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Background Hereditary spastic paraplegia (HSP) refers to a heterogeneous group of genetic disorders with more than 90 causative genes. Clinically, HSP is classified into pure and complicated forms. Pure forms are characterized primarily by lower-limb spasticity and weakness, whereas complicated forms include additional neurological or non-neurological symptoms alongside spasticity and weakness. We aimed to characterize the clinical and genetic landscapes of HSP in an Iranian cohort. Whole-exome sequencing (WES) was performed on 103 unrelated clinically suspected HSP probands. Multiple ligation-dependent probe amplification (MLPA) was performed to validate identified copy number variants (CNVs) in two probands. Results 71 pathogenic/likely pathogenic and VUS variants were identified in 81 probands; total genetically solved probands: 78.6%. Among these solved cases, 64 probands harbored variants in known HSP genes, 14 had variants in other neuromuscular/neurodegenerative-related genes, and the remaining 3 probands carried variants in four novel candidate genes including NMNAT1, SEMA3A, KCNJ14 , and EMP3 . Among all 71 identified genomic variants, two were CNVs and one was a trinucleotide repeat expansion. Taken together, these variants were located in 37 genes; 21 of these genes have been previously implicated in HSP, and four common HSP subtypes (SPG11, SPG4, SPG7, and SPG15) accounted for ~40% of our cohort. Conclusions This study demonstrates significant clinical and genetic heterogeneity of HSP within our cohort. In addition to variants in 21 known HSP-related genes, we identified variants in 14 genes related to other neurological disorders -highlighting shared biological pathways- as well as variants in four novel candidate genes. Notably, a genetic diagnosis could not be established in 22 probands, underscoring that additional, as yet unidentified genes likely contribute to HSP pathogenesis.

Introduction: The findings of previous studies are inconclusive in terms of psychological abnormalities and sexual function in asymptomatic human lymphotropic virus type 1 (HTLV-1) carriers. Aim: This study aimed to evaluate the prevalence of sexual dysfunction and its relationship with psychological abnormalities in asymptomatic HTLV-1 carriers. Materials and Methods: This cross-sectional study was conducted on asymptomatic HTLV-1 patients who were referred to the Neurology Clinic of a tertiary hospital in Mashhad, Iran. Patients with spastic paraparesis, leukemia, and uveitis, and those with an expanded disability status scale (EDSS) score higher than 2 were excluded. Sexual function in male and female subjects was evaluated using the brief male sexual function inventory (BMSFI) and female sexual dysfunction index (FSFI) questionnaires, respectively. The severity of psychological symptoms was evaluated in all patients using the symptom checklist-90-revised (SCL-90-R) questionnaire. Results: A total of 117 patients (61 males and 56 females) with a mean age of 35.3 ± 6.3 years were evaluated. Overall, 50.9% of males had a high and 39.3% of females had a good sexual function. Both male and female patients with poor sexual function were older and had more children compared to those with good sexual function (P < 0.05). There was no significant difference in the distribution pattern of SCL-90 domains between patients with high and low to moderate sexual function among male patients (P > 0.05). Depression, hostility, interpersonal sensitivity, paranoid ideation, and psychological abnormality were significantly more prevalent in female patients with poor sexual function compared to those with good sexual function (P < 0.05). Conclusion: The prevalence of psychological abnormalities was high in female with sexual dysfunction and these disorders might have a negative effect on various dimensions of sexual function.

Human T cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), as the most common neurological emersion related to HTLV-1, is a debilitating and lifelong treating disease with no definitive treatment. Furthermore, it has been determined that dietary compositions (inflammatory and anti-inflammatory) and some micronutrients (such as vitamin D and selenium) have an effect on inflammatory and immune processes and with this background; the study was done to compare the nutritional status between age- and sex-matched with infected and non-infected HTLV-1. In a multi-center setting, 70 healthy controls (HCs), 35 asymptomatic carriers (ACs), and 35 HAM/TSP patients were recruited in the HTLV-1 Foundation, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran. Nutritional status including anthropometric indices, dietary (micro- and macronutrient) intake, and serum vitamin D, vitamin B12, zinc, and selenium were measured. In anthropometric indices, mean waist circumference (WC) in the carrier group was significantly higher than the patient and the control groups (p = 0.008). In the dietary intake, the patient group received less energy, protein, mono-unsaturated fatty acids (MUFA), and oleic, but more fat than the HTLV-1 carrier and control groups, and these differences were remarkable in three groups (p = 0.002, 0.005, 0.001, 0.01, and 0.001, respectively), whereas the carrier group received more saturated fatty acid and less poly-unsaturated fatty acids (PUFA), linoleic, and linolenic than patient and control groups with a different significant (p = 0.01, 0.007, 0.005, and 0.006, respectively) in three groups. In micronutrient intake, although selenium, zinc, and vitamins B12 and D were lower in the patient group than the carrier and control group, however, no significant differences were observed. In comparison with micronutrient serum concentrations, vitamins B12 and D and selenium in the patient group were lower than the carrier and control groups, but statistically, the considerable difference was found only in the selenium concentration (p = 0.001). The study showed that there were differences in dietary intake (including energy, macronutrients, and fatty acids), WC, and selenium serum levels between HAM/TSP patients and HTLV-1 carriers, suggesting that nutritional statues influence the inflammatory immune response in HTLV-1 infection.

