Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease characterized by marked clinical heterogeneity. While the genetic architecture underlying disease susceptibility is well established, the role of genetic factors in shaping disease prognosis remains clearly defined. In this structured narrative review, we examine available evidence on genetic contribution to key MS prognostic domains. This includes clinical outcomes, such as age at onset, relapse rate, disability progression, neurological sequelae, and cognitive impairment. We also consider radiological measures like brain and spinal cord lesion burden, gadolinium-enhancing lesions, and atrophy, as well as laboratory biomarkers, such as oligoclonal bands and Immunoglobulin G (IgG) index. Overall, current evidence suggests that genetic influences on prognosis are modest and highly heterogeneous. Only a limited number of associations-primarily from genome-wide association studies (GWAS)-have shown consistent replication, whereas many reported findings come from small candidate-gene studies and remain unconfirmed. Among these, the largest GWAS on age-related Multiple Sclerosis Severity Score (MSSS) identified a locus in the DYSF-ZNF638 region reaching genome-wide significance. The strongest evidence from GWAS relates to relapse rate, magnetic resonance imaging (MRI) measures (e.g., thalamic atrophy) and intrathecal IgG synthesis, the latter also reaching genome-wide significance. Interpretation of genotype-phenotype associations is further limited by small sample sizes, limited replication, heterogeneity in study design with the predominance of candidate-gene approaches, variability in outcome definitions, treatment exposure, and population ancestry. These limitations currently preclude the routine use of genetic markers for prognostic stratification in clinical practice. Larger studies and collaborative genetic consortia efforts are needed to improve statistical power and reproducibility. Additionally, emerging epigenetic studies may provide valuable insights into prognosis and disease management. Understanding which genetic factors can predict diverse MS courses could enhance patient management and enable personalized treatment approaches.

BackgroundThe kappa free light chain (κ-FLC) index is a well-established biomarker in multiple sclerosis (MS). While the prognostic value of the κ-FLC index has been demonstrated in early relapsing–remitting MS, its prognostic value in primary progressive MS (PPMS) has not yet been investigated.MethodsIn this multicenter, retrospective cohort study, patients diagnosed with PPMS with diagnostic lumbar puncture and clinical follow-up of at least 12 months were recruited from nine MS centers across five countries. At baseline, age, sex, disease duration, and the number of T2 hyperintense (T2L) and contrast-enhancing T1 lesions (CEL) on MRI were determined. κ-FLC was measured using nephelometry/turbidimetry, and the κ-FLC index was calculated as (CSF κ-FLC/serum κ-FLC)/albumin quotient. At follow-up, the occurrence of disability progression and the administration of disease-modifying treatment (DMT) were registered. The primary endpoint was time to disability progression.ResultsA total of 121 PPMS patients were included with a median age of 53 years (25th–75th percentile: 46–59) and a balanced sex distribution (48.8% female). Multivariable Cox regression analysis revealed no significant association between the κ-FLC index and disability progression [hazard ratio (HR) 1.0, p = 0.950]. Prior use of DMT (HR 0.60, p = 0.023) and brain T2L > 9 at baseline (HR 2.22, p = 0.026) were significantly associated with disability progression. The remaining covariates, including age, sex, disease duration, and CEL, showed no significant associations.ConclusionThe κ-FLC index does not predict disability progression in PPMS, contrasting its growing role as a prognostic biomarker in relapsing MS. This highlights phenotypic differences in MS pathophysiology and underscores the need for prognostic biomarkers in PPMS.

