Research Article| Volume 73, 104627, May 2023

Download started.


Familial neuromyelitis optica spectrum disorders: Case series and systematic review


      • Neuromyelitis optica spectrum disorder (NMOSD) is a complex multifactorial disorder in which most cases are sporadic.
      • Familial clustering of NMOSD is more common than would be expected in the general population.
      • The demographic, clinical, and outcome profiles of familial cases were not different from sporadic cases.
      • Our systematic review highlighted complex genetic predisposition to NMOSD.



      Neuromyelitis optica spectrum disorders (NMOSD) is considered a complex multifactorial disorder. Most cases are sporadic, and familial NMOSD is assumed as a rare occurrence. However, few studies reported familial aggregation of the disorder.


      To report familial NMOSD cases in Thailand and conduct a systematic review of familial NMOSD.


      A retrospective chart review of familial NMOSD patients at the university hospital was performed. Articles related to “genetic” and “NMOSD” were systematically searched and reviewed. We included NMOSD patients whose one or more relatives were diagnosed with the same disease or multiple sclerosis (MS). Data regarding demographics, clinical features, disease outcomes, and genetic testing were collected and analyzed using descriptive statistics.


      We identified 6 familial cases from 165 NMOSD cases (3.6%) at our hospital and gathered 77 cases from a systematic review, totaling 83 cases from 40 families. The mean (SD) age at onset was 37.2 (18.0) years. Familial NMOSD involved 1–2 generations with mainly 2 affected individuals. The most common kinship pattern was siblingship in 21 families (52.5%). Initial syndromes were mostly optic neuritis and transverse myelitis. Serum aquaporin-4 IgG was positive in 79.7% of cases. Median number of relapses was 3 (range 1–26). Median expanded disability status scale in the last visit was 2 (range 0–8). Reported human leukocyte antigens (HLA) alleles shared between familial cases were HLA-A*01 and HLA-DRB1*03.


      Familial clustering of NMOSD is more common than would be expected in the general population. The demographic, clinical, and outcome profiles of familial cases were not different from sporadic cases. Certain specific HLA haplotypes were shared among familial cases. Our systematic review highlighted complex genetic predisposition to NMOSD.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Multiple Sclerosis and Related Disorders
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Wingerchuk D.M.
        • Lucchinetti C.F.
        Neuromyelitis optica spectrum disorder.
        N. Engl. J. Med. 2022; 387: 631-639
        • Wingerchuk D.M.
        • Lennon V.A.
        • Pittock S.J.
        • et al.
        Revised diagnostic criteria for neuromyelitis optica.
        Neurology. 2006; 66: 1485-1489
        • Wingerchuk D.M.
        • Banwell B.
        • Bennett J.L.
        • et al.
        International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
        Neurology. 2015; 85: 177-189
        • Ghafouri-Fard S.
        • Azimi T.
        • Taheri M.
        A comprehensive review on the role of genetic factors in neuromyelitis optica spectrum disorder.
        Front. Immunol. 2021;
        • Bonnan M.
        • Berthelot E.
        • Cabre P.
        Familial clustering of neuromyelitis optica and multiple sclerosis: clues pointing towards shared risks?.
        Mult. Scler. Relat. Disord. 2020;
        • Matiello M.
        • Kim H.J.
        • Kim W.
        • et al.
        Familial neuromyelitis optica.
        Neurology. 2010; 75: 310-315
        • Gelibter S.
        • Mazzi B.
        • Tassara M.
        • et al.
        Neuromyelitis optica spectrum disorder and multiple sclerosis in a Sardinian family.
        Mult. Scler. Relat. Disord. 2018; 25: 73-76
        • Cabrera-Gómez J.A.
        • Ramón-Pérez L.
        • Saiz A.
        • et al.
        Neuromyelitis optica and multiple sclerosis in sisters.
        Mult. Scler. 2009; 15: 269-271
        • Yoshimine S.
        • Sakai T.
        • Ogasawara M.
        • et al.
        Anti-aquaporin-4 antibody-positive familial neuromyelitis optica in mother and daughter.
        Jpn. J. Ophthalmol. 2011; 55: 647-650
        • Page M.J.
        • McKenzie J.E.
        • Bossuyt P.M.
        • et al.
        The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
        BMJ. 2021;
        • Anamnart C.
        • Tisavipat N.
        • Owattanapanich W.
        • et al.
        Newly diagnosed neuromyelitis optica spectrum disorders following vaccination: case report and systematic review.
        Mult. Scler. Relat. Disord. 2022;
        • Tanaka Y.
        • Yoshikura N.
        • Harada N.
        • et al.
        Neuromyelitis optica in Japanese sisters.
        Intern. Med. 2011; 50: 2829-2832
      1. Kadoya M., Higashihara M., Shiozaki Y., et al. (2013). A clinicopathological study of familial neuromyelitis optica: a case report. [Unpublished manuscript].

