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Dihydrolipoamide dehydrogenase (DLD) deficiency is an ultra-rare autosomal-recessive inborn error of metabolism, affecting no less than five mitochondrial multienzyme complexes. With approximately 30 patients reported to date, DLD deficiency was associated with three major clinical presentations: an early-onset encephalopathic phenotype with metabolic acidosis, a predominantly hepatic presentation with liver failure, and a rare myopathic phenotype. To elucidate the demographic, phenotypic, and molecular characteristics of patients with DLD deficiency within the Israeli population, data were collected from metabolic disease specialists in four large tertiary medical centers in the center and south of Israel. Pediatric and adult patients with biallelic variants in DLD were included in the study. A total of 53 patients of 35 families were included in the cohort. Age at presentation ranged between birth and 10 years. Wide phenotypic variability was observed, from asymptomatic individuals in their sixth decade of life, to severe, neonatal-onset disease with devastating neurological sequelae. Six DLD variants were noted, the most common of which was the c.685G>T (p.G229C) variant in homozygous form (24/53 patients, 45.3%; 13/35 families), observed mostly among patients of Ashkenazi-Jewish descent, followed by the homozygous c.1436A>T (p.D479V) variant, found in 20 patients of Bedouin descent (37.7%; 16/35 families). Overall, patients did not necessarily present as one of the previously described distinct clinical phenotypes. DLD deficiency is a panethnic disorder, with significant phenotypic variability, and comprises a continuum, rather than three distinct clinical presentations., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) is a demyelinating central nervous system disorder. We aimed to uncover immune pathways altered in MOGAD to predict disease progression. Using nanostring nCounter technology, we analyzed immune gene expression in PBMCs from MOGAD patients and compare it with healthy controls (HCs). We found 35 genes that distinguished MOGAD patients and HCs. We then validated those results in a larger cohort including MS and NMOSD patients. Expressions of HLA-DRA was significantly lower in MOGAD patients. This reduction in HLA-DRA, correlated with a monophasic disease course and greater brain volume, enhancing our ability to predict MOGAD progression., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Co-inhibitory receptors (CIR)s regulate T cell-mediated immune responses and growing evidence links co-inhibitory receptors to the progression of neuroimmunological diseases. We studied the expression levels of CIRs: TIM-3, TIGIT, PD-1 and LAG-3 in the peripheral blood mononuclear cells (PBMCs) of 30 patients with Neuromyelitis optica spectrum disorder (NMOSD), 11 Multiple sclerosis (MS) patients and 31 Healthy controls (HC). We found that the mRNA expression levels of TIM-3 were significantly increased in NMOSD compared with HC, and increased LAG-3 surface protein expression was also observed on T-cells of NMOSD patients. Moreover, we observed a negative correlation between LAG-3 expression and disease severity in NMOSD. Our findings suggest a protective effect of LAG-3 in the setting of NMOSD, and that the differential expression of CIRs observed in this study may play a role in the pathological process of NMOSD., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier B.V.)

