipation in successive generations

BackgroundMultiple Sclerosis (MS) may cluster in families, an entity known as familial MS (FMS), possibly due to aggregation of genetic and environmental factors. Though previous studies have characterized FMS in different populations, no study to the best of our knowledge has yet characterized FMS in the unique Israeli population, which is comprised of relatively endogamous ethnicities. Our goal in this study was to compare demographic and clinical characteristics between FMS and sporadic MS (SMS), and to search for intra-familial patterns. MethodsIn a retrospective study of 101 FMS patients and 508 SMS patients, ethnicity and sex distribution was assessed. Clinical aspects were compared between 172 paired FMS and SMS patients, matched for sex, age and ethnicity, and between generations of the FMS cohort. ResultsFemales comprised 75.3 % of FMS and 67.5 % of SMS patients (p = 0.1). Ethnic distribution was significantly different between FMS and SMS (p = 0.014), with the former comprising a higher proportion of Christian-Arabs (15.4% vs. 5.1 %, p = 0.004) and lower proportion of Jews (60% vs. 74.2 %, p = 0.016). Age at disease onset or diagnosis, frequency of positive Oligoclonal bands and comorbidity of other autoimmune/inflammatory disease or chronic diseases was comparable between FMS and SMS, yet motor symptoms at onset were more prevalent in FMS (34% vs. 20 %, p = 0.02). Annualized relapse rates throughout 10 years from onset were comparable. Among FMS, mean Expanded-Disability-Status-Scale (EDSS) and slope of deterioration in EDSS over 20 years from diagnosis were higher (p = 0.0004 and p = 0.023, respectively), time to EDSS ≥ 3 was shorter (7.1 vs. 12.1 years, HR 1.6, p = 0.036) and MS-Severity-Score (MSSS) was higher (3.84 vs. 2.95, p = 0.04), compared to SMS. Following adjustment for smoking, which tended to be higher among FMS patients (P = 0.06), mean EDSS and slope of deterioration in EDSS over 20 years remained significantly higher (p = 0.0006 and p = 0.025, respectively) in FMS, time to EDSS ≥ 3 tended to be higher (HR 1.5, p = 0.06), while MSSS was comparable. An inter-generational analysis of the total FMS cohort, as well as an intra-familial analysis, both adjusted for year of diagnosis, revealed significantly earlier age of onset (p < 0.0001 and p < 0.0001) and diagnosis (p = 0.001 and p < 0.0001) in the younger compared to the older generations, respectively. ConclusionIn this Israeli cohort, the proportions of specific ethnicities differ between FMS and SMS, indicating that FMS has a population-specific prevalence pattern, and that further investigation for susceptibility genes is warranted. Disease progression is faster in FMS patients and anticipation is observed in families with multiple cases of MS. Closer surveillance and application of a pro-active induction or early highly-effective therapeutic strategy for FMS patients should be considered, to reduce high disease activity and fast disability progression.

Multiple Sclerosis in Comparison to Sporadic Multiple Sclerosis in Iraqi Patients

Multiple Sclerosis (MS) is a complex autoimmune disease affecting the central nervous system, characterized by diverse symptoms based on lesion locations. Familial MS (FMS) indicates a genetic predisposition, potentially leading to a more severe disease course than sporadic MS, which lacks familial clustering. This distinction is critical for diagnosing and treating MS, particularly in the Iraqi patient population. The study aims to evaluate and compare the clinical and radiological features of FMS and sporadic MS among patients at the Baghdad Teaching Hospital's MS outpatient clinic. In this observational retrospective cross-sectional study, conducted from July 1, 2023, to December 31, 2023, at the Baghdad M.S outpatient clinic within the Medical City complex in Baghdad, Iraq, 100 MS patients were enrolled, with an equal division between FMS (n=50) and sporadic MS (n=50) cases. Participants were selected based on a definitive MS diagnosis, with FMS patients having a first or second-degree relative with MS. Data were collected via a questionnaire focusing on demographics, clinical presentations, MRI findings, and EDSS scores. Analysis was performed using SPSS version 26, employing Pearson Chi-square tests and Fisher's Exact test, with significance set at P ≤ 0.05. The demographic analysis revealed a predominant female representation (89%), with a significant age range between 20-30 years (48%). Time to diagnosis was notably longer for FMS cases, averaging 25.235 months, compared to 10.295 months for sporadic cases (P=0.002). Clinical presentations did not significantly differ between groups, but FMS cases exhibited greater disability severity, with higher EDSS scores indicating moderate to severe disability in 31% of FMS cases compared to only 19% in sporadic cases (P=0.035). MRI findings showed a higher prevalence of spinal cord and corpus callosum lesions in FMS (P=0.001 and P=0.027, respectively), with no significant differences in juxtacortical, cortical, or infratentorial lesions. This study illuminates that MS mainly affects females in their twenties and thirties, with familial MS cases taking longer to diagnose than sporadic ones. Familial cases exhibited more severe disabilities and more lesions in the spinal cord and corpus callosum. This indicates a complex interplay between genetics and MS, underscoring the importance of further research to enhance our understanding of the disease.

