Earlier age of symptom onset in younger generation of familial cases of multiple sclerosis.

AIM: The aim of this study was to assess the prevalence of familial MS (fMS) in Belgrade MS population, discern the differences between the persons with fMS and sporadic MS, and to detect the presence of anticipation phenomenon in fMS patients. METHODS: The data on the demographic and clinical characteristics of MS patients was obtained from the Belgrade MS population Registry. In cases of vertical transmission of MS, the family members were divided into the younger and older generation, in order to assess the potential presence of anticipation phenomenon. To adjust for follow-up time bias, a secondary analysis including only patients who had the onset of symptoms before 39 years (75.percentile), and those who were 39 + years, was performed. RESULTS: The prevalence of fMS in Belgrade MS population is 6.4%. FMS cases had earlier age at MS symptom onset (30.4 vs. 32.3 years) compared to sporadic MS cohort. When comparing fMS cases across generations, the younger generation had significantly lower age at onset compared with the older one (25.8 vs. 35.7 years, p < 0.001). After adjustment for the different length of the follow-up, the difference in age at symptom onset between the groups was reduced, but it still existed and was statistically significant (30.0 years in younger vs. 36.4 years in older generation, p = 0.040). CONCLUSION: In our study, the analysis of fMS cases across generations, showed an earlier age of symptom onset in the younger generation, even after adjustment. These results indicate the possibility of existence of anticipation phenomenon.

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

BACKGROUND: Admittedly, little is known about the epidemiological signatures of familial multiple sclerosis (FMS) in different geographical regions of Iran. OBJECTIVE: To 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). METHODS: This 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. RESULTS: A 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). CONCLUSIONS: In 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.

Exome sequencing reveals novel rare variants in Iranian familial multiple sclerosis: The importance of POLD2 in the disease pathogenesis.

The prevalence of familial multiple sclerosis (FMS) is increasing worldwide which endorses the heritability of the disease. Given that many genome variations are ethnicity-specific and consanguineous marriage could affect genetic diseases, hereditary disease gene analysis among FMS patients from Iran, a country with high rates of parental consanguinity, could be highly effective in finding mutations underlying disease pathogenesis. To examine rare genetic mutations, we selected three Iranian FMS cases with ≥3 MS patients in more than one generation and performed whole exome sequencing. We identified a homozygous rare missense variant in POLD2 (p. Arg141Cys; rs372336011). Molecular dynamics analysis showed reduced polar dehydration energy and conformational changes in POLD2 mutant. Further, we found a heterozygote rare missense variant in NBFP1 (p. Gly487Asp; rs778806175). Our study revealed the possible role of novel rare variants in FMS. Molecular dynamic simulation provided the initial evidence of the structural changes behind POLD2 mutant.

ACE2, TMPRSS2, and Furin variants and SARS-CoV-2 infection in Madrid, Spain.

It has been suggested that some individuals may present genetic susceptibility to SARS-CoV-2 infection, with particular research interest in variants of the ACE2 and TMPRSS2 genes, involved in viral penetration into cells, in different populations and geographic regions, although insufficient information is currently available. This study addresses the apparently reasonable hypothesis that variants of these genes may modulate viral infectivity, making some individuals more vulnerable than others. Through whole-exome sequencing, the frequency of exonic variants of the ACE2, TMPRSS2, and Furin genes was analyzed in relation to presence or absence of SARS-CoV-2 infection in a familial multiple sclerosis cohort including 120 individuals from Madrid. The ACE2 gene showed a low level of polymorphism, and none variant was significantly associated with SARS-CoV-2 infection. These variants have previously been detected in Italy. While TMPRSS2 is highly polymorphic, the variants found do not coincide with those described in other studies, with the exception of rs75603675, which may be associated with SARS-CoV-2 infection. The synonymous variants rs61735792 and rs61735794 showed a significant association with infection. Despite the limited number of patients with SARS-CoV-2 infection, some variants, especially in TMPRSS2, may be associated with COVID-19.

The global prevalence of familial multiple sclerosis: an updated systematic review and meta-analysis.