Background: Thyroid hormones play a critical role in both neuronal and glial cell functions. Multiple sclerosis (MS) has increased co-occurrence with autoimmune thyroid diseases, and recent studies have suggested a potential link between neuromyelitis optica spectrum disorder (NMOSD) and thyroid hormones. However, no previous studies have examined the relationship between thyroid hormones and myelin oligodendrocyte glycoprotein-associated demyelination (MOGAD)., Methods: We investigated the role of thyroid hormones in central nervous system (CNS) autoimmune demyelinating diseases in 26 MOGAD patients, 52 NMOSD patients, 167 patients with MS, and 16 patients with other noninflammatory neurological disorders. Thyroid hormone levels and clinical data (Expanded Disability Status Scale [EDSS]) were analyzed. Volumetric brain information was determined in brain magnetic resonance imaging (MRI) using the MDbrain platform., Results: MOGAD patients had significantly higher levels of free triiodothyronine (FT3) compared to NMOSD patients. No correlation was found between FT3 levels and disease severity or brain volume. Thyroid-stimulating hormone (TSH) levels did not differ significantly between the groups, but in NMOSD patients, higher TSH levels were associated with lower disability scores and increased brain volume. No significant differences in free thyroxine (FT4) levels were observed between the different groups, however, FT4 levels were significantly higher in relapsing versus monophasic MOGAD patients and increased FT4 levels were associated with a higher EDSS and lower brain volume in NMOSD patients., Conclusion: Our findings highlight the potential involvement of thyroid hormones specifically in MOGAD patients and other demyelinating CNS disorders. Understanding the role of thyroid hormones in relapsing vs monophasic MOGAD patients and in comparison to other demyelinating disorder could lead to the development of therapeutic interventions. Further studies are needed to explore the precise mechanisms and potential interventions targeting the thyroid axis as a treatment strategy., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Background: Pregnancy has been observed to reduce the frequency of relapses in Multiple Sclerosis (MS) patients, but the relapse risk tends to increase during the early post-partum period. Increased pre- and post-partum disease activity may predict a poor long-term prognosis. This study aimed to evaluate the correlation between magnetic resonance imaging (MRI) activity during the year before pregnancy and long-term clinically meaningful worsening in Expanded Disability Status Scale (EDSS)., Methods: This observational, retrospective, case-control study included 141 pregnancies in 99 females with MS. Statistical analyses were used to evaluate the correlation between MRI activity during the year pre-pregnancy and post-partum clinical worsening during a 5-year follow-up. Clustered logistic regression was used to investigate the predictors of 5-year clinically meaningful worsening in EDSS (lt-EDSS)., Results: We found a significant correlation between an active MRI pre-pregnancy and lt-EDSS (p = 0.0006). EDSS pre-pregnancy and lt-EDSS were also significantly correlated (p = 0.043). Using a multivariate model, we predicted which females would not experience long-term clinical deterioration by a stable MRI pre-pregnancy (92.7% specificity; p = 0.004)., Conclusions: An active MRI pre-conception is a strong predictor of lt-EDSS and a higher annual relapse rate during the follow-up period, regardless of whether the female had clinical evidence of disease activity prior to conception and delivery. Optimizing disease control and achieving imaging stability prior to conception may reduce the risk of long-term clinical deterioration., (© 2023. Fondazione Società Italiana di Neurologia.)

To date, there are no accepted soluble markers for disease activity and progression of neuromyelitis optica spectrum disorder (NMOSD). We aimed to evaluate longitudinal interleukin (IL)-6 levels in sera of NMOSD patients in correlation with disease activity and brain volume. We analyzed IL-6 serum levels of 26 NMOSD patients during relapse and remission. Significantly increased IL-6 levels were detected in patients with NMOSD during relapse. Furthermore, increased IL-6 levels correlated with relapse severity and brain atrophy. Our findings suggest that IL-6 serum level could serve as a biomarker for disease activity in NMOSD., (Copyright © 2022. Published by Elsevier B.V.)

Background: Multiple sclerosis (MS) patients receive immunomodulatory treatments which can influence their ability to maintain vaccine specific serological response overtime. MS patients treated with cladribine tablets developed a positive serology response following two doses of mRNA COVID-19 vaccine. However, there is only limited data regarding the effect of cladribine tablets on long-term humoral response after the second and the third booster., Methods: Serology response to SARS-CoV-2 was tested in healthy controls (HCs) and MS patients treated with cladribine tablets 6 and 9-12 months after the second dose, and 1 and 3-6 months following the third booster-dose of the BTN162b2 mRNA vaccine., Results: Thirty-five out of 36 MS patients treated with cladribine tablets and 100% (46/46) of HCs had a positive serology response up to 10 months after the second vaccine dose. In addition, all cladribine tablets -treated MS patients (22/22) and HCs (24/24) had a positive robust serology response following the third vaccine with a positive humoral response sustain up to 6 months. One month after the third vaccine dose IgG levels were significantly lower in patients treated with cladribine tablets compared to HCs (15,598+11,313 vs 26,394+11,335, p<0.01). Six-month post second vaccine and 3-6 months post third vaccine there was no difference in IgG levels between the groups (1088.0 ± 1072.0 vs 1153.0 ± 997.1, p = 0.79; 5234+4097 vs 11,198+14,679, p = 0.4)., Conclusion and Relevance: MS patients treated with cladribine tablets have sustained positive vaccine specific serology response following the second and third SARS-CoV-2 vaccine dose., (Copyright © 2022. Published by Elsevier B.V.)

