Analysis of pedigrees of multiplex families with NMO may be helpful in understanding the pattern of transmission and ultimately, combined with molecular genetic analysis, in discovering susceptibility genes. Four multiplex families with NMO (8 affected individuals) have been reported, all but one report from the pre-NMO-IgG1
era and before formal diagnostic criteria4
were proposed. Identical twin sisters (24 and 26 years of age at disease onset) with NMO were reported in 1938. Both had severe episodes of transverse myelitis and bilateral blindness and died of NMO-related complications. The autopsy evaluation showed demyelination of the optic nerve and diffuse inflammation and demyelination extending from the cervical to the lower thoracic cord.14
These reports were followed by those of 2 infant sisters (age 2 and 3 at onset) who had relapses of bilateral ON and thoracic myelitis15
; of 2 sisters with late onset of NMO (62 and 59)16
; and of a daughter (aged 29 at onset) with myasthenia gravis and NMO and a mother (62 years at onset) with NMO-IgG seropositive NMO.17
Recently, 2 sisters, 1 with NMO and 1 with prototypic MS, were reported.18
The frequency of NMO in family members of our NMO index cases is greater than expected based on the best estimate of its prevalence frequency in the general population of 1/100,000.7,8
If the average pedigree size consisted of 100 first- and second-degree relatives, which is likely an overestimate, one would expect 0.38 affected relatives among the 386 sporadic cases from which familial cases were derived at the collaborating institutions; we detected 12 cases (p
< 0.0001; χ2
). Familial cases accounted for 3% of NMO but considering the cases that were excluded this is a minimum estimate.
In both the historical sporadic and the current familial series, NMO was characterized by acute relapses. The distribution of presenting symptoms (ON, myelitis, or both) was very similar. In both series, ON and myelitis were the dominant clinical manifestations. We had not recognized the extended spectrum of NMO, which includes patients who have recurrent myelitis or recurrent ON, in the sporadic series published in 1999, and NMO-IgG serology was unavailable at that time; therefore, some differences in the characteristics of cases reflects improved understanding of the spectrum of NMO in the familial series. Comparison of outcome data and response to therapy is difficult, because early diagnosis, consistent early treatment with immunosuppressive drugs, and systematic follow-up are much more typical of the contemporary series than it was for the sporadic series.3
Only 1 or 2 generations were affected. There was no evidence of bias of transmission from either paternal or maternal line; the excess of maternal line transmission reflects the increased predisposition of women for NMO.
Analysis of age and calendar year of onset in the NMO relative pairs did not strongly support either common environmental exposure or a purely genetic basis for susceptibility. The linear regression analysis of the age at onset with age indicated that age, rather than a specific common exposure, was the principal determinant of age at onset. Furthermore, intraclass correlation of age at onset revealed no excess similarity between members of a pair compared to the interpair differences contrary to expectation if genetic factors solely determined susceptibility to NMO. The lack of intraclass correlation of age at onset and the age dependence of onset may largely be explained by the predilection for NMO to occur in late middle-aged individuals that may obscure pedigree-specific effects on age at onset.3,19
There was wide variation between members of pairs in years of onset, suggesting that common exposure was unlikely to be an important etiologic factor.
Genetic association studies for this disease are limited. Human leukocyte antigen (HLA) associations have been observed in studies of sporadic cases of NMO. HLA-DPB1*0501
allele was more frequent in 38 Japanese patients seropositive for NMO-IgG compared to 52 patients with MS.20
Forty-five French Caucasian NMO cases were compared to healthy controls and patients with MS for HLA class II A and B alleles; no association was found of DRB1*1501
with NMO (odds ratio [OR] 1.74; 95% confidence interval [CI] 0.97–3.11, p
= 0.06). HLA-DRB1*03 was associated with NMO-IgG-seropositive NMO (OR 3.08; 95% CI 1.52–6.27, p
No mutation was found in genes known to harbor the majority of LHON mutations in 32 patients with NMO.22
No association was found in a study of 7 AQP4 SNPs genotyped in 901 MS trio families, including 69 in which the affected offspring had clinical history of optic-spinal disease.23
Recently, genome scan was performed with samples of 53 NMO Korean cases and 240 controls. The study was underpowered but the strongest SNP association signals were tested in a cohort of 93 NMO patients and 368 controls. A common promoter SNP in CYP7A1
, a gene that encodes a member of the cytochrome P450 superfamily of enzymes, had a dose-dependent protective effect against NMO (p
Although certain infections25
have been reported to co-occur with NMO, no environmental or disease trigger has been rigorously associated with NMO. In the families we report, we did not find clear indicators of common exposure to infections. One patient had breast cancer a year prior to the development of NMO. We are unaware of NMO occurring in unrelated household members. There does not appear to be any geographic or ethnic restriction of familial occurrence of NMO. Several of the NMO families had members with other autoimmune diseases, suggesting that these individuals may share common genetic risk factors for autoimmunity in addition to factors that lead to AQP4-specific autoimmunity.
The small number of cases within affected pedigrees, the lack of multigenerational pedigrees, the high ratio of sporadic to familial cases, and lack of distinctive characteristics of familial cases, taken together, support the hypothesis that NMO is a complex genetic disease.