Differences in the Differential Expression of MicroRNAs Between Patients with Familial Multiple Sclerosis and Those with Sporadic Multiple Sclerosis

Differences in the Differential Expression of MicroRNAs Between Patients with Familial Multiple Sclerosis and Those with Sporadic Multiple Sclerosis

Exclusive breastfeeding may be a protective factor in individuals with familial multiple sclerosis. A population registry-based case-control study

BackgroundMultiple sclerosis (MS) is an immune-mediated disease that affects the central nervous system, which most likely results from the interplay between environmental and genetic factors. The aim of our study was to assess the effect of breastfeeding on the risk of developing familial multiple sclerosis (fMS) in persons with positive MS history, being the first such investigation performed in fMS cohort. MethodsA case-control study based on the Belgrade population MS Registry was conducted. Cases for the sporadic MS (sMS) control group were randomly selected from the Registry, and matched with individuals with fMS at a ratio of 1:1. Spouses of the persons with fMS were included as a healthy control (HC) group. A specific questionnaire that was previously validated was used to obtain the data. To evaluate risk factors associated with breastfeeding for fMS occurrence compared with sMS and HC, multinomial regression analysis was performed to compute the relative risk ratios (RRR) along with 95% confidence intervals (95% CI). The analysis was afterwards repeated, stratified by sex. Both models were adjusted for potential confounding factors. ResultsA total of 393 participants were included in our case-control study, 131 per group. There were more individuals who were exclusively breastfed longer than six months in the sMS group compared to fMS group (RRR 2.01, 95% CI 1.22–3.32). After stratification by sex, exclusive breastfeeding was shown to be a protective factor for fMS only in male population, for individuals breastfed ≥4 months. The results of both the main and stratified analysis remained robust after adjustment. ConclusionOur study findings indicate that breastfeeding reduces the risk of MS in infants with family history of the disease, although this protective effect may be limited to the male population. Further investigation into the differences in risk factors between fMS and sMS is warranted to gain a more comprehensive understanding of the disease.

Comparing Clinical and Radiological Features in Familial and Sporadic Multiple Sclerosis.

Objective To compare the initial presentation, clinical features, disease courses, and radiological parameters between familial multiple sclerosis (fMS) and sporadic multiple sclerosis (sMS) to determine if the two represent distinct clinical entities. Methods This retrospective study was conducted at the Neurology Clinic at Kocaeli University Hospital. Records of 114 fMS and 150 sMS patients, aged 18-65, diagnosed based on either the Poser criteria or the McDonald 2001 criteria were analyzed. Radiological data and Expanded Disability Status Scale (EDSS) evaluations were conducted by a specialist neurologist. Variables included age at MS onset, first symptoms, relapses, EDSS scores at diagnosis and last examination, and MRI findings. Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, IBM Corp., Version 28, Armonk, NY) was utilized for data analysis. Results Both fMS and sMS groups were comparable in age (43.55±12.50 and 42.35±10.61 years, respectively) and gender distribution (females: fMS 71.9%, sMS 71.3%). No significant difference was noted regarding disease onset age (fMS 29.83±10.77, sMS 30.42±9.7). Age of onset, final EDSS, and relapse rate didn't significantly vary among sMS, fMS with first-degree relatives having MS (fMS(1)), and fMS with second or third-degree relatives having MS (fMS(2)). The fMS group showed a significantly higher incidence of initial spinal cord lesions on MRI compared to the sMS group (38.6% vs. 17.3%; p<0.001). Within the fMS group, the presence of spinal cord lesions on initial MRI correlated with a higher relapse rate and elevated initial and final EDSS scores. Conclusion Despite overarching similarities between fMS and sMS, spinal cord lesions' prevalence and implications in fMS may point to a genetic underpinning warranting in-depth exploration.