Neuromyelitis optica (NMO) is a rare disease usually presenting with bilateral or unilateral optic neuritis with simultaneous or sequential transverse myelitis. Autoantibodies directed against aquaporin-4 (AQP4-IgG) are found in most patients. They are believed to cross the blood−brain barrier, target astrocytes, activate complement, and eventually lead to astrocyte destruction, demyelination, and axonal damage. However, it is still not clear what the primary pathological event is. We hypothesize that the interaction of AQP4-IgG and astrocytes leads to DNA damage and apoptosis. We studied the effect of sera from seropositive NMO patients and healthy controls (HCs) on astrocytes’ immune gene expression and viability. We found that sera from seropositive NMO patients led to higher expression of apoptosis-related genes, including BH3-interacting domain death agonist (BID), which is the most significant differentiating gene (p < 0.0001), and triggered more apoptosis in astrocytes compared to sera from HCs. Furthermore, NMO sera increased DNA damage and led to a higher expression of immunological genes that interact with BID (TLR4 and NOD-1). Our findings suggest that sera of seropositive NMO patients might cause astrocytic DNA damage and apoptosis. It may be one of the mechanisms implicated in the primary pathological event in NMO and provide new avenues for therapeutic intervention.

Oligodendrocyte progenitor cells (OPCs) are responsible for remyelination in the central nervous system (CNS) in health and disease. For patients with multiple sclerosis (MS), remyelination is not always successful, and the mechanisms differentiating successful from failed remyelination are not well-known. Growing evidence suggests an immune role for OPCs, in addition to their regenerative role; however, it is not clear if this helps or hinders the regenerative process. We studied the effect of cerebrospinal fluid (CSF) from relapsing MS (rMS) and progressive MS (pMS) patients on primary OPC differentiation and immune gene expression and function. We observed that CSF from either rMS or pMS patients has a differential effect on the ability of mice OPCs to differentiate into mature oligodendrocytes and to express immune functions. CSF of pMS patients impaired differentiation into mature oligodendrocytes. In addition, it led to decreased major histocompatibility complex class (MHC)-II expression, tumor necrosis factor (TNF)-α secretion, nuclear factor kappa-B (NFκB) activation, and less activation and proliferation of T cells. Our findings suggest that OPCs are not only responsible for remyelination, but they may also play an active role as innate immune cells in the CNS., (© 2022 The Authors. GLIA published by Wiley Periodicals LLC.)

Background: Myelin oligodendrocyte glycoprotein antibody disorders (MOGAD) have evolved as a distinct group of inflammatory, demyelinating diseases of the CNS. MOGAD can present with a monophasic or relapsing disease course with distinct clinical manifestations.However, data on the disease course and disability outcomes of these patients are scarce. We aim to compare brain volumetric changes for MOGAD patients with different disease phenotypes and HCs., Methods: Brain magnetic resonance imaging (MRI) scans and clinical data were obtained for 22 MOGAD patients and 22 HCs. Volumetric brain information was determined using volBrain and MDbrain platforms., Results: We found decreased brain volume in MOGAD patients compared to HCs, as identified in volume of total brain, gray matter, white matter and deep gray matter (DGM) structures. In addition, we found significantly different volumetric changes between patients with relapsing and monophasic disease course, with significantly decreased volume of total brain and DGM, cerebellum and hippocampus in relapsing patients during the first year of diagnosis. A significant negative correlation was found between EDSS and volume of thalamus., Conclusions: Brain MRI analyses revealed volumetric differences between MOGAD patients and HCs, and between patients with different disease phenotypes. Decreased gray matter volume during the first year of diagnosis, especially in the cerebrum and hippocampus of MOGAD patients was associated with relapsing disease course., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rechtman, Brill, Zveik, Uliel, Haham, Bick, Levin and Vaknin-Dembinsky.)

