Neuromyelitis Optica Spectrum Disorder (NMOSD)

Neuromyelitis optica spectrum disorder (NMOSD) is a chronic disease of the central nervous system in which recurrent attacks affect predominantly the optic nerves, spinal cord, and area postrema. NMOSD was formerly thought to be a variant of multiple sclerosis (MS); however, since the identification of highly specific NMO immunoglobulin G (NMO-IgG), an autoantibody against aquaporin-4 (AQP4), which is the most abundant astrocytic water channel, NMOSD is now considered to be separate from MS. Some cases of NMOSD are associated with antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG), and occasionally, autoantibodies are absent.1 Research has determined that environmental and genetic factors play a role in the development of NMOSD.2 However, very few studies have investigated genetic risk factors for NMOSD.3 Usually, the disorder is sporadic. However, in a minimum of 3% of cases, a familial pattern has been identified, which is important owing to the rarity of the disease. Recent data on familial segregation are most compatible with nonmendelian polygenic disease inheritance.4 

Family History 

The percentage of cases with a family history is the first consideration in an evaluation of genetic risk factors for any disease.3 The percentage of familial cases of NMOSD was reported to be 2.8% in 2 studies.5,6 Very few cases of NMOSD in families have been reported in the literature.The first report of NMOSD in a family was published in 1938, in which NMOSD was diagnosed in 2 identical twin sisters. The disease manifested in the first sister at the age of 24 with initial symptoms of acute dorsal myelitis, and in the second sister at the age of 26 with initial symptoms of dorsal myelitis and cervical spread.7 

Association With Classic HLA Alleles

HLA typing has been the focus of the best-known investigations of this disease. In one study, it was discovered that HLA-DRB1 03 was linked to NMOSD, but not to MS.8 Another study showed similar findings.9 In a study of 116 patients with NMOSD, the HLA-DRB1*1602 and HLA-DPB1*0501 alleles appeared to be potential risk factors for NMO-IgG-positive NMOSD.10 In another study, of Arab Muslims residing in Israel, a higher level of anti-AQP4 seropositivity was found in individuals with NMOSD. A positive association was found with the HLA-DRB1*04:04 and HLA-DRB1*10:01 alleles in these individuals, whereas a strongly negative association was found with the HLA-DRB1*07 and HLA-DQB1*02:02 alleles.11 

Other Genetic Associations With NMOSD

A study in which the genome-wide association studies (GWAS) approach was used to examine single-nucleotide polymorphisms (SNPs) discovered that a common promoter SNP in the CYP7A1 gene prevented or lowered the risk for NMOSD. Cholesterol 7a-hydroxylase, which catalizes the breakdown of cholesterol into bile acids, is encoded by this gene. The variant does, however, increase the risk for other ailments, such as adenomas of the colon, gallstones, hypertriglyceridemia, and coronary atherosclerosis.12 Similar findings were noted in a Chinese population study.13

A higher frequency of the rs2104286(G) allele in the IL2RA gene was observed in patients with NMOSD than in healthy subjects in a Southern Han Chinese population study.14

A strong association was noted between CD58 polymorphisms and NMOSD in a Korean population. In addition, a strong link was found between NMOSD and the SNPs rs2300747, rs13355332, rs12044852, and rs1016140. The first 3 SNPs were found to be significantly linked to MS as well.15 

Polymorphisms in the human AQP4 gene were investigated in 122 seropositive patients. The study revealed that the frequency of two 3ʹ prime untranslated region (UTR) SNPs—the A/T genotype of SNP rs1058424 and the C/T genotype of SNP rs3763043—was significantly higher in seropositive patients than in normal subjects. In addition, the 3ʹ UTR haplotype ATATGGAT was found to have a protective role and appeared to reduce the risk for NMOSD.16 

A study in a Chinese population showed that the G allele in the −1901A> G polymorphism and the T allele in the −658C> T polymorphism are risk factors for NMOSD.17 Copy number variations (CNVs) comprising 5- to 50-kb deletions are seen in cell receptors gamma and alpha loci in both MS and NMOSD. Surprisingly, patients who had NMOSD with these CNVs were mainly seronegative, and in the seropositive patients, the antibody titers were lower.18

Several genetic variations in the major histocompatibility complex (MHC) region have been found to be risk factors for NMOSD seropositivity. A study of patients with NMOSD found the most important genetic marker of the disease, rs28383224, in both seropositive and seronegative variants of the condition. C4 CNV, however, is found exclusively in seropositive patients with NMOSD. C4A and C4B genes on the MHC class III domain encode C4.19

Variant rs117026326 upstream of the general transcription factor II-I (GTF2I) has been shown to be strongly associated with diseases like systemic lupus erythematosus, primary Sjögren syndrome, and rheumatoid arthritis. A strong association with NMOSD has also been reported, whereas a link with MS has not been found.20 


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Reviewed by Debjyoti Talukdar, MD, on 10/17/2021.

Reviewed by Debjyoti Talukdar, MD, on 10/17/2021.