The incidence and prevalence of crude and familial multiple sclerosis in Tehran, Iran in 2021.

Our registry-based cross-sectional study covered 27,508 PwMS in Tehran with a point incidence rate and prevalence of 7.87 and 194.62 per 100,000 in 2021, respectively. We found that the incidence and prevalence of MS in Tehran are still on an upward trend which requires general attention and measures to overcome. The proportion of men with a family history of MS was significantly higher. Whilst IMSS deals with economic difficulties, it continues to collect new PwMS to reach regional-level coverage in Tehran for better MS care services.

Frequency of family forms of multiple sclerosis in a center in Rio de Janeiro

Familial multiple sclerosis(fMS) is defined as multiple sclerosis cases occurring in at least two family members, and there is no data on the recurrence risk of fMS in the Brazilian population. This study estimated the multiple sclerosis recurrence risk in patient families in RJ and investigated the relationship with Caucasian and African ancestry. A study was conducted in RJ (Brazil), with 197 patients followed by a RJ specialized outpatient clinic. Recurrence risks were calculated by relative MS patient categories through Age-adjusted and Crude recurrence risks. fMS frequency (7.10%) was identified in the RJ study population. The risk of Age-adjusted recurrence (ARR) was high among grandparents, at 2.72 (95% CI 2.16 - 3.28). Concerning the parent relationship, ARR was 1.57 (95% CI 1.36 - 1.78) and increased to 1.76 (95% CI 1.41 - 2.11) in the presence of a European ancestor. Among uncles/aunts, a significant increase from 1.42 (95% CI 1.01 - 1.83) to 2.91 (95% CI 2.28 - 3.54) risk in individuals with Caucasian ancestry was observed, and to 2.65 (95% CI 2.02 - 3.27) in individuals with African ancestry. A higher risk among individuals with Caucasian ancestry was observed compared to Afro-descendant ancestry.

Familial amyotrophic lateral sclerosis and multiple sclerosis in an Egyptian family. A family report

Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are two neurological disorders with very different etiologies, genetic basis, clinical picture and prognosis. Thus their occurrence with in the same family is very unusual. Here we report a case of a 60 years old woman with familial ALS(fALS) meanwhile her daughter has relapsing remitting MS (RRMS).

Familial Mediterranean Fever and multiple sclerosis treated with ocrelizumab: Case report

BackgroundFamilial Mediterranean Fever (FMF) is associated with increased risk of multiple sclerosis (MS). Optimal treatment of patients with comorbid FMF and MS remains uncertain. CaseA 28-year-old woman with FMF, treated with colchicine, had symptomatic onset of relapsing remitting MS following four simultaneous vaccines. MRI brain with a 7-Tesla magnet demonstrated several areas of leptomeningeal enhancement with predominant linear, spread/fill and rare nodular patterns. Central vein signs were present in supratentorial white matter lesions. She received four cycles of ocrelizumab and achieved no evidence of disease activity (NEDA-3) at 20 months' follow up. DiscussionFMF with incident CNS demyelinating disease demonstrated neuroimaging features typical for classic RRMS including the central vein sign and leptomeningeal enhancement. Treatment with B-cell depleting therapy for FMF-MS led to clinical stability and symptomatic improvement at 20 months' follow up. We add to the sparse literature characterizing the course of FMF as a genetic risk factor for CNS demyelinating disease, demonstrating pathognomonic imaging features of MS on 7 T imaging and treatment efficacy with B-cell depletion.

Familial versus sporadic multiple sclerosis in Palestine: a retrospective cross-sectional pilot study

Background: Multiple sclerosis (MS) is a prevalent multifactorial neurological condition caused by hereditary and environmental factors. No research in Palestine has focused on family instances and the likely influence of paternal consanguinity (PC). In this study, researchers evaluated numerous risk variables, clinical course, early symptoms, and disability prevalence in familial MS (FMS) cases and sporadic MS (SMS) cases in the Palestinian community. Methods: A suitable sample of 90 SMS and 31 FMS patients was used in a retrospective cross-sectional analysis. Neurology clinics provided the data. Data were examined using IBM SPSS 22 to compare FMS with SMS in numerous risk factors, clinical course, early symptoms, and disability prevalence. Results: The research included 90 SMS instances and 31 FMS cases. Males developed FMS at a higher rate (45.2 %) than females (35 %) in the SMS group. In contrast, more females (64.4 %) had SMS than men (54.8 %) in the FMS group. However, ladies were more likely than men to have any MS. Parental consanguinity was identified in around 40% of the SMS and FMS groups. The mean age of onset was the same in both groups (28.5 in SMS and 27.26 in FMS), and practically all patients in both groups had recurrent MS episodes. There is no statistically significant difference between SMS and FMS regarding risk factors and lifestyle variables. Only within the SMS was the occurrence of autoimmune disorders mentioned. Within the two groups, the relapsing-remitting clinical course predominates. The proportion of first presenting symptoms and impairments did not differ substantially between the SMS and FMS. Conclusion: There were no significant variations between SMS and FMS regarding demographics, risk factors, disability, clinical course, and PC.

