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.

Dalfampridine in the treatment of primary fatigue in patients with multiple sclerosis: a randomized clinical trail.

INTRODUCTION: Fatigue is a highly prevalent debilitating symptom among patients with multiple sclerosis (PwMS), which markedly affects the quality of life. The present study aimed to evaluate the effect of extended-release fampridine on fatigue in PwMS. METHODS: This was a randomized, double-blind clinical trial on 77 PwMS with a complaint of fatigue, aged over 18 years old, randomized to extended-release fampridine (n = 44) or placebo (n = 35) for 12 weeks. Fatigue and motor function were assessed at baseline and end point. RESULTS: A total of 88 patients were recruited, of whom 77 were analyzed. 80.5% were female, with a median age of 38. 87% were diagnosed with relapsing-remitting MS (RRMS) with a median disease duration of 96 months. Fingolimod (37.7%) was considered the most frequently used DMT, followed by ani-CD20s (32.5%). The total median MFIS score was 43.5 and 37 in the fampridine and placebo groups which were not significantly different (p > 0.05). After 12 weeks, the total MFIS improved in both groups compared to the baseline, which was significant in the active group (p = 0.04). However, the final end point total MFIS was still comparable between the two groups (p = 0.11). CONCLUSION: The present study revealed a positive short-term effect of extended-release fampridine on MFIS in PwMS. However, this effect was not significantly superior to the placebo.

Time interval between the onset of symptoms and diagnosis of multiple sclerosis and the influential factors: A national registry-based study.

OBJECTIVE: The time to diagnosis of multiple sclerosis (MS) is of great importance for early treatment, thereby reducing the disability and burden of the disease. The purpose of this study was to determine the time from the onset of clinical symptoms to the diagnosis of MS and to evaluate the factors associated with a late diagnosis in Iranian MS patients. METHODS: The present cross-sectional study was conducted on patients with MS who were registered in the National MS Registry System of Iran (NMSRI). RESULTS: Overall, 23291 MS patients registered in 18 provinces of Iran were included in this study. The mean (standard deviation) interval between the onset of the disease and diagnosis of MS was 13.42 (32.40) months, and the median was one month. The diagnostic interval of 41.6% of patients was less than one month, and 14.8% of them had a one-month time to diagnosis. Patients with an age of onset below 18 years and those diagnosed after the age of 50 years had a longer time to diagnosis (P<0.001). Patients with primary progressive MS (PPMS) had the longest time to diagnose and those with relapsing-remitting MS (RRMS) had the shortest time (P<0.001). The results of negative binominal regression showed that the average rate of delay in diagnosis in women was 12% less than that in men. The average delay in diagnosis in patients with a positive family history of MS was 23% more than that in others. The rate of delay in the diagnosis of patients with PPMS and secondary progressive MS was 2.22 and 1.66 times higher, respectively, compared with RRMS. CONCLUSION: The findings of the present study revealed that more than half of the MS patients were diagnosed within a one-month interval from the symptom onset, which is an acceptable period. More attention should be paid to patients' access to medical facilities and MS specialists.

Identification of a Novel Variant in CC2D1A Gene Linked to Autosomal Recessive Intellectual Disability 3 in an Iranian Family and Investigating the Structure and Pleiotropic Effects of this Gene.