BACKGROUND: Considering that many recent studies have reported the prevalence of familial multiple sclerosis (FMS), we performed an updated meta-analysis of the worldwide prevalence of FMS by the addition of recent publications. METHODS: A search in PubMed, Scopus, the ISI Web of Science, and Google Scholar was undertaken up to 20 December 2020. The inclusion criteria were based on the CoCoPop approach (condition, context, and population). Meta-analysis of the qualified studies was conducted by comprehensive meta-analysis ver. 2 software. RESULTS: The pooled prevalence of MS in relatives of 16,179 FMS cases was estimated to be 11.8% (95% CI: 10.7-13) based on a random-effects model. The pooled mean age of disease onset in adult probands was calculated to be 28.7 years (95% CI: 27.2 ± 30.2). Regarding 13 studies that reported the data of FMS in pediatrics (n = 877) and adults (n = 6636), the FMS prevalence in pediatrics and adults was 15.5% (95% CI: 13.8-17.4) and 10.8% (95% CI: 8.1-14.2), respectively. The prevalence of FMS in affected males (n = 5243) and females (n = 11,503) was calculated to be 13.7% (95% CI: 10.1-18.2) and 15.4% (95% CI: 10.3-22.4), respectively. The odds ratio of male/female in FMS cases was not statistically significant (OR = 0.9; 95% CI: 0.6-1.2, P = 0.55). Subgroup analysis demonstrated a significant difference in the prevalence of FMS between the geographical areas (P = 0.007). The meta-regression model indicated that the prevalence of FMS is lower with higher latitude and higher MS prevalence (P < 0.001). In contrast, meta-regression based on prevalence day was not statistically significant (P = 0.29). CONCLUSIONS: The prevalence of FMS is higher in the pediatric group than that of adults, distinct between geographical areas, and diminishes with the increment of MS prevalence and latitude. Also, the symptoms initiate relatively at younger ages in the FMS cases. Interestingly, our analysis unveiled that FMS is not more prevalent in men than women and the risk of MS development in relatives is not higher when the affected proband is male.

Analysis of Vitamin D Receptor Polymorphisms in Patients with Familial Multiple Sclerosis.

OBJECTIVE: Genetic and environmental factors are important in the development of the multiple sclerosis (MS). Vitamin D shows its effects on the immune system with the vitamin D receptor (VDR) in the nucleus. Single nucleotide polymorphisms (SNPs) in the VDR gene can lead to alterations in vitamin D functions and metabolism.Taq I, Apa I, Fok I and Bsm I polymorphisms and MS associations have been investigated in many studies. VDR gene polymorphism has not been previously studied in patients with familial MS. AIM: We aimed to investigate the relationship between familial MS patients present in Turkish population and VDR genotypes Taq I, Apa I and Fok I polymorphisms. METHODS: 29 patients with a family history of MS and 120 healthy control subjects were included in the present study. We studied present VDR genotypes Taq I, Apa I and Fok I polymorphisms. RESULTS: We observed a significant difference between controls and patient group only in Taq I polymorphism (p: 0.025). Homozygousity of G allele was not seen in the patients whereas in controls frequency of that genotype was p:0.208. When gender was considered males show significant difference for GG genotype. There were no significant association for the Apa I and Fok I polymorphisms. CONCLUSION: Although our findings suggest association between VDR Taq I polymorphism and the familial MS, additional studies are needed to establish detailed relationships.

Multiple sclerosis in families: risk factors beyond known genetic polymorphisms.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that predominantly affects young adults. The genetic contributions to this multifactorial disease were underscored by genome wide association studies and independent replication studies. A weighted genetic risk score (wGRS) was recently established using the identified MS risk loci in order to predict MS outcome including clinical and paraclinical features. Here, we present the results on a family with several affected siblings including a monozygotic triplet. The individuals were genotyped for 57 non-MHC risk loci as well as the HLA DRB1*1501 tagging SNP rs3135388 with subsequent calculation of the wGRS. Additionally, SNP array based analyses for aberrant chromosomal regions were performed for all individuals.

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

Background: The 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 methods: A 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. Results: Out 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. Conclusion: Our 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.

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

BACKGROUND: Several 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. METHODS: This 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. RESULTS: A 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). CONCLUSION: PC 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.

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

BACKGROUND: Multiple 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. METHODS: In 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. RESULTS: Females 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. CONCLUSION: In 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.

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

Background: 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. Methods: 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). Results: 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. Conclusions: Significant differences were found among different groups of patients in terms of demographical and clinical characteristics.

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

BACKGROUND: Limited 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. OBJECTIVES: The 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. METHODS: In 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. RESULTS: A 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). CONCLUSION: The 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.

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

INTRODUCTION: Genomic 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. METHODS: We 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. RESULTS: Variant 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. CONCLUSIONS: Variant 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.

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

Objective: To assess axonal and neuronal damage of the retina in patients with familial (fMS) and sporadic multiple sclerosis (sMS). Methods: 87 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. Results: A 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). Conclusion: We 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.

Exonic variants of the P2RX7 gene in familial multiple sclerosis.

INTRODUCTION: Several studies have analysed the presence of P2RX7 variants in patients with MS, reporting diverging results. METHODS: Our study analyses P2RX7 variants detected through whole-exome sequencing (WES). RESULTS: We 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. CONCLUSIONS: Our 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.

Widespread Disruptions of White Matter in Familial Multiple Sclerosis: DTI and NODDI Study.