Demographic and Clinical Characteristics of Familial and Sporadic Multiple Sclerosis Patients.

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, immune-mediated disease of the central nervous system. It is still unestablished whether heredity correlates with the disease's progression and severity. This study includes the patients with MS seen in the MS clinic of Kashani Hospital, affiliated with Isfahan University of Medical Sciences, from January 2019 to January 2020. We gathered data regarding the demographic and clinical characteristics, such as type of disease and family history of MS. Patients were grouped based on having relatives with MS. We compared demographic and clinical characteristics between those with a family history of MS (familial MS: FMS) and those without a family history of MS (sporadic MS: SMS). We included 2,929 MS patients, 523 (17.2%) with FMS and 2,406 (82.8%) with SMS. Patients with FMS were found to have active lesions in the thoracic spine more frequently than those with SMS (P = 0.022). We also found differences in the distribution of gender (P = 0.036) and the frequency of having active brain lesions (P = .024) among patients with FMS and SMS. No difference was found between the demographic/clinical characteristics and the number of affected relatives in the family. Significant differences were found among different groups of patients in terms of demographical and clinical characteristics.

Exonic variants of the P2RX7 gene in familial multiple sclerosis

IntroductionSeveral studies have analysed the presence of P2RX7 variants in patients with MS, reporting diverging results. MethodsOur study analyses P2RX7 variants detected through whole-exome sequencing (WES). ResultsWe analysed P2RX7, P2RX4, and CAMKK2 gene variants detected by whole-exome sequencing in all living members (n = 127) of 21 families including at least 2 individuals with multiple sclerosis. P2RX7 gene polymorphisms previously associated with autoimmune disease. Although no differences were observed between individuals with and without multiple sclerosis, we found greater polymorphism of gain-of-function variants of P2RX7 in families with individuals with multiple sclerosis than in the general population. Copresence of gain-of-function and loss-of-function variants was not observed to reduce the risk of presenting the disease. Three families displayed heterozygous gain-of-function SNPs in patients with multiple sclerosis but not in healthy individuals. We were unable to determine the impact of copresence of P2RX4 and CAMKK2 variants with P2RX7 variants, or the potential effect of the different haplotypes described in the gene. No clinical correlations with other autoimmune diseases were observed in our cohort. ConclusionsOur results support the hypothesis that the disease is polygenic and point to a previously unknown mechanism of genetic predisposition to familial forms of multiple sclerosis. P2RX7 gene activity can be modified, which suggests the possibility of preventive pharmacological treatments for families including patients with familial multiple sclerosis.

Epidemiology of familial multiple sclerosis and its comparison to sporadic form in Markazi Province, Iran

BackgroundLimited data have been published about the epidemiology of familial multiple sclerosis (FMS) and its comparison to the sporadic form. Additionally, the epidemiology of FMS varies significantly in numerous provinces of Iran. ObjectivesThe current study aimed to establish the epidemiology and clinical presentations of FMS and compare this form of the disease to sporadic multiple sclerosis (SMS) in Markazi province, Iran. MethodsIn this cross-sectional registry-based study, the data were collected by the Multiple Sclerosis (MS) Society of Markazi province within 2012-2021. The demographic and clinical characteristics, diagnosis, and treatment of the MS patients living in the province were registered in this system. ResultsA total of 924 MS cases who completed the data about the familial history of MS participated in this study. Based on the results, the female/male ratios were equal to 3.11 and 3.96 in FMS and SMS groups, respectively. Furthermore, 29.4% of the individuals had a history of the disease in their first- to third-degree relatives. The prevalence of primary-progressive multiple sclerosis was higher among the FMS patients (8.5%) than in the SMS patients (4.6%). Along with motor, sphincter, cognitive, and brain stem signs as the onset symptoms, the FMS group experienced a higher rate of polysymptomatic onset (P = 0.000). Moreover, significantly more autoimmune diseases and consanguineous marriages (P = 0.000) were observed in the FMS group than in the SMS group. The individuals with FMS reported a higher mean number of recurrences and higher Expanded Disability Status Scale (EDSS) scores (P = 0.000). ConclusionThe results showed a significant prevalence of FMS in Markazi province. The FMS and SMS patients were significantly different regarding first presentations, onset symptoms, MS clinical characteristics, and EDSS scores. Finally, consanguineous marriage was significantly more common in the FMS group than in the SMS group.

