Intra-family phenotype variations in familial neuromyelitis optica spectrum disorders

Background: The aim of the current study was to examine intra-family phenotype variations in familial neuromyelitis optica (NMO) spectrum disorder. Methods: The clinical presentation and neuroimaging features of two family members (mother and daughter) from a NMO spectrum disorder family (index family) were analyzed. Multiplex polymerase chain reaction was performed based on targeted re-sequencing on the AQP4 gene and the human leukocyte antigen (HLA) loci. The clinical and neuroimaging features of the members of six other previously reported NMO spectrum disorder families were also included for analysis. Results: In the core family, the mother was aged 39 at disease onset and the initial presentation was spinal cord involvement, whereas the daughter was 22 years old at disease onset and the initial presentation was brainstem involvement. No coding pathogenic variants or single nucleotide polymorphisms of the AQP4 gene were identified in the mother, daughter or father. As for HLA genotyping, the HLA-DRB1*03 and HLA-DPB1*04 alleles were shared by the mother and daughter. The HLA-DPB1*05 was present in the affected daughter and was inherited from the unaffected father. As for the other six reported families with familial NMO spectrum disorder, four mother-daughter pairs had a different age at disease onset and/or a different initial presentation. The other two affected family groups were sister-sister pairs; they had a similar age of onset and similar initial presentations. Conclusion: The present study offers a preliminary view of the clinical and neuroimaging features of patients with familial NMO spectrum disorder. Clinical heterogeneities were found among the family members, especially the mother and daughter pairs. The presence of risk allele HLA-DR*03:01 may be an important genetic finding for familial NMO spectrum disorder patients. To the best of our knowledge, this clinical heterogeneity has not been previously examined or reported in the literature. For better delineation of the intra-familial phenotype variations in familial NMO spectrum disorder, further large-scale studies are needed.