Meniere’s Disease: Genetics and the Immune System
- 78 Downloads
Purpose of Review
The purpose of this review was to describe the ongoing research that supports that Meniere’s disease (MD) is a heterogeneous set of clinical disorders.
Different clinical subgroups of patients have been identified, which may have different etiological factors. Genes associated to the initiation or progression of MD can be classified in four main categories: immune-associated, proliferation and cell survival, cell surface channels, and extracellular matrix proteins. Two major mechanisms have been involved in MD, the innate immune response involving proinflammatory cytokines and NF-κB-mediated inflammation, but the molecular events that initiate the disorder are not known. The challenge of the immune system by antigens or allergic reactions may involve several targets in the cochlea, such as the endolymphatic sac or the spiral ligament, leading to inflammation and finally endolymphatic hydrops.
Several clinical variants have been described, and genetic and immunological factors seem to play a central role in MD.
KeywordsMeniere’s disease Autoimmune inner ear Vertigo Sensorineural hearing loss Genetics Interleukin-1-beta
JALE is supported by Grants from Meniere’s Society, UK, PI17/01644 Grant from ISCIII by FEDER Funds from EU and H2020-MSCA-ITN-2016–722046 from EU.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they do not have any conflict of interest.
Human and Animal Rights and Informed Consent
All reported studies with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional research committee standards, and international guidelines.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.• Lopez-Escamez JA, Carey J, Chung WH, Goebel JA, Magnusson M, Mandalà M, et al. Diagnostic criteria for Menière’s disease. J Vestib Res. 2015;25(1):1–7. https://doi.org/10.3233/VES-150549. Consensus document developed by the Barany Society Classification Committee in acordance with AAO-HNS, EAONO, Japan Society for Equilibrium Research and Korean Balance Society. PubMedGoogle Scholar
- 2.Espinosa-Sanchez JM, Lopez-Escamez JA. Menière’s disease. In: Furman J, Lempert T, editors. Handb. Clin. Neurol. Amsterdam: Elsevier; 2016. p. 257–77.Google Scholar
- 17.• Tyrrell JS, DJD W, Ukoumunne OC, Fleming LE, Osborne NJ. Prevalence, associated factors, and comorbid conditions for Ménière’s disease. Ear Hear. 2014;35(4):e162–9. https://doi.org/10.1097/AUD.0000000000000041. Population-based epidemiology study of Meniere disease confirmed previous observation that autoimmune disorders are associated with Meniere disease. CrossRefPubMedGoogle Scholar
- 20.• Belinchon A, Perez-Garrigues H, Tenias JM, Lopez A. Hearing assessment in Menière’s disease. Laryngoscope. 2011;121(3):622–6. https://doi.org/10.1002/lary.21335. This longitudinal study showed that age-normlized audiograms were able to identify unilateral (involving low and mid-frequencies) and bilateral Meniere disease (involving all frequencies). CrossRefPubMedGoogle Scholar
- 21.Hietikko E, Kotimäki J, Sorri M, Männikkö M. High incidence of Meniere-like symptoms in relatives of Meniere patients in the areas of Oulu University Hospital and Kainuu Central Hospital in Finland. Eur J Med Genet. 2013;56(6):279–85. https://doi.org/10.1016/j.ejmg.2013.03.010.CrossRefPubMedGoogle Scholar
- 23.•• Requena T, Espinosa-Sanchez JM, Cabrera S, Trinidad G, Soto-Varela A, Santos-Perez S, et al. Familial clustering and genetic heterogeneity in Meniere’s disease. Clin Genet. 2014;85(3):245–52. https://doi.org/10.1111/cge.12150. This is the largest cross-sectional study performed that was able to demosntrate a familial aggregation in Meniere disease and identified 76 multicase families with Meniere disease. CrossRefPubMedGoogle Scholar
- 24.•• Frejo L, Soto-Varela A, Santos-Perez S, Aran I, Batuecas-Caletrio A