Optical coherence tomography assessment of axonal and neuronal damage of the retina in patients with familial and sporadic multiple sclerosis.

ObjectiveTo assess axonal and neuronal damage of the retina in patients with familial (fMS) and sporadic multiple sclerosis (sMS).Methods87 relapsing-remitting MS patients (45 patients with sMS, 42 patients with fMS) and 30 healthy controls were included in the study. Optical coherence tomography (OCT) was performed with the spectral domain optical coherence tomography (SD-OCT, Heidelberg Engineering, Germany). The peripapillary retinal nerve fiber layer (pRNFL) thickness, ganglion cell-inner plexiform layer (GCIPL) thickness, total macular volume (TMV) and the inner nuclear layer (INL) thickness were measured.ResultsA significant reduction of the pRNFL thickness was detected in sMS and fMS compared to the control group (86.29 (+/- 16.13) μm in sMS, 84.78 (+/- 12.92) μm in fMS, 98.93 (+/- 6.71) μm in control group; p < 0.001). There was no significant difference in the pRNFL thickness between sMS and fMS (p = 0.5239). The GCIPL thickness was significantly decreased in sMS and fMS compared to the control group [66.0581 (+/- 11.2674) μm in sMS, 63.8386 (+/-10.004) μm in fMS, 76.5074 (+/- 5.0004) μm in control group; p < 0.001]. A significant reduction of the TMV was shown in sMS and fMS compared to the control group [8.4541(+/- 0.4727) mm3 in sMS, 8.3612 (+/- 0.4448) mm3 in fMS, 8.8387 (+/- 0.314) mm3 in control group; p < 0.0011]. No difference in the GCIPL thickness and TMV between sMS and fMS was found (p = 0.3689 and p = 0.3758, respectively). The INL thickness in sMS and fMS did not differ compared to the control group [34.2323 (+/- 2.7006) μm in sMS, 34.5159 (+/- 2.9780) μm in fMS, 33.6148 (+/- 2.0811) μm in control group; p = 0.5971 and p = 0.1870, respectively] and between the two forms (p = 0.4894).ConclusionWe confirmed the presence of axonal and neuronal damage of the retina in sMS and fMS. Both forms of MS did not differ significantly from each other with respect to RFNL, GCIPL, MV and INL. ON induced significant reduction of the pRNFL, GCIPL and MV in both groups of pwMS.

Variant rs4149584 (R92Q) of the TNFRSF1A gene in patients with familial multiple sclerosis

IntroductionGenomic studies have identified numerous genetic variants associated with susceptibility to multiple sclerosis (MS); however, each one explains only a small percentage of the risk of developing the disease. These variants are located in genes involved in specific pathways, which supports the hypothesis that the risk of developing MS may be linked to alterations in these pathways, rather than in specific genes. We analyzed the role of the TNFRSF1A gene, which encodes one of the TNF-α receptors involved in a signaling pathway previously linked to autoimmune disease. MethodsWe included 138 individuals from 23 families including at least 2 members with MS, and analyzed the presence of exonic variants of TNFRSF1A through whole-exome sequencing. We also conducted a functional study to analyze the pathogenic mechanism of variant rs4149584 (-g.6442643C > G, NM_001065.4:c.362 G > A, R92Q) by plasmid transfection into human oligodendroglioma (HOG) cells, which behave like oligodendrocyte lineage cells; protein labeling was used to locate the protein within cells. We also analyzed the ability of transfected HOG cells to proliferate and differentiate into oligodendrocytes. ResultsVariant rs4149584 was found in 2 patients with MS (3.85%), one patient with another autoimmune disease (7.6%), and in 5 unaffected individuals (7.46%). The 2 patients with MS and variant rs4149584 were homozygous carriers and belonged to the same family, whereas the remaining individuals presented the variant in heterozygosis. The study of HOG cells transfected with the mutation showed that the protein does not reach the cell membrane, but rather accumulates in the cytoplasm, particularly in the endoplasmic reticulum and near the nucleus; this suggests that, in the cells presenting the mutation, TNFRSF1 does not act as a transmembrane protein, which may alter its signaling pathway. The study of cell proliferation and differentiation found that transfected cells continue to be able to differentiate into oligodendrocytes and are probably still capable of producing myelin, although they present a lower rate of proliferation than wild-type cells. ConclusionsVariant rs4149584 is associated with risk of developing MS. We analyzed its functional role in oligodendrocyte lineage cells and found an association with MS in homozygous carriers. However, the associated molecular alterations do not influence the differentiation into oligodendrocytes; we were therefore unable to confirm whether this variant alone is pathogenic in MS, at least in heterozygosis.