        • Kavoussi S.C.
        • Lesser R.L.
        Genetic anticipation in familial neuromyelitis optica: case and literature review.
        Conn. Med. 2015; 79: 207-209
      2. Vialatte A.L., Papeix C., Maugest L., et al. (2016). Familial Neuromyelitis optica spectrum. [Unpublished manuscript].

        • Lee J.J.
        • Tsai M.H.
        • Lien C.Y.
        • et al.
        Intra-family phenotype variations in familial neuromyelitis optica spectrum disorders.
        Mult. Scler. Relat. Disord. 2019; 30: 57-62
        • Ganaraja V.H.
        • Subasree R.
        • Netravathi M.
        Familial neuromyelitis optica and Sjogren's overlap syndrome-a rare case report.
        Neurol. India. 2022; 70: 1191-1193
        • McAlpine D.
        Familial neuromyelitis optica: its occurrence in identical twins.
        Brain. 1938; 61: 430-448
        • Ch'ien L.T.
        • Medeiros M.O.
        • Belluomini J.J.
        • et al.
        Neuromyelitis optica (Devic's syndrome) in two sisters.
        Clin. Electroencephalogr. 1982; 13: 36-39
        • Yamakawa K.
        • Kuroda H.
        • Fujihara K.
        • et al.
        Familial neuromyelitis optica (Devic's syndrome) with late onset in Japan.
        Neurology. 2000; 55: 318-320
        • Braley T.
        • Mikol D.D.
        Neuromyelitis optica in a mother and daughter.
        Arch. Neurol. 2007; 64: 1189-1192
        • Azevedo C.
        • Riley C.
        A mother-daughter pair with neuromyelitis optica spectrum disorder.
        Neurology. 2012; 78 (P07.063)
      3. Hongyu Z. (2013). Familial neuromyelitis optica in mother and daughter with different anti-aquaporin-4 antibody. [Unpublished manuscript].

      4. Wen X., Wei Q., et al. (2013). Chinese sisters with NMOSD: one with AQP4 antibody and another with seronegative. [Unpublished manuscript].

        • Braz L.
        • Sampaio M.
        • Sa M.J.
        • et al.
        Neuromyelitis optica spectrum disorders in siblings.
        Sinapse. 2015; 15: 1
        • Papais-Alvarenga R.M.
        • Pereira F.F.
        • Bernardes M.S.
        • et al.
        Familial forms of multiple sclerosis and neuromyelitis optica at an MS center in Rio de Janeiro State, Brazil.
        J. Neurol. Sci. 2015; 356: 196-201
        • Chuquilin M.
        • Mullaguri N.
        • Weinshenker B.
        Pediatric familial neuromyelitis optica in two sisters with long term follow-up.
        J. Clin. Neurosci. 2016; 29 (–4): 183
        • Wei X.
        • Zhang S.
        • Yang W.
        • et al.
        Neuromyelitis optica spectrum disorder in three generations of a Chinese family.
        Mult. Scler. Relat. Disord. 2019; 32: 94-96
        • Esmaeili S.
        • Akhondi F.H.
        • Zamani B.
        • et al.
        First report of neuromyelitis optica in a mother-daughter pair from Iran.
        J. Neurol. Sci. 2019; (Poster presented at)
        • Cheo S.W.
        • Ong S.
        • Low Q.J.
        • et al.
        Familial neuromyelitis optica spectrum disorder in a pair of sisters.
        QJM. 2020; 113: 743-746
        • Ang C.L.
        • Schee J.P.
        • Ng E.K.
        • et al.
        A case series of familial neuromyelitis optica spectrum disorder (NMOSD).
        Clin. Neurophysiol. 2021; 132: e123
        • Cabrera-Gomez J.A.
        • Ramon-Perez L.
        • Saiz A.
        • et al.
        Neuromyelitis optica and multiple sclerosis in sisters.
        Mult. Scler. 2009; 15: 269-271
      5. Zheng M.M., Zhang X.H. (2013). Multiple Sclerosis And Neuromyelitis Optica In Sisters. [Unpublished manuscript].

