Pediatric Case Study Suggests IgG1 Deficiency May Influence IgG3-Dominant MOG Antibody Disease Presentation

A recently published case study of a 12-year-old boy showed that myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) can be characterized by isolated immunoglobulin G3 (IgG3) subclass positivity and persistent IgG1 deficiency, suggesting that immunoglobulin subclass composition may influence disease presentation and antibody detection.¹

In this case study, researchers tested the serum and cerebrospinal fluid (CSF) samples of the patient for MOG-antibodies (MOG-Abs) and aquaporin-4 antibodies (AQP4-Abs) using a live cell-based assay. Overall, findings revealed that the AQP4-IgG was negative whereas the MOG-IgG was positive in the serum and CSF using an anti-human IgG-Fcγ–specific secondary antibody. Notably, the MOG-IgG–specific antibody index was 2.2, indicating no intrathecal synthesis, and MOG-IgG1 was undetectable.

Results of a subclass analysis demonstrated isolated MOG-IgG3 positivity in the serum and CSF, whereas MOG-IgG2 and IgG4 were undetectable. Additionally, 6 months following symptom onset, serum MOG-IgG titers decreased with persistent MOG-IgG3 positivity. At the 1-year follow-up, authors reported that both MOG-IgG and MOG-IgG3 were undetectable; MOG-IgG1, IgG2, and IgG4 remained undetectable throughout.

“Our findings suggest that subclinical IgG1 deficiency may underlie MOG-IgG3 predominance or selective detection, highlighting how variability total IgG subclass composition could affect the interpretation of subclass-specific antibody assays in MOGAD. They also point to a possible pathogenic contribution for MOG-IgG3, particularly in the context of altered subclass expression or switching and/or in the early phases of the disease,” lead author Anna Fetta, MD, junior assistant professor in the Department of Medical and Surgical Sciences at the University of Bologna in Italy, and colleagues wrote.¹

The patient initially presented with subacute neurologic symptoms, including cervical pain, limb weakness, paresthesia, and intermittent fever, without recent infections or relevant exposures. Researchers reported that the prior MRI demonstrated multiple T2–fluid-attenuated inversion recovery hyperintense lesions involving supratentorial, infratentorial, and longitudinally extensive spinal cord regions.

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In a neurologic examination, findings revealed severe tetraparesis, pyramidal signs, lower limb sensory loss, and neurogenic bladder, with preserved consciousness and normal electroencephalography findings. Results of a CSF analysis showed pleocytosis and elevated protein, Ig G, interleukin-6, and albumin quotient, with normal QIgG and negative oligoclonal bands. Authors noted also that visual acuity remained intact, and optical coherence tomography demonstrated borderline thinning of the left retinal nerve fiber layer and ganglion cell complex.

All told, treatment with intravenous (IV) methylprednisolone and Ig was associated with marked clinical improvement, followed by a 6-week oral prednisone taper. At 2-year follow-up, the patient remained relapse-free with a normal neurologic examination. In addition, serologic evaluation showed protective responses to measles and rubella, a borderline response to mumps, and nonprotective antibody titers to hepatitis B, diphtheria, tetanus, and pertussis at baseline and at 8 months.

Investigators also conducted a systematic review in which 4 of 30 screened studies met inclusion criteria, highlighting the limited number of reported cases with isolated MOG-IgG3 positivity, whereas most patients with MOGAD demonstrate predominantly IgG1 antibodies.^2-5 In the prior studies, findings have suggested that IgG3 dominance may reflect temporal changes in antibody subclass expression, treatment effects, or variability in disease mechanisms rather than a distinct clinical phenotype. Moreover, authors noted that previously reported cases have largely involved transverse myelitis and/or optic neuritis.

“Our case suggests that isolated MOG-IgG3 positivity may, in some instances, reflect an epiphenomenon of subclinical selective IgG1 deficiency. Alongside this, our patient's failure of the normally unidirectional IgG3-to-IgG1 switch6 may reflect a “two-hit” mechanism where pre-existing IgG1 deficiency created a permissive environment for a sustained IgG3-skewed response,” Fetta et al noted.¹ “The single-case nature limits generalizability of these findings and larger cohorts are needed to clarify the role of IgG3 in MOGAD pathogenesis, phenotype and diagnosis, and its potential as a therapeutic target.”

REFERENCES
1. Fetta A, Conti F, Lopalco A, et al. MOG IgG3-Subclass Antibodies in MOG-Associated Disease: Insights From a Pediatric Case With IgG1 Deficiency and Literature Review. Neurol Neuroimmunol Neuroinflamm. 2026;13(1):e200523. doi:10.1212/NXI.0000000000200523
2. Waters P, Woodhall M, O'Connor KC, et al. MOG cell-based assay detects non-MS patients with inflammatory neurologic disease. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e89. Published 2015 Mar 19. doi:10.1212/NXI.0000000000000089
3. Gastaldi M, Scaranzin S, Jarius S, et al. Cell-based assays for the detection of MOG antibodies: a comparative study. J Neurol. 2020;267(12):3555-3564. doi:10.1007/s00415-020-10024-0
4. Mariotto S, Ferrari S, Monaco S, et al. Clinical spectrum and IgG subclass analysis of anti-myelin oligodendrocyte glycoprotein antibody-associated syndromes: a multicenter study. J Neurol. 2017;264(12):2420-2430. doi:10.1007/s00415-017-8635-4
5. Jarius S, Ringelstein M, Schanda K, et al. Improving the sensitivity of myelin oligodendrocyte glycoprotein-antibody testing: exclusive or predominant MOG-IgG3 seropositivity-a potential diagnostic pitfall in patients with MOG-EM/MOGAD. J Neurol. 2024;271(7):4660-4671. doi:10.1007/s00415-024-12285-5