Epidemiology of familial multiple sclerosis in Iran: a national registry-based study

BackgroundAdmittedly, little is known about the epidemiological signatures of familial multiple sclerosis (FMS) in different geographical regions of Iran.ObjectiveTo determine the epidemiology and the risk of FMS incidence in several provinces of Iran with a different ethnic population including, Fars, Tehran, Isfahan (Persians), and Mazandaran (Mazanis), Kermanshah (Kurds), and Chaharmahal and Bakhtiari (Lors).MethodsThis cross-sectional registry-based study was performed on nationwide MS registry of Iran (NMSRI) data collected from 2018 to 2021. This system, registers baseline characteristics, clinical presentations and symptoms, diagnostic and treatments at regional and national levels.ResultsA total of 9200 patients including, 7003 (76.1%) female and 2197 (23.9%) male, were participated. About 19% of patients reported a family history of MS; the order from highest to lowest FMS prevalence was as follows: Fars (26.5%), Chaharmahal and Bakhtiari (21.1%), Tehran (20.5%), Isfahan (20.3%), Mazandaran (18.0%), and Kermanshah (12.5%). Of all FMS cases, 74.7% (1308 cases) were female and 25.3% (442 cases) were male. FMS occurrence was much more common in females than males (P-value = 0.001). Further, the mean age at onset was 30 years among FMS cases. A substantially higher probability of relapsing-remitting MS and secondary-progressive MS was found among FMS cases than sporadic MS (SMS) (P_value = 0.001). There was no significant difference in Expanded Disability Status Scale (EDSS) scores between FMS and SMS. The majority of FMS cases were observed among first-degree relatives, with the highest rate in siblings. There was a significant association between MS risk and positive familial history in both maternal and paternal aunt/uncle (P_value = 0.043 and P_value = 0.019, respectively). Multiple sclerosis occurrence among offspring of females was higher than males (P_value = 0.027).ConclusionsIn summary, our findings imply a noteworthy upward trend of FMS in Iran, even more than the global prevalence, which suggests a unique Atlas of FMS prevalence in this multi-ethnic population. Despite the highest rate of FMS within Persian and Lor ethnicities, no statistically significant difference was observed among the provinces.

Burden of rare coding variants in an Italian cohort of familial multiple sclerosis

BackgroundMultiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative demyelinating disease of the central nervous system. It is a complex and heterogeneous disease caused by a combination of genetic and environmental factors, and it can cluster in families. Objectiveto evaluate at gene-level the aggregate contribution of predicted damaging low-frequency and rare variants to MS risk in multiplex families. MethodsWe performed whole exome sequencing (WES) in 28 multiplex MS families with at least 3 MS cases (81 affected and 42 unaffected relatives) and 38 unrelated healthy controls. A gene-based burden test was then performed, focusing on two sets of candidate genes: i) literature-driven selection and ii) data-driven selection. ResultsWe identified 11 genes enriched with predicted damaging low-frequency and rare variants in MS compared to healthy individuals. Among them, UBR2 and DST were the two genes with the strongest enrichment (p = 5 × 10−4 and 3 × 10−4, respectively); interestingly enough the association signal in UBR2 is driven by rs62414610, which was present in 25% of analysed families. ConclusionDespite limitations, this is one of the first studies evaluating the aggregate contribution of predicted damaging low-frequency and rare variants in MS families using WES data. A replication effort in independent cohorts is warranted to validate our findings and to evaluate the role of identified genes in MS pathogenesis.