Single-nucleotide polymorphisms (SNP) of the USP18 gene appear to be involved in the pathogenesis of familiar neuromyelitis optica spectrum disorder (NMOSD) and might be responsible for its transmission across generations, according to a recently published study in Neurogenetics.

Familiar NMOSD is rare, representing only 3% of all NMOSD cases. Furthermore, families with a history of familiar NMOSD rarely have more than 3 members with the disease, Yanyu Chang, of the Third Affiliated Hospital of Sun Yat-sen University in Guangdong, China, and colleagues noted. A number of series reporting familiar NMOSD cases suggest that familiar and sporadic NMOSD are almost identical in clinical characteristics; however, genetic research on familiar NMOSD is still scarce, the researcher added.

Therefore, the authors aimed to analyze the clinical characteristics and genetic background of familiar NMOSD in 10 Chinese families with NMOSD aggregation. Clinical information such as onset age, annualized relapse rate (ARR), and episode types was gathered using medical records. A genetic study to detect potential genes involved in NMOSD pathogenesis was conducted through whole-exome sequencing (WES) in 7 patients from 13 families. 

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In the included families, 4 had a familiar occurrence in 2 generations and the others only in 1. The relationship between affected family members was always mother-child or siblings. All patients were seropositive for aquaporin 4-IgG. NMOSD clinical manifestations were similar among family members. 

A comparison between family members with familiar NMOSD and 400 patients with sporadic NMOSD showed both entities were indistinguishable in clinical characteristics, as reported in previous studies. 

WES data from 13 patients with familiar NMOSD and 13 healthy family members revealed a potential pathogenic SNP in the USP18 gene. The alternative allele frequency was over 80% in familiar NMOSD, 66% in patients with sporadic NMOSD, and just over 50% in healthy family members. The variant showed a recessive inheritance pattern in 4 families.

The authors hypothesize that the detected SNP variant has important regulatory functions of the intronic regions in USP18, thus preventing it from functioning as a regulator in the JAK/STAT pathway.

The authors noted that SNP variants in USP18 have been previously associated with multiple sclerosis and that the close relationship between the 2 diseases further supports their findings. 

“Overall, the genetic background of NMOSD is complex and a deeper investigation is demanded,” the authors concluded. 


Chang Y, Zhou L, Zhong X, et al. Clinical and genetic analysis of familial neuromyelitis optica spectrum disorder in Chinese: associated with ubiquitin-specific peptidase usp18 gene variants. J Neurol Neurosurg Psychiatry. Published online November 14, 2022. doi:10.1136/jnnp-2022-329623