Background:Comorbidities are a critical concern for clinicians in both the treatment and diagnosis of multiple sclerosis. Autoimmune diseases, including multiple sclerosis, often co-occur within individuals. However, most studies examining the incidence or prevalence of autoimmune diseases in persons with multiple sclerosis compared to healthy controls have used relatively small sample sets, with only a few being population-based. Objectives:To analyze the co-occurrence of other autoimmune diseases in persons with multiple sclerosis and determine whether common genetic susceptibility factors contribute to the co-occurrence of autoimmune diseases. Methods:We conducted a population-based study using administrative health records to include all residents of Piedmont, an Italian Region with about 4.3 million inhabitants, identifying individuals with multiple sclerosis and 14 other autoimmune diseases. For a subset of persons with multiple sclerosis with available genome-wide genotyping data, we investigated the influence of their genetic backgrounds using a polygenic risk score. Results:The prevalence of all 14 tested autoimmune diseases was higher in persons with multiple sclerosis compared to those without multiple sclerosis. Furthermore, persons with multiple sclerosis with autoimmune disease comorbidities had a higher polygenic risk score compared to persons with multiple sclerosis without comorbidities. Conclusion:Our findings confirm the co-occurrence of multiple sclerosis with several autoimmune diseases, and suggest that shared genetic susceptibility factors may influence this association.

Importance:Early treatment choice in relapsing-remitting multiple sclerosis (RRMS) is prognostically crucial, yet robust comparative data on cladribine vs sphingosine-1-phosphate receptor modulators (S1PRMs) in treatment-naive patients with RRMS are limited. Objective:To compare the clinical effectiveness of cladribine vs S1PRMs in treatment-naive individuals with RRMS. Design, Setting, and Participants:This comparative effectiveness research study used data from 108 Italian multiple sclerosis (MS) centers affiliated with the Italian Multiple Sclerosis and Related Disorders Register. All treatment-naive patients with RRMS who initiated cladribine or an S1PRM (fingolimod, ozanimod, or ponesimod) between January 2011 and October 2021 and had at least 12 months of follow-up were included. Propensity score matching and pairwise censoring were used to balance baseline differences and follow-up duration. Patient data were extracted from the register in September 2024. Exposure:Initiation of cladribine or an S1PRM, with duration reflecting clinical practice. Main Outcomes and Measures:The primary outcome was no evidence of disease activity (NEDA-3) and its subcomponents. Secondary analyses evaluated disability accrual subdivided into progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW), plus variables associated with treatment response. Cox proportional hazards models, adjusted for visit and magnetic resonance imaging (MRI) frequency, were used to compare outcomes. Results:Of the 1587 patients (485 taking cladribine and 1102 taking S1PRMs), matching yielded 475 pairs (950 individuals; mean [SD] age, 34.7 [10.7] years; 686 female [72.2%]), with a median (IQR) follow-up period of 25 (12-60) months. For the cladribine vs S1PRM groups, no significant differences were observed in relapse rates (72 patients [15.2%] vs 76 patients [16.0%]), MRI activity (137 patients [31.3%] vs 145 patients [34.8%]), or NEDA-3 loss (194 patients [44.4% vs 219 patients [52.2%]). Cladribine was associated with a lower risk of disability worsening vs S1PRM (54 patients [11.4%] vs 70 patients [14.7%]; hazard ratio [HR], 0.64; 95% CI, 0.42-0.96; P = .03), a finding that was confirmed in sensitivity analyses for patients younger than 40 years, those whose diagnoses were made according to the 2017 McDonald Criteria, and those with Expanded Disability Status Scale score less than or equal to 3.0. This was mainly driven by reduced PIRA risk with cladribine (HR, 0.40; 95% CI, 0.20-0.79; P = .009), with no RAW difference. After 36 months, patients treated with cladribine showed higher relapse risk (HR, 1.81; 95% CI, 1.02-3.20; P = .04) and increased NEDA-3 loss (HR, 2.08; 95% CI, 1.18-3.67; P = .01). Discontinuation rates were similar (HR, 0.92; 95% CI, 0.67-1.15; P = .58). Conclusions and Relevance:These findings suggest cladribine was associated with superior effectiveness in reducing disability progression over 25 months, likely due to reduced PIRA, despite comparable short-term NEDA-3 outcomes. However, relapse prevention declined after 36 months, suggesting retreatment or therapy modification within 3 years may be needed to maintain long-term disease control.