Prevention and treatment of the Human T-cell leukemia virus, type 1 (HTLV-1) which was discovered nearly 40 years ago, still remain challenging. The reported high prevalence of HTLV-1 in some countries around the world triggered an open letter to the World Health Organization (WHO), urging action against HTLV-1 infection in 2018. This highlights the importance of virus elimination strategies to eradicate HTLV-1 infection. In Iran, we have documented our experiences with the virus in order to achieve and promote the possible ways to manage, control, and eliminate HTLV-1. Although there has been considerable progress apropos of HTLV-1, a series of additional challenges need to be tackled to control HTLV-1 infection in Iran.

HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory disorder associated with HTLV-1. Cytokines and inflammatory mediators have a major role in forming inflammation in HAM/TSP patients. This study aimed to measure the levels of IL-32, a proinflammatory cytokine associated with autoinflammatory disorders, and also cyclooxygenase -2 (COX-2) as a key mediator of inflammatory pathways in HAM/TSP patients and HTLV-1 asymptomatic carriers (ACs). Peripheral blood monocyte cells (PBMCs) were isolated from HAM/TSP patients, ACs, and healthy controls (HCs), and DNA and RNA were extracted to evaluate HTLV-1 proviral load (PVL) and expression of IL-32 and COX-2, using real-time PCR. Serum levels of IL-32 were determined by using an ELISA assay. The expression level of IL-32 was significantly higher in ACs compared with HAM/TSP patients and HCs ( <0.0001 and >0.05, respectively). There were no statistically significant differences in the expression levels of Cox-2 and protein levels of IL-32 between the study groups. HTLV-1 PVL was higher in HAM/TSP patients compared with ACs. Results showed increased mRNA levels of IL-32 in ACs. Since HTLV-1 PVL in ACs is lower than in HAM/TSP patients, it could be concluded that IL-32 might be an HTLV-1 inhibitor that seems to control virus replication. Despite the difference in IL-32 mRNA levels between study groups, no statistically significant differences were observed in IL-32 serum levels. Also, there were no significant differences in COX-2 expression.

The microRNAs are non-coding RNA molecules involved in physiological and pathological processes, causing autoimmune diseases such as systemic lupus erythematosus (SLE). Probiotics are living microorganisms that possess beneficial effects on the host immune system and modulate it. The effect of Lactobacillus rhamnosus and Lactobacillus delbrueckii on the expression of miR-125a and miR-146a was studied in peripheral blood mononuclear cells (PBMCs) from newly diagnosed lupus patients in this in vitro study. During this study, 20 recently diagnosed SLE patients and 20 healthy individuals participated. Ficoll method was used to isolate the PBMCs from whole blood, which were cultured for 48 h with Lactobacillus rhamnosus and Lactobacillus delbrueckii . In the next step, total RNA containing microRNA was extracted. cDNA was synthesized for miR-125a and miR-146a genes and analyzed by real-time PCR. Results were presented as fold changes. As compared to healthy controls, SLE patients expressed lower levels of miR-125a and miR-146a. PBMCs treated with Lactobacillus rhamnosus , Lactobacillus delbrueckii , or both probiotics had significantly higher levels of miR-125a and miR-146a compared to the untreated group. Treatment of PBMCs with both L. rhamnosus and L. delbrueckii upregulated the expression of miR-125a and miR-146a in treated cells compared with untreated cells in SLE patients ( p = 0.02, p = 0.001). Lactobacillus rhamnosus and Lactobacillus delbrueckii modify lupus patients’ immune responses and disease effects by regulating miR-125a and miR-146a.

Background HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disease of the central nervous system (CNS). Teriflunomide is an oral agent developed for the treatment of multiple sclerosis (MS) by suppressing the proliferation of autoreactive lymphocytes. This study was conducted to evaluate the efficacy of teriflunomide in HAM/TSP patients in Northeast Iran. Methods This study was a triple-blind, randomized, placebo-controlled trial involving 22 patients with HAM/TSP. The intervention group ( n  = 11) received one tablet of teriflunomide (14 mg daily), while the control group ( n  = 11) received one placebo tablet for 12 months. Muscle strength, spasticity, motor disability, urinary disorders, walking speed, laboratory factors, and drug complications were examined during the study. Results In the intervention group, consumption of teriflunomide decreased the duration of walking according to the T25FW test ( p  = 0.01). The severity of OMDS disability also significantly decreased ( P  < 0.001). Additionally, the total score of UDS in the intervention group decreased. The levels of HTLV-1 proviral load significantly decreased ( p  = 0.003). No adverse effects were observed, and the increase in liver enzyme levels was tolerable and controllable. Conclusions Teriflunomide effectively reduced the proviral load, improved the severity of disability and walking speed, and better controlled urinary and constipation symptoms without any adverse effects. Therefore, teriflunomide can be considered a disease-modifying therapy for patients with HAM/TSP. However, further studies with a large number of patients and longer duration, along with the determination of specific HAM/TSP-associated biomarkers, are needed to validate the results of the present study. Trial registration IRCT20180618040127N3; November 19, 2021.

Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus known to be associated with adult T-cell lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Previous researches and brain imaging techniques have suggested cognitive abnormalities as well as brain damage in individuals infected with this virus. Given the insufficient amount of studies on how this virus can impact the affected person’s cognition, we aimed to assess and compare the cognitive abnormalities of HAM/TSP patients, asymptomatic HTLV-1 carriers, and healthy controls. This cross-sectional study was conducted on 51 patients divided into 3 groups; a group of HAM/TSP patients, a group of asymptomatic HTLV-1 carriers, and an uninfected control group. Each group contained 17 members. The cognitive state of the studied population was assessed using the Mini-Mental State Exam (MMSE), Symbol Digit Modalities Test (SDMT), Rey–Osterrieth complex figure test (ROCF), the “Verbal Fluency Test” and the “Trail Making Test” (TMT) components of the Delis–Kaplan executive function system (D-KEFS) test, the Rey Auditory Verbal Learning Test (RAVLT), and digit span memory test. Patients diagnosed with HAM/TSP received significantly lower scores on the SDMT, ROCF, TMT, RAVLT, digit span memory test, and the orientation, calculation, and recall component of the MMSE assessment ( p -value < 0.001). In addition, the asymptomatic HTLV-1 carriers obtained lower scores on the SDMT, ROCF, digit span memory test, and the orientation, calculation, and recall component of the MMSE assessment compared to the control group ( p -value < 0.001). Overall, the findings suggest that HAM/TSP, or an asymptomatic infection with HTLV-1 could lead to cognitive deficits in the affected individuals. This can further emphasize the importance of assessing the cognitive function and psychiatric abnormalities of those infected with this virus.

Human T-cell lymphotropic virus type 1 (HTLV-1) can induce a neuroinflammatory condition that leads to myelopathy. Pentraxin 3 (PTX3) is an acute-phase protein that its plasma concentration increases during inflammation. We aimed to determine whether PTX3 serum level is elevated in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients and HTLV-1 asymptomatic carriers (ACs) and evaluate its association with proviral load and clinical features. The serum level of PTX3 was measured using an enzyme-linked immunosorbent assay in 30 HAM patients, 30 HTLV-1 ACs, and 30 healthy controls. Also, the HTLV-1 proviral load was determined via real-time PCR technique. The findings showed that PTX3 serum level was significantly higher in HAM patients than in both asymptomatic carriers and healthy controls (p values < 0.0001). No correlation between PTX3 and the proviral load was observed in HAM patients and asymptomatic carriers (r = − 0.238, p = 0.205 and r = − 0.078, p = 0.681, respectively). The findings showed that there was no significant correlation between PTX3 and motor disability grading (MDG) (r = − 0.155, p = 0.41) nor urinary disturbance score (UDS) (r = − 0.238, p = 0.20). Higher levels of PTX3 are associated with HTLV-1-associated myelopathy compared to asymptomatic carriers. This finding may support the idea that PTX3 has the potential as a diagnostic biomarker.

The findings of previous studies are inconclusive in terms of psychological abnormalities and sexual function in asymptomatic human lymphotropic virus type 1 (HTLV-1) carriers. This study aimed to evaluate the prevalence of sexual dysfunction and its relationship with psychological abnormalities in asymptomatic HTLV-1 carriers. This cross-sectional study was conducted on asymptomatic HTLV-1 patients who were referred to the Neurology Clinic of a tertiary hospital in Mashhad, Iran. Patients with spastic paraparesis, leukemia, and uveitis, and those with an expanded disability status scale (EDSS) score higher than 2 were excluded. Sexual function in male and female subjects was evaluated using the brief male sexual function inventory (BMSFI) and female sexual dysfunction index (FSFI) questionnaires, respectively. The severity of psychological symptoms was evaluated in all patients using the symptom checklist-90-revised (SCL-90-R) questionnaire. A total of 117 patients (61 males and 56 females) with a mean age of 35.3 ± 6.3 years were evaluated. Overall, 50.9 of males had a high and 39.3 of females had a good sexual function. Both male and female patients with poor sexual function were older and had more children compared to those with good sexual function (P < 0.05). There was no significant difference in the distribution pattern of SCL-90 domains between patients with high and low to moderate sexual function among male patients (P > 0.05). Depression, hostility, interpersonal sensitivity, paranoid ideation, and psychological abnormality were significantly more prevalent in female patients with poor sexual function compared to those with good sexual function (P < 0.05). The prevalence of psychological abnormalities was high in female with sexual dysfunction and these disorders might have a negative effect on various dimensions of sexual function.