      6. Hatteb S.A., Bouzar M., Daoudi S. (2016). Multiple sclerosis and NMO spectrum disorder association in sisters. [Unpublished manuscript].

        • Tisavipat N.
        • Lapanakoakiat S.
        • Siengwattana P.
        • et al.
        A quarter-century report on neuromyelitis optica spectrum disorder in Thailand: a single-center tertiary care cohort.
        Mult. Scler. Relat. Disord. 2022;
        • Hor J.Y.
        • Wong C.K.
        • Ew J.V.
        • et al.
        Neuromyelitis optica spectrum disorder in Asia: epidemiology and risk factors.
        Neurol. Clin. Neurosci. 2021; 9: 274-281
      7. StatPearls, 2022. Twin Births., (accessed 12 January 2023).

        • Kleiter I.
        • Gahlen A.
        • Borisow N.
        • et al.
        Neuromyelitis optica: evaluation of 871 attacks and 1,153 treatment courses.
        Ann. Neurol. 2016; 79: 206-216
        • Ebers G.C.
        • Koopman W.J.
        • Hader W.
        • et al.
        The natural history of multiple sclerosis: a geographically based study: 8: familial multiple sclerosis.
        Brain. 2000; 123: 641-649
        • Fricska-Nagy Z.
        • Bencsik K.
        • Rajda C.
        • et al.
        Epidemiology of familial multiple sclerosis in Hungary.
        Mult. Scler. 2007; 13: 260-261
        • Sazdovitch V.
        • Verdier-Taillefer M.H.
        • Heinzlef O.
        • et al.
        Familial multiple sclerosis: study of 357 consecutive patients.
        Rev. Neurol. 2000; 156: 638-640
        • Amela-Peris R.
        • Aladro Y.
        • Conde-Sendín M.A.
        • et al.
        Familial multiple sclerosis in Canary Islands.
        Rev. Neurol. 2004; 39: 911-914
        • Robertson N.P.
        • Fraser M.
        • Deans J.
        • et al.
        Age-adjusted recurrence risks for relatives of patients with multiple sclerosis.
        Brain. 1996; 119: 449-455
        • O'Gorman C.
        • Freeman S.
        • Taylor B.V.
        • et al.
        Familial recurrence risks for multiple sclerosis in Australia.
        J. Neurol. Neurosurg. Psychiatry. 2011; 82: 1351-1354
        • Brum D.G.
        • Barreira A.A.
        • Santos A.C.
        • et al.
        HLA-DRB association in neuromyelitis optica is different from that observed in multiple sclerosis.
        Mult. Scler. 2010; 16: 21-29
        • Zephir H.
        • Fajardy I.
        • Outteryck O.
        • et al.
        Is neuromyelitis optica associated with human leukocyte antigen?.
        Mult. Scler. 2009; 15: 571-579
        • Alonso V.R.
        • de Jesus Flores Rivera J.
        • Garci Y.R.
        • et al.
        Neuromyelitis optica (NMO IgG+) and genetic susceptibility, potential ethnic influences.
        Cent. Nerv. Syst. Agents Med. Chem. 2018; 18: 4-7
        • Bruijstens A.L.
        • Wong Y.Y.M.
        • Pelt D.E.
        • et al.
        HLA association in MOG-IgG- and AQP4-IgG-related disorders of the CNS in the Dutch population.
        Neurol. Neuroimmunol. Neuroinflamm. 2020;
        • Wang H.
        • Dai Y.
        • Qiu W.
        • et al.
        HLA-DPB1* 0501 is associated with susceptibility to anti-aquaporin-4 antibodies positive neuromyelitis optica in Southern Han Chinese.
        J. Neuroimmunol. 2011; 233 (1-2–4): 181
        • Hofer L.S.
        • Ramberger M.
        • Gredler V.
        • et al.
        Comparative analysis of T-cell responses to aquaporin-4 and myelin oligodendrocyte glycoprotein in inflammatory demyelinating central nervous system diseases.
        Front. Immunol. 2020; 11
        • Matsushita T.
        • Masaki K.
        • Isobe N.
        • et al.
        Genetic factors for susceptibility to and manifestations of neuromyelitis optica.
        Ann. Clin. Transl. Neurol. 2020; 7: 2082-2093
        • Romero-Hidalgo S.
        • Flores-Rivera J.
        • Rivas-Alonso V.
        • et al.
        Native American ancestry significantly contributes to neuromyelitis optica susceptibility in the admixed Mexican population.
        Sci. Rep. 2020; 10: 13706