Objectives: Intellectual disability (ID) represents a significant health challenge due to its diverse and intricate nature. A multitude of genes play a role in brain development and function, with defects in these genes potentially leading to ID. Considering that many of these genes have yet to be identified, and those identified have only been found in a small number of patients, no complete description of the phenotype created by these genes is available. CC2D1A is one of the genes whose loss-of-function mutation leads to a rare form of non-syndromic ID-3(OMIM*610055), and four pathogenic variants have been reported in this gene so far. Materials & Methods: n the current study, two affected females were included with an initial diagnosis of ID who were from an Iranian family with consanguineous marriage. Whole-exome sequencing was used to identify the probable genetic defects. The Genotypic and phenotypic characteristics of the patients were compared with a mutation in the CC2D1A gene, and then the structure of the gene and its reported variants were investigated. Results: The patients carried a novel homozygous splicing variant (NM_017721, c.1641+1G>A) in intron 14, which is pathogenic according to the ACMG guideline. Loss-of-function mutations in CC2D1A have severe phenotypic consequences such as ID, autism spectrum disorder (ASD), and seizures. However, missense mutations lead to ASD with or without ID, and in some patients, they cause ciliopathy. Conclusion: This study reports the fifth novel, probably pathogenic variant in the CC2D1A gene. Comparing the clinical and molecular genetic features of the patients with loss-of-function mutation helped to describe the phenotype caused by this gene more precisely. Investigating the CC2D1A gene's mutations and structure revealed that it performs multiple functions. The DM14 domain appears more pivotal in triggering severe clinical symptoms, including ID, than the C2 domain.

Soft Palate Malignant Melanoma as an Adverse Effect of Fingolimod in Multiple Sclerosis: A Case Report and Literature Review.

Fingolimod has been approved as a disease-modifying drug in multiple sclerosis since 2010. There are a few reports of melanoma as a side effect of Fingolimod in the literature. Herein we aim to report a known case of multiple sclerosis under Fingolimod presenting with persistent nasal congestion who was eventually diagnosed with soft palate malignant melanoma.

Late-onset multiple sclerosis in Iran: A report on demographic and disease characteristics.

BACKGROUND: Today, it is estimated that around 5% of multiple sclerosis (MS) patients are in the late-onset category (age at disease onset ≥ 50). Diagnosis and treatment in this group could be challenging. Here, we report the latest update on the characteristics of Iranian patients with late-onset MS (LOMS). METHODS: This cross-sectional study used the information provided by the nationwide MS registry of Iran (NMSRI). The registrars from 14 provinces entered data of patients with a confirmed diagnosis of MS by neurologists. Patients with disease onset at or later than 50 years of age were considered LOMS. RESULTS: Of 20,036 records, the late-onset category included 321 patients (1.6%). The age-standardized LOMS prevalence was around 75 per 100,000 people. 215 patients (67%) were female. Median Expanded Disability Status Scale (EDSS) was 3 (interquartile range: 1.5-5). The majority of the cases (56%) suffered from relapsing-remitting (RR) course while 20% were diagnosed with primary progressive (PP) MS. Significantly higher proportion of male sex, PPMS, and higher EDSS were seen in the late-onset group compared with early-onset and adult-onset cases (p-value < 0.05). Seventy-five (23%) patients did not receive any disease-modifying treatment. DISCUSSION: The more prominent degenerative pathology of LOMS may be the underlying mechanism of the observed differences in comparison to non-LOMS. CONCLUSION: There are substantial differences and knowledge gaps regarding LOMS which could be the subject of further research.

Economic and Social Standing of Individuals in Iran Diagnosed with Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) may be affected by socioeconomic status (SES). This study aims to explore the determinants of SES among Iranian patients with MS and examine how these factors relate to disability and disease progression. METHODS: All patients with MS listed in the nationwide MS registry of Iran (NMSRI) until January 8, 2022, were included in this population-based study. RESULTS: Among the 5153 patients, most were female (74.5%), married (70.8%), and did not hold an academic degree (53.8%). Unemployment (OR: 3.75) and being unmarried (OR: 2.60) were significantly associated with Expanded Disability Status Scale (EDSS)≥6, and the time to progression was shorter in the unemployed group (P value: 0.03). There was also a significant negative correlation between the time to progression and the age at disease onset. CONCLUSION: The study suggests that providing financial and social support to MS patients and their families through investment could reduce both individual and societal burdens.

Prescription trends of disease-modifying treatments for multiple sclerosis in Iran over the past 30 years.