(1) Background: Multiple sclerosis (MS) is a biologically highly heterogeneous disease and has poor predictability at diagnosis. Moreover, robust data indicate that early disease activity strongly correlates with future disability. Therefore, there is a need for strong and reliable biomarkers from diagnosis to characterize and identify patients who require highly effective disease-modifying treatments (DMTs). Several biomarkers are promising, particularly neurofilament light chains (NFLs), but the relevance of others is less consolidated. (2) Methods: We evaluated a panel of axonal damage and inflammatory biomarkers in cerebrospinal fluid (CSF) and matched serum obtained from a cohort of 60 newly diagnosed MS patients. Disability at diagnosis, negative prognostic factors, and the initial DMT prescribed were carefully recorded. (3) Results: We observed correlations between different axonal biomarkers: CSF and serum NFL versus CSF total tau; and between the inflammatory marker osteopontin (OPN) and axonal biomarkers CSF p-Tau, CSF total tau, and serum NFL. CSF and serum NFL and total tau, as well as CSF OPN, positively correlated with EDSS at diagnosis. Moreover, CSF and serum NFL levels were increased in patients with gadolinium-enhancing lesions (p = 0.01 and p = 0.04, respectively) and in those treated with highly effective DMT (p = 0.049). Furthermore, CSF OPN and both CSF and serum NFL levels significantly differentiated patients based on EDSS, with a combined ROC AUC of 0.88. We calculated and internally validated biomarker (in particular serum NFL) thresholds that significantly identified patients with higher disability. Finally, CSF OPN levels and dissemination in the spinal cord were significant predictors of EDSS at diagnosis. (4) Conclusions: These preliminary exploratory data confirm the pathological interconnection between inflammation and axonal damage from early disease stages, contributing to early disability. Follow-up data, such as longitudinal disability scores, repeated serum measurements, a healthy control group, and external validation of our results, are needed. We suggest that combining several fluid biomarkers may improve the clinical characterization of patients.

The pathophysiology of cognitive impairment (CI) in multiple sclerosis (MS) remains unclear. Meningeal B cell aggregates may contribute to cortical grey matter pathology. Cerebrospinal fluid (CSF), kappa free light chains (KFLC), and KFLCs-Index (kappa-Index) are reliable quantitative markers of intrathecal synthesis, but few data have been presented exploring the association with CI, and no data are present for lambda FLC (LFLC) in MS. We evaluated cognition using the Brief International Cognitive Assessment for MS (BICAMS) battery and collected serum and CSF at diagnosis in newly diagnosed drug-naïve MS patients. We observed that patients with impaired verbal memory and overall CI showed increased CSF KFLCs (respectively p: 0.0003 and p: 0.003) and kappa-Index (respectively p: 0.01 and p: 0.02) compared to those with normal verbal memory and no CI. Patients with CI also displayed lower CSF LFLCs (p: 0.04) and lambda-Index (p: 0.001); however, only CSF KFLC negatively correlated with normalized results of verbal memory (for age, sex, and educational levels), even after correction for EDSS (r: −0.27 p: 0.01). Finally, CSF FKLC and kappa-Index were significant predictors of verbal memory in a multivariate analysis. Our results, suggest that intrathecal B cell activity might contribute to CI development in MS patients.

Ravulizumab, a monoclonal antibody against C5, is not currently approved for juvenile myasthenia gravis (MG). We are presenting a 14-year-old Moroccan girl diagnosed with antibody-positive generalized MG first treated with pyridostigmine 240 mg, prednisone 1 mg/kg/day, and thymectomy. Her clinical status remained unchanged (MG Foundation of America Clinical Classification: IIIa) with azathioprine 3 mg/kg, and steroids up to 2 mg/kg/day. She also required three rescue therapies over the subsequent 8 months, gained 10 kg, and had insomnia. We started compassionate ravulizumab treatment, as part of Alexion Pharmaceuticals expanded access program. At screening, the Myasthenia Gravis–Activities of Daily Living scale total score was 4, and Quantitative Myasthenia Gravis total scores were 13 (handgrip and forced vital capacity not performed). She continued her treatment every 8 weeks, and, at week 60, her Myasthenia Gravis–Activities of Daily Living scale total score was 0, and Quantitative Myasthenia Gravis total score was 1. This status was achieved despite an ongoing steroid tapering, that was possibly allowed using a rapidly-acting treatment. No significant infection or adverse effects were collected. We are presenting the first case of juvenile MG treated with ravulizumab. Clinical assessment showed at week 60 an improvement of 12 points according to the Quantitative Myasthenia Gravis scoring system, and 3 points to the Myasthenia Gravis–Activities of Daily Living scale total score. This case report supports the efficacy and safety of ravulizumab in MG patients aged <18 years.

