The Genetic Differences Between Multiple Sclerosis (MS) and Neuromyelitis Optica (NMO)

Multiple Sclerosis (MS) and Neuromyelitis Optica (NMO) are autoimmune inflammatory disorders of the central nervous system, presenting with demyelination and neurological symptoms. Despite their similarities, these conditions differ significantly in their genetic architecture and phenotypic manifestations. This blog post delves into the genetic distinctions between MS and NMO, focusing on the association of CYP27B1 and CYP7A1 gene variants, the involvement of Aquaporin 4 (AQP4), HLA associations, and the GTF2I gene variant. It also explores their phenotypic differences and similarities.

Genetic Differences and Similarities
CYP27B1 and CYP7A1 Gene Variants Association
Research has highlighted the association of variants in the CYP27B1 gene, which is involved in vitamin D metabolism, with both MS and NMO in the Han Chinese population. Specifically, variants rs703842 and rs10876994 are associated with MS and NMO, respectively. Additionally, variants in the promoter region of CYP7A1 are linked with NMO but not MS, indicating distinct genetic risk factors for these conditions (Zhuang et al., 2015); (Zhao et al., 2013).

Aquaporin 4 (AQP4) Involvement
A significant difference between MS and NMO is the role of AQP4. Studies show extensive loss of AQP4 immunoreactivity in NMO lesions, distinct from MS, suggesting a pathogenetic role of AQP4 and humoral immunity in NMO (Misu et al., 2007); (Roemer et al., 2007).

HLA Associations
The genetic susceptibility between MS and NMO diverges in their association with human leukocyte antigen (HLA) alleles. NMO is associated with HLA-DRB103 and HLA-DRB110 alleles in a Mexican population, differing from MS-associated alleles, suggesting distinct immune-genetic risk factors (Alonso et al., 2018).

GTF2I Gene Variant Association
The GTF2I rs117026326 polymorphism is associated with NMOSD but not with MS in a Northern Han Chinese population, further supporting the genetic distinction between these disorders (Liang et al., 2019).

Phenotypic Differences and Similarities Similarities
Both MS and NMOSD present as autoimmune inflammatory disorders of the central nervous system, causing neurological symptoms due to demyelination. Specific diagnostic criteria and serologic testing, such as for aquaporin-4 antibodies in NMOSD, help in differentiating them despite some overlapping clinical features.

Differences
Brain MRI Lesions: White matter lesions are a focus for classifying MS and NMOSD, though distinguishing NMOSD from MS based solely on MRI at onset is challenging since 10% of brain MRIs of patients with NMOSD onset met the MS MRI criteria (Seok et. al, 2023).

Optical Coherence Tomography Angiography (OCTA) and Spectral-Domain OCT (SD-OCT): In NMOSD + Optic Neuritis (ON) eyes, the vessel density and retinal nerve fiber layer (RNFL) were more affected compared to MS + ON eyes, indicating more severe retinal damage in NMOSD (Rogaczewska et. al, 2021).

HLA Associations: NMO shows a strong association with certain HLA alleles, notably DRB1*03, which is significantly more prevalent in NMO patients compared to controls, differentiating NMO from MS (Alvarenga et. al, 2021).

Conclusion
Understanding the genetic and phenotypic differences between MS and NMO is crucial for accurate diagnosis and treatment. Genetic markers like CYP27B1, CYP7A1, AQP4, and specific HLA alleles play a significant role in distinguishing between these conditions. Moreover, phenotypic differences, especially in MRI lesions and OCT findings, further help in their differentiation. Research continues to evolve, offering deeper insights into these complex diseases.

Reference:

Zhuang, J. C., Huang, Z. Y., Zhao, G. X., Yu, H., Li, Z. X., & Wu, Z. Y. (2015). Variants of CYP27B1 are associated with both multiple sclerosis and neuromyelitis optica patients in Han Chinese population. Gene, 557(2), 236-239.
Zhao, G. X., Liu, Y., Li, Z. X., Lv, C. Z., Traboulsee, A., Sadovnick, A. D., & Wu, Z. Y. (2013). Variants in the promoter region of CYP7A1 are associated with neuromyelitis optica but not with multiple sclerosis in the Han Chinese population. Neuroscience bulletin, 29, 525-530.
Misu, T., Fujihara, K., Kakita, A., Konno, H., Nakamura, M., Watanabe, S., ... & Itoyama, Y. (2007). Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis. Brain, 130(5), 1224-1234.
Roemer, S. F., Parisi, J. E., Lennon, V. A., Benarroch, E. E., Lassmann, H., Bruck, W., ... & Lucchinetti, C. F. (2007). Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain, 130(5), 1194-1205.
Alonso, V. R., de Jesus Flores Rivera, J., Garci, Y. R., Granados, J., Sánchez, T., Mena-Hernández, L., & Corona, T. (2018). Neuromyelitis optica (NMO IgG+) and genetic susceptibility, potential ethnic influences. Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Central Nervous System Agents), 18(1), 4-7.
Liang, H., Gao, W., Liu, X., Liu, J., Mao, X., Yang, M., ... & Jin, T. (2019). The GTF2I rs117026326 polymorphism is associated with neuromyelitis optica spectrum disorder but not with multiple sclerosis in a Northern Han Chinese population. Journal of neuroimmunology, 337, 577045.
Seok, J. M., Cho, W., Chung, Y. H., Ju, H., Kim, S. T., Seong, J. K., & Min, J. H. (2023). Differentiation between multiple sclerosis and neuromyelitis optica spectrum disorder using a deep learning model. Scientific reports, 13(1), 11625.
Rogaczewska, M., Michalak, S., & Stopa, M. (2021). Differentiation between multiple sclerosis and neuromyelitis optica spectrum disorder using optical coherence tomography angiography. Scientific Reports, 11(1), 10697.
Alvarenga, M. P., do Carmo, L. F., Vasconcelos, C. C. F., Alvarenga, M. P., Alvarenga-Filho, H., de Melo Bento, C. A., ... & Papais-Alvarenga, R. M. (2021). Neuromyelitis optica is an HLA associated disease different from Multiple Sclerosis: a systematic review with meta-analysis. Scientific reports, 11(1), 152.