BACKGROUND: Iran, as a middle income country, is one of the places with high and rising prevalence of multiple sclerosis (MS). Regarding the substantial economic burden, reviewing the trend in prescribed disease modifying treatments (DMTs) could be of help. Here we studied the DMT information of nearly 14000 MS cases and its trends change for 30 years to improve health services to patients. METHODS: The population base of this descriptive-analytical (cross-sectional) study consisted of all MS patients in the nationwide MS registry of Iran (NMSRI), up to August 1, 2021. Registrars from 15 provinces, 24 cities, 13 hospitals,8 MS associations, 16 private offices, and 7 clinics had entered the data. RESULTS: Overall, 14316 cases were enrolled. The majority (76.1%) were female. The youngest and eldest patients were 5 and 78 years old, respectively. Diagnosis delay was under one year in most cases (median: 0, IQR: 0 - 1). Most (61.4%) had RRMS. Generally, platform injectables (IFN beta, glatiramer acetate) were the most used DMTs until 2010. It seems that introduction of newer agents (antiCD20s and oral DMTs) resulted in a decrease in the use of former drugs since around 2015. Some unusual practices are prominent such as using not approved DMTs for PPMS over the years, or administering high efficacy drugs like natalizumab for CIS. The results indicate the remaining popularity of first line injectable DMTs in female and pediatric patients. DISCUSSION: Mean age (SD) at onset in our study (29 ± 8.8) is near the statistics in Asia and Oceania (28 ± 0.7). Concerns about COVID-19 had a noticeable impact on administering high efficacy drugs like rituximab and fingolimod. However, in male patients this approach has not been the case. It may be related to more aggressive disease course in this group. The other possible explanation could be planning for pregnancy in female cases. The popularity of platform injectable drugs in pediatric MS may be related to its favorable safety profile over the years. Another point in this group, is the superiority of rituximab over other highly efficient medications.

Characteristics of COVID-19 in patients with multiple sclerosis.

BACKGROUND: Regarding the high prevalence of multiple sclerosis (MS) and COVID-19 in Iran, a multicenter study of COVID-19 in Iranian MS patients with is carried out to address the concerns of this population. METHODS: Data on MS patients with COVID-19 from nine provinces of Iran were entered in a web-based registry system, between July 2020 and March 2021. Among the COVID-19 symptoms, dyspnea, altered mental status, or those resulting in hospital admission were considered severe. RESULTS: A total of 397 eligible patients were identified. In addition, 310 (78%) were female. The mean age was 36.5 ± 9.5. 294 (74%) patients had relapsing- remitting form. Also, four patients (1%) expired due to COVID-19 infection. The mean duration of admission in hospitalized patients was 9 (± 5.3) days. MRI was performed on 111 (28%) patients after developing COVID-19. MRI changes were observed in 27 (24%) of these cases. MS drug was changed in 26 (6%) patients. Steroid use in the past three months (OR: 2.43, 95% CI: 1.003-5.88) (p value: 0.049) and antiCD20s (OR: 4.03, 95% CI: 2.41-6.68) (p value < 0.001) showed significant association with severe COVID-19 symptoms. CONCLUSION: The death rate of COVID-19 among MS patients (1%) is lower than the overall death rate of the pandemic in Iran (3%). Those who received steroid in the past three months may be at increased risk of more severe forms of COVID-19. There are still doubts about the effect of anti CD20s on COVID-19 severity.

Evaluation of the "partnership care model" on quality of life and activity of daily living in stroke patients: A randomized clinical trial.

BACKGROUND: Stroke is a widespread chronic disease which remains a serious problem for public health and is the cause of major disability and death in adults. Despite valuable efforts, these patients still need new care programs for recovery and rehabilitation. AIM: The aim of this study is to determine the effect of the partnership care model (PCM) on quality of life (QOL) and activities of daily living (ADL) in stroke participants. METHOD: The study is a randomized clinical trial carried out in an educational and therapeutic center in 2019. Sixty-seven participants (allocated randomly in intervention and control groups) with cerebrovascular accident who had hospitalization histories were selected. Data collection instruments were the Stroke-Specific QOL scale and Lawton questionnaires. The care plan was developed and implemented for the intervention group after evaluating and recording basic information including demographic variables, care needs, and problems identified in the first PCM-based stage. Ethics approval was obtained from the University / Regional Research Ethics Committee (IR.NIMAD.REC.1397.236). RESULTS: The results show that the mean scores of the QOL significantly increased after the intervention in the intervention group (before = 130.80; 3 months = 172.19; 6 months = 205.29) compared to the control group (before = 150; 3 months = 144.86; 6 months = 160.66). Also, the mean scores of the ADL significantly increased after the intervention in the intervention group (before = 1.96; 3 months = 3.64; 6 months = 4.87) compared to the control group (p < .05). The effect size is equal to 0.501 and 0.245 for QOL and ADL, respectively. CONCLUSION: The findings show that the care program based on a PCM recovered the QOL and ADL of stroke participants more than other interventions.