Background: multiple sclerosis (MS) patients are treated with immunomodulatory treatments that can influence their ability to develop a protective antibody response to the SARS-CoV-2 vaccine. Vaccine efficacy is important for treatment decision and for patients' reassurance. The main objective is to assess antibody response to SARS-CoV-2 vaccine in MS patients treated with cladribine., Methods: Serology response was tested in 97 participants, 67 MS patients and 30 healthy controls (HCs), using two independent methods, 2-3 weeks following the second dose of the BNT162b2 vaccine., Results: HCs (n = 30) and MS patients treated with cladribine (n = 32) had 100% positive serology response against the SARS-CoV-2 spike protein following the second vaccine dose (mean S1/S2-IgG and RBD-IgG:284.5 ± 104.9, 13,041±9411 AU/mL and 226.3 ± 121.4, 10,554±11,405 AU/mL respectively). Comparable findings were observed for untreated MS patients, and interferon beta-1a-treated MS patients (mean S1/S2-IgG: 282.1 ± 100.1, 276.9 ± 94.31 AU/mL respectively). No correlation was found between lymphocyte counts, treatment duration, or time between cladribine dose and vaccination, and serology response or antibody titers., Conclusion and Relevance: Cladribine treated MS patients are able to produce antibodies to the SARS-CoV-2 mRNA vaccine. In the era of the COVID-19 pandemic, it is reassuring and important for both patients and physicians and will allow to develop consensus guidelines., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Importance: B-cell-depleting therapies may affect the development of a protective immune response following vaccination. Understanding the ability to develop vaccine-specific immunity to COVID-19 in patients with multiple sclerosis (MS) treated with B-cell-depleting therapy is of importance for clinical decisions., Objective: To assess SARS-CoV-2 vaccine-specific humoral and cellular responses in patients treated with ocrelizumab compared with healthy controls., Design, Setting, and Participants: This single-center study performed at Hadassah Medical Center in Jerusalem, Israel, included patients with MS treated with ocrelizumab, healthy controls, and untreated patients with MS. Vaccination occurred between December 2020 and April 2021. Participants donated blood 2 to 4 and 2 to 8 weeks after the second vaccine dose for antibody and T-cell assessments, respectively., Exposures: All participants received 2 doses of BNT162b2 vaccine (Pfizer/BioNTech) and completed the study., Main Outcomes and Measures: Proportion of patients treated with ocrelizumab with SARS-CoV-2-specific serology and/or T-cell responses following vaccination. All participants underwent SARS-CoV-2 antibody testing; 29 patients treated with ocrelizumab and 15 healthy controls had evaluation of SARS-CoV-2-specific T-cell responses., Results: Of 112 participants, 49 (43.8%) had MS and were treated with ocrelizumab (33 [67.3%] female; mean [SD] age, 47.9 [13.3] years), 23 (20.5%) had MS and were not treated with disease-modifying therapies (18 [78.3%] female; mean [SD] age, 49 [13.4] years), and 40 (35.7%) were healthy controls (25 [62.5%] female; mean [SD] age, 45.3 [16] years). Twenty-six of 29 patients (89.7%) treated with ocrelizumab and 15 of 15 healthy controls (100%) had SARS-CoV-2-specific T cells following vaccination at similar levels (mean [SD], 15.4 [7.6] and 14.3 [6.3] spot-forming cells, respectively). Mean antibody titers and positive serology rate were lower in the group of patients treated with ocrelizumab (mean [SD] antibody titers and positive serology rate, 26.2 [49.2] and 376.5 [907.6] AU/mL; 10 of 40 [25%] and 20 of 49 [40.8%] for S1/S2 and receptor-binding domain, respectively) compared with healthy controls (mean [SD] antibody titers and positive serology rate, 283 [100] and 12 712 [9114] AU/mL; 100% S1/S2 and receptor-binding domain) and untreated patients (mean [SD] antibody titers and positive serology rate, 288.3 [113.8] and 10 877 [9476] AU/mL; 100% S1/S2 and receptor-binding domain), with positive association to time from ocrelizumab infusion (S1/S2: r = 0.7, P < .001; receptor-binding domain: r = 0.4, P = .04)., Conclusion and Relevance: In this study, patients with MS who were treated with ocrelizumab generated comparable SARS-CoV-2-specific T-cell responses with healthy controls and had lower antibody response following vaccination. Given the potential role of T cells in protection from severe disease, this is reassuring and will help physicians develop consensus guidelines regarding MS treatment in the era of the COVID-19 pandemic.

Case report describing a patient infected with COVID-19 after initiation of Cladribine, with a favorable disease course and positive seroconversion., (Copyright © 2021. Published by Elsevier B.V.)

