Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune CNS disease that frequently causes severe optic neuritis, yet the molecular mechanisms driving retinal damage remain incompletely understood, especially across different NMOSD subgroups. Müller glial cells, which maintain retinal water-ion homeostasis through AQP4 and Kir4.1 channels, may represent a primary retinal target of circulating NMOSD-related autoantibodies and serum factors. We investigated how sera from AQP4-IgG+, MOG-IgG+, and double-seronegative (DSN) NMOSD patients affect the expression and localization of key Müller cell biomarkers. Human MIO-M1 Müller cells were stimulated with complement-inactivated patient or healthy control sera, and protein/mRNA levels of AQP4, Kir4.1, CRALBP, VEGF, and IL-6 were evaluated using immunofluorescence, Western blotting, and RT-qPCR. AQP4 membrane localization and internalization were assessed using WGA and EEA1 colocalization analyses. AQP4-IgG+ sera uniquely induced a marked reduction in AQP4 and Kir4.1 protein expression, together with mild AQP4 internalization and reduced membrane association. Despite protein loss, AQP4 and Kir4.1 transcripts were significantly upregulated, indicating a compensatory transcriptional response to antibody-mediated depletion. MOG-IgG + sera produced no major changes in the examined markers. In contrast, DSN sera selectively increased VEGF expression at both protein and mRNA levels, suggesting an alternative, antibody-independent mechanism of Müller cell activation. IL-6 expression showed non-significant changes across groups. These findings demonstrate subgroup-specific retinal glial responses to patient sera, with AQP4-IgG mediating early complement-independent loss of the AQP4-Kir4.1 water-ion channel complex, and DSN sera engaging distinct VEGF-related pathways. Our study establishes Müller cells as active contributors to NMOSD-associated retinal pathology and provides a foundation for exploring subgroup-tailored changes.

Neuromyelitis optica spectrum disorder (NMOSD) constitutes a demyelinating condition of the central nervous system driven by autoimmune inflammation. A hallmark of its pathogenesis is the antibody-mediated injury of astrocytes, primarily targeting the water channel aquaporin-4 (AQP4). Animal models are indispensable for dissecting disease mechanisms and accelerating the development of new therapies. However, creating models that closely mirror NMOSD remains difficult, in part because immune tolerance limits the induction of the autoreactive responses central to the disease. This review follows NMOSD over time and surveys experimental systems across four interconnected mechanistic themes: breakdown of immune tolerance, T-B cell collaboration, antibody-mediated effector injury, and the formation of pro-inflammatory tissue milieus that sustain pathology. For each theme, we outline the rationale for model design, evaluate how well key pathological features are produced, and discuss the limitations that shape interpretation. Rather than offering a single continuous reconstruction of human NMOSD, these platforms capture complementary and only partially overlapping aspects of pathogenesis. Taken together, they provide a mechanism-oriented framework for understanding how upstream immune dysregulation, humoral immunity, and tissue-level permissive factors shape disease expression. At the same time, they also highlight the distance between experimental systems and the heterogeneous, dynamic course seen in patients. We further discuss how findings from animal studies are informing therapeutic target discovery and outline priorities for the development of next-generation models with greater translational relevance.

Background and Objectives: Visual evoked potentials (VEPs) are a simple, noninvasive method for detecting subclinical visual pathway involvement in multiple sclerosis. This study investigated the frequency of VEP abnormalities and their associations with baseline clinical, radiological, and cerebrospinal fluid (CSF) features in treatment-naïve patients with clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) without prior optic neuritis. Materials and Methods: We retrospectively reviewed newly diagnosed, treatment-naïve CIS/early RRMS patients evaluated between January 2022 and July 2024 who underwent CSF analysis. Pattern-reversal VEPs were recorded under standardized conditions. VEP abnormalities were analyzed as any or bilateral, and associations were assessed using group comparisons and multivariable logistic regression. Results: In 101 patients (mean age 31.8 ± 9.7 years; 72% female; median EDSS 1.0), latency prolongation occurred in 69 (42 any,27 bilateral) and amplitude reduction in 33 (22 any, 11 bilateral). Among patients with latency prolongation, both the number of OCB bands and the IgG index were higher (bilateral p = 0.032; any p = 0.007). In multivariable analysis, male sex (p = 0.032) and pyramidal/brainstem-onset presentation (p = 0.006) were independently associated with any amplitude reduction; neither was associated with latency abnormalities. Conclusions: VEP abnormalities are common early in the disease, even without a history of optic neuritis. Male sex and pyramidal/brainstem-onset presentation were associated with reduced amplitude, suggesting that amplitude decrease may reflect early tissue dysfunction and may be related to adverse baseline clinical features. Associations between intrathecal immune activation and prolonged latency may indicate subclinical demyelination of the visual pathways related to inflammatory activity. Larger longitudinal studies are needed to clarify the clinical significance of VEP abnormalities in early RRMS.

Mitochondrial complex III (CIII) deficiency, resulting from abnormalities in its subunits or assembly factors, presents with diverse clinical manifestations. LYRM7-associated CIII deficiency is rare and typically presents with progressive neurodegeneration. We report a case series of LYRM7-associated CIII deficiency in two brothers, highlighting inflammatory demyelinating-like presentations, intrafamilial variability, and atypical disease progression. We present an investigational case series highlighting continuing challenges in diagnosing and managing LYRM7-associated mitochondrial complex III deficiency. Whole-exome sequencing (WES) was performed for diagnostic evaluation, followed by confirmatory Sanger sequencing and literature review of previously reported cases. Two brothers from a consanguineous family presented with ataxia, visual impairment, and progressive neurological deterioration including spasticity, seizures, cognitive decline, and motor weakness. Patient 1 (P1) experienced recurrent ataxic episodes beginning at 7 years of age, initially suspected to represent an inflammatory demyelinating disorder, while patient 2 (P2) demonstrated a more aggressive disease course with rapid neurological deterioration and early mortality at 8 years of age. Neuroimaging revealed cystic white matter changes suggestive of mitochondrial leukodystrophy and longitudinally extensive transverse myelitis (LETM) in both patients, differing from typical inflammatory demyelinating patterns. Genetic testing confirmed a pathogenic LYRM7 variant. Notably, intrafamilial clinical variability and the inflammatory-like presentation in P1- including LETM and optic neuritis mimicking neuromyelitis optica spectrum disorder (NMOSD)- distinguished our cases from previously reported patients. These findings expand the phenotypic spectrum of LYRM7-associated CIII deficiency and highlight diagnostic challenges. This case series expand the clinical spectrum of LYRM7-associated complex III deficiency and highlights relapsing inflammatory-like presentations as a potential diagnostic pitfall. Our findings emphasize the importance of considering mitochondrial disorders in children presenting with recurrent demyelinating-like episodes, atypical progression, or familial patterns. Early genetic diagnosis is essential for accurate diagnosis, counseling, and management of mitochondrial disorders.