Diffusion tensor imaging (DTI) is a noninvasive, quantitative MRI technique that measures white matter (WM) integrity. Many brain dimensions are heritable, including white matter integrity measured with DTI. Family studies are valuable to provide insights into the interactive effects of non-environmental factors on multiple sclerosis (MS). To examine the contribution of familial factors to the diffusion signals across WM microstructure, we performed DTI and calculated neurite orientation dispersion plus density imaging (NODDI) diffusion parameters in two patient groups comprising familial and sporadic forms of multiple sclerosis and their unaffected relatives. We divided 111 subjects (49 men and 62 women: age range 19-60) into three groups conforming to their MS history. The familial MS group included 30 participants (patients; n = 16, healthy relatives; n = 14). The sporadic group included 41 participants (patients; n = 10, healthy relatives; n = 31). Forty age-matched subjects with no history of MS in their families were defined as the control group. To study white matter integrity, two methods were employed: one for calculating the mean of DTI, FA, and MD parameters on 18 tracts using Tracts Constrained by Underlying Anatomy (TRACULA) and the other for whole brain voxel-based analysis using tract-based spatial statistics (TBSS) on NDI and ODI parameters derived from NODDI and DTI parameters. Voxel-based analysis showed considerable changes in FA, MD, NDI, and ODI in the familial group when compared with the control group, reflecting widespread impairment of white matter in this group. The analysis of 18 tracts with TRACULA revealed increased MD and FA reduction in more tracts (left and right ILF, UNC, and SLFT, forceps major and minor) in familial MS patients vs. the control group. There were no significant differences between the patient groups. We found no consequential changes in healthy relatives of both patient groups in voxel-based and tract analyses. Considering the multifactorial etiology of MS, familial studies are of great importance to clarify the effects of certain predisposing factors on demyelinating brain pathology.

Identification of differential DNA methylation associated with multiple sclerosis: A family-based study.

Multiple Sclerosis (MS) is caused by a still unknown interplay between genetic and environmental factors. Epigenetics, including DNA methylation, represents a model for environmental factors to influence MS risk. Twenty-six affected and 26 unaffected relatives from 8 MS multiplex families were analysed in a multicentric Italian study using MeDIP-Seq, followed by technical validation and biological replication in two additional families of differentially methylated regions (DMRs) using SeqCap Epi Choice Enrichment kit (Roche®). Associations from MeDIP-Seq across families were combined with aggregation statistics, yielding 162 DMRs at FDR ≤ 0.1. Technical validation and biological replication led to 2 hypo-methylated regions, which point to NTM and BAI3 genes, and to 2 hyper-methylated regions in PIK3R1 and CAPN13. These 4 novel regions contain genes of potential interest that need to be tested in larger cohorts of patients.

MRI but not demographic or clinical characteristics differ between familial and sporadic MS cases.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease. The prevalence and incidence of MS in Iran is high and is rising over time. This study was conducted to compare the demographic, clinical features and MRI findings of MS patients with history of the disease in the first-degree family members (fMS) with sporadic MS patients (sMS) to determine the importance of genetic or non-genetic factors in the development of the disease and its effect in diagnostic and therapeutic modalities. METHODS: Among the 185 patients admitted to the study, 62 were fMS patients and 123 were sMS patients. All patients underwent clinical examination and data was gathered on age, sex, age of onset, symptoms, number of attacks, disease course, family history, disease-modifying drugs, and other accompanying diseases as well as MRI findings and EDSS scores. RESULTS: In this study, we demonstrated that the frequency of plaques in the periventricular area was significantly higher in sMS patients (97.56% vs 88.71%, p = 0.01) while the callosal plaques were more common in fMS patients (62.9% vs 47.97%, p = 0.05) which was statistically borderline and nonsignificant. In other evaluated parameters, no significant difference was observed. CONCLUSION: In our study, no significant difference was observed between the demographic and clinical characteristics of fMS and sMS patients, while there was a significant difference between the two groups in MRI findings.

Demographic and clinical characteristics of familial and sporadic multiple sclerosis: A single center exploratory study from Abu Dhabi.

Demographic and clinical characteristics of Familial Multiple Sclerosis (FMS) have not been fully investigated yet in Abu Dhabi. The aim of this single center exploratory study was to investigate demographic and clinical characteristics of FMS compared to sporadic MS (SMS) in Abu Dhabi. A chart review single center study was conducted in 98 patients with MS. Group comparisons were performed using Mann-Whitney and Chi-Square tests as appropriate. A p < 0.05 was considered statistically significant. 24.5% were patients with FMS and 83% were Emirates. No significant differences in demographic and clinical characteristics were found between patients with FMS and SMS in overall all MS patients and in the Emirati group analyzed alone. Patients with FMS did not differ in demographic and clinical characteristics compared to patients with SMS. Further prospective studies are needed to elucidate environmental and genetic risk factors contributing to FMS in the Emirati population.

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

BACKGROUND: The 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. METHODS: This 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. RESULTS: We 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. CONCLUSION: The 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.