Cerebrospinal fluid (CSF) kappa-free light chains (KFLC) are becoming a diagnostic biomarker for multiple sclerosis (MS). We aimed to compare the diagnostic performance of intrathecal synthesis biomarkers to that of oligoclonal bands (OB) in diagnosing MS, radiological and clinical isolated syndromes (RIS-CIS) on a large cohort of patients collected over 10 years. We collected 1124 patients (58

Background/Objectives: Axonal Charcot-Marie-Tooth disease type 2 (CMT2) accounts for 24% of Hereditary Motor/Sensory Peripheral Neuropathies. CMT2 type GG, due to four distinct heterozygous mutations in the Golgi brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1) gene (OMIM 606483), was described in seven cases from four unrelated families with autosomal dominant inheritance. It is characterized by slowly progressive distal muscle weakness and atrophy, primarily affecting the lower limbs. Here, we present two siblings sharing a novel GBF1 variant. Methods: Patient II.1 (male, 61 years at onset) presented lower limb hypoesthesia and walking difficulty; the examination revealed a postural tremor, a positive Romberg test, and muscle atrophy in the lower limbs and hands. Patient II.2 (his sister, 59 years at onset) had lower limb dysesthesias, hand paresthesia, and lower-limb stiffness. They underwent clinical evaluations, blood tests, and electroneurography. Their father represents a potentially affected individual, although a genetic analysis was not conducted. Results: All tests for peripheral neuropathies were unremarkable, including metabolic and autoimmune screening. Both showed a mixed demyelinating-axonal sensory-motor neuropathy. Genetic analysis revealed a new heterozygous GBF1 variant of uncertain significance. Conclusions: Based on autosomal dominant inheritance, as well as clinical and physiological features, a possible novel CMT2GG was diagnosed. Further research, including functional assays and in vitro studies, is necessary to confirm this variant's causal link.

BACKGROUND:Evidence on the impact of dimethyl fumarate (DMF) during pregnancy in women with multiple sclerosis (MS) is limited. OBJECTIVES:To investigate disease activity and pregnancy outcomes in a retrospective cohort of women exposed to DMF in early pregnancy. METHODS:Women discontinuing DMF after pregnancy confirmation were identified from 29 Italian MS Centers. Disease activity 12 months before conception, during pregnancy, and 12 months postpartum were recorded, exploring reactivation predictors. Pregnancy and fetal outcomes were assessed. RESULTS:The study analyzed 137 pregnancies (12 pregnancy losses, 125 live births) from 137 women (mean age 32.9 ± 4.7 years), discontinuing DMF within a median (interquartile range (IQR)) interval of 4.9 (3.7-5.7) weeks from conception. In live birth pregnancies, annualized relapse rate (ARR) significantly decreased during pregnancy (ARR = 0.07, 95% confidence interval (CI): 0.03-0.14, p = 0.021) compared to pre-conception (ARR = 0.21 (95% CI: 0.14-0.30)) and increased postpartum ((ARR = 0.22 (95% CI: 0.15-0.32), p = 0.006). Median time to first relapse (TTFR) was 3.16 (IQR: 1:87-5.42) months. Higher pre-conception relapse number (hazard ratio (HR) = 2.33, 95% CI: 1.08-5.02) and Expanded Disability Status Scale (EDSS; HR = 1.81, 95% CI: 1.17-2.74) were associated with shorter TTFR, while treatment resumption with longer TTFR (HR = 0.29, 95% CI: 0.11-0.74). Fetal outcomes were unaffected by DMF exposure. CONCLUSION:DMF discontinuation does not increase relapse risk during pregnancy. Early therapy restart prevents postpartum relapses. Early DMF exposure shows no adverse fetal outcomes.