Background: The COVID-19 pandemic presents two main concerns for patients with myasthenia gravis (MG); chronic immunosuppression may put them at greater risk, and some proposed treatments for COVID-19 could cause MG exacerbation., Case Description: We present three patients with generalized seropositive MG who developed COVID-19. All patients had a favorable outcome, with only one patient experiencing exacerbation. In this case, exacerbation began before COVID-19; she required ICU admission, non-invasive ventilatory support, and received hydroxychloroquine, lopinavir and ritonavir which were well tolerated. One patient received IVIG in place of scheduled plasma exchange., Conclusion: Outcome was favorable in all cases despite immunosuppressive therapy, use of experimental COVID-19 medication and switching of plasma exchange for IVIG., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Our knowledge about genetic factors that drive the worsening of neuromyelitis optica (NMO) is limited. Herein, we analyzed the macrophage migration inhibitory factor (MIF) -173G/C functional polymorphism in NMO patients and controls. Our data reveal that the frequency of the high-expression MIF genotypes (CC/GC) did not differ between the two groups. However, frequency of this genotypes was elevated in patients diagnosed with both optic neuritis and myelitis compared with patients that were diagnosed with only one symptom. Furthermore, patients carrying the CC/CG genotypes had significantly higher disability score. We conclude that MIF is associated with NMO severity rather than susceptibility., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Electrostatic fields tune the ground state of interfaces between complex oxide materials. Electronic properties, such as conductivity and superconductivity, can be tuned and then used to create and control circuit elements and gate-defined devices. Here we show that naturally occurring twin boundaries, with properties that are different from their surrounding bulk, can tune the LaAlO 3 /SrTiO 3 interface 2DEG at the nanoscale. In particular, SrTiO 3 domain boundaries have the unusual distinction of remaining highly mobile down to low temperatures, and were recently suggested to be polar. Here we apply localized pressure to an individual SrTiO 3 twin boundary and detect a change in LaAlO 3 /SrTiO 3 interface current distribution. Our data directly confirm the existence of polarity at the twin boundaries, and demonstrate that they can serve as effective tunable gates. As the location of SrTiO 3 domain walls can be controlled using external field stimuli, our findings suggest a novel approach to manipulate SrTiO 3 -based devices on the nanoscale.

Oxide interfaces, including the LaAlO3/SrTiO3 interface, have been a subject of intense interest for over a decade due to their rich physics and potential as low-dimensional nanoelectronic systems. The field has reached the stage where efforts are invested in developing devices. It is critical now to understand the functionalities and limitations of such devices. Recent scanning probe measurements of the LaAlO3/SrTiO3 interface have revealed locally enhanced current flow and accumulation of charge along channels related to SrTiO3 structural domains. These observations raised a key question regarding the role these modulations play in the macroscopic properties of devices. Here we show that the microscopic picture, mapped by scanning superconducting quantum interference device, accounts for a substantial part of the macroscopically measured transport anisotropy. We compared local flux data with transport values, measured simultaneously, over various SrTiO3 domain configurations. We show a clear relation between maps of local current density over specific domain configurations and the measured anisotropy for the same device. The domains divert the direction of current flow, resulting in a direction-dependent resistance. We also show that the modulation can be significant and that in some cases up to 95% of the current is modulated over the channels. The orientation and distribution of the SrTiO3 structural domains change between different cooldowns of the same device or when electric fields are applied, affecting the device behavior. Our results, highlight the importance of substrate physics, and in particular, the role of structural domains, in controlling electronic properties of LaAlO3/SrTiO3 devices. Furthermore, these results point to new research directions, exploiting the STO domains' ability to divert or even carry current., Competing Interests: The authors declare no competing financial interest.

Manipulating individual vortices in a deterministic way is challenging; ideally, manipulation should be effective, local, and tunable in strength and location. Here, we show that vortices respond to local mechanical stress applied in the vicinity of the vortex. We utilized this interaction to move individual vortices in thin superconducting films via local mechanical contact without magnetic field or current. We used a scanning superconducting quantum interference device to image vortices and to apply local vertical stress with the tip of our sensor. Vortices were attracted to the contact point, relocated, and were stable at their new location. We show that vortices move only after contact and that more effective manipulation is achieved with stronger force and longer contact time. Mechanical manipulation of vortices provides a local view of the interaction between strain and nanomagnetic objects as well as controllable, effective, and reproducible manipulation technique.