Anticipatory coping: how women deal with the hassles of living with multiple sclerosis.

BACKGROUND: People living with MS confront a variety of changes and challenges that need to cope with. The aim of this study was to explore the coping patterns related to the impact of MS on people's lives including; daily, family, and social functions. METHODS: A constructivist grounded theory approach was taken. A purposive sample of 16 women living with MS were recruited from a MS clinic at a teaching hospital in the north of Iran. Participants completed 22 semi-structured interviews. The interviews were digitally recorded, transcribed and analyzed using initial, focused and theoretical coding. RESULTS: Participants described coping with a certain pattern that reflected direction and orientation of coping. Anticipating outcomes related to disease, self or others led the participants to plan ahead to deal with the challenges of living with MS. Indeed, they develop and employed anticipatory coping in disease-directed, self-directed and other-directed. Then they focused on the orientation of coping patterns, which involved actions, reactions, and interactions in order to manage anticipated outcomes. CONCLUSION: The majority of participants used coping pattern that were anticipatory rather than a reactionary to past or present challenges. The results highlight the value of engaging with people with MS in order to identify ways that they cope with the impact of this condition. This is an important distinction and one that health professionals not only need to be aware of but highlights the value of engaging with people with MS in this frame to develop informed and positive approaches to anticipated outcomes and in responding to anticipated changes and challenges.IMPLICATIONS FOR REHABILITATIONPeople develop the pattern of anticipatory coping in order to deal with issues related to the disease, self and others that they anticipate will happen in order to manage potential dysfunctions related to living with multiple sclerosis.People living with MS employ anticipatory coping based on existing and anticipated abilities and disabilities in order to maintain normality for as long as possible in daily, family and social activities.Proactive approaches to dealing with MS can be promoted in a number of ways, for example through support groups, social media or the development of networks with the aim of providing peer support and education.Developing rehabilitation programmes that reflect individual responses to living with MS would improve the ability of healthcare systems to meet clients' needs related to adjusting to living with a chronic condition.

Association of COVID-19 Infection and Juvenile Stroke: a Case Series.

Ischemic stroke has been increasingly reported as a consequence of COVID-19 infection. However, the underlying etiology is not well determined. The objective of this study is to discuss association of juvenile stroke with COVID-19 infection. We analyzed 5 COVID-19 positive and stroke patients with a mean age of 41.2 years-old. Three patients developed large vessel occlusion, one small vessel occlusion and one PRES with superimposed lobar ICH, respectively. The mean initial NIHSS of our patients was 11.6. Except the one with massive cerebellar infarct, a desirable outcome occurred with a mean mRS 2.6 at discharge. The mean ESR and CRP level was elevated to 30.4 ml and 32 mg/dl. The severity of COVID-19 infection was considered mainly as mild. COVID-19 infection has the potential to induce hypercoagulability state contributing to stroke development even in the mild form of disease. Keywords: Cerebrovascular Accident, CVA, Stroke, COVID-19, Novel Coronavirus Acta.

Identification of two novel homozygous nonsense mutations in TRAPPC9 in two unrelated consanguineous families with intellectual Disability from Iran.

BACKGROUND: Pathogenic mutations in TRAPPC9 are associated with autosomal recessive Intellectual Disability (ID), a major public health issue that affects about 1-3% of children worldwide. METHOD: Clinical evaluation, magnetic resonance imaging, peripheral blood karyotype, Multiplex ligation-dependent probe amplification (MLPA), array CGH, and whole-exome sequencing were used to characterize etiology in three patients from two unrelated consanguineous families of Iranian descent with intellectual disability. RESULTS: Whole-exome sequencing showed two novel homozygous nonsense mutations (c.937C>T) in exon 3 and (c.3103C>T) in exon 19 of TRAPPC9 (NM_031466.7) in two unrelated consanguineous families. CONCLUSION: The two novel variants found in TRAPPC9 caused truncated protein and clinical manifestations such as ID, developmental delay, microcephaly, and brain abnormalities in three patients.

A Rare Axonal Variant of Guillain-Barré Syndrome as a Neurological Complication of COVID-19 Infection.

Guillain-Barré syndrome (GBS) is a neurological disorder accompanied by several neurological signs and symptoms including progressive weakness and diminished or decreased reflexes. GBS was reported as one of the several neurological complications in MERS-CoV and SARS-CoV outbreaks. Several studies have reported GBS as a neurological complication in recent COVID-19 outbreak. We report on the case of a 55-years -old female who was hospitalized with dyspnea, dry cough, and myalgia. She developed Acute Motor & Sensory Axonal Neuropathy (AMSAN), a rare variant of GBS signs and symptoms including decreased muscle strength and pinprick sensation in both lower extremities during her hospitalization.

Evaluation of different types of arsenic methylation and its relationship with metabolic syndrome in an area chronically exposed to arsenic.

Evidence suggests that the relationship between arsenic metabolism and diseases, including metabolic syndrome, is complex. The aim of this study was to evaluate the different types of arsenic methylation and its association with metabolic syndrome in an arsenic endemic area. A cross-sectional study was conducted on 132 subjects from Shahid-Abad Village, Qazvin province, Iran (arsenic endemic area). Demographic characteristics, metabolic syndrome, and urinary arsenic species, including iAs (inorganic arsenic), MMA (monomethylarsonic acid), and DMA (dimethylarsinic acid) were measured for all patients and their relationship was analyzed by appropriate statistical methods. In this study, 34.5% of the participants had metabolic syndrome. The decrease in %MMA, increase in %DMA and increase in secondary methylation index (DMA/MMA) were associated with increased risk of metabolic syndrome (p<0.05). We did not find any association between the incidence of metabolic syndrome with primary methylation index (MMA/iAs) and %iAs (p>0.05). This study showed that the prevalence of metabolic syndrome was significantly higher in people with metabolic syndrome than in the general population. A closer examination revealed that the secondary methylation index is related to the metabolic syndrome and its components. Given the higher prevalence of cardiovascular disease and diabetes in patients with metabolic syndrome, it is necessary to change the pathogenesis of the disease using comprehensive management methods for decreasing patient complications.

Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability.

Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild-type DNA constructs as well as in silico protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with intellectual disability.

The impact of pneumonia on hospital stay among patients hospitalized for acute stroke.

OBJECTIVE: To determine the impact of pneumonia on length of hospital stay in cases of acute stroke. METHODS: This was a retrospective cross-sectional study on 368 stroke patients admitted with a diagnosis of stroke at the Avicenna Hospital, Qazvin, Iran between January 2010 and March 2011. By reviewing the hospital patient records, the demographic characteristics, stroke characteristics, and complications of stroke in these patients were determined during their hospital stay. In surviving patients, the impact of each variable on length of hospital stay was calculated by logistic regression analysis and the Log-Rank test. RESULTS: Patients with pneumonia during the post stroke period had an increased length of hospital stay (11.5+/-6.4 days), compared with other patients (7.2+/-4.1 days), (p=0.0005). Multiple logistic regression analysis showed a significant association between length of hospital stay and urinary tract infection (p=0.001), steroid consumption (p=0.028), index of stroke severity (p=0.039), pneumonia (p=0.042), and swallowing disorder (p=0.048). CONCLUSION: Considering the impact of pneumonia on the length of hospital stay and its consequences, prophylactic activities, rapid diagnosis, and treatment of pneumonia may improve outcome and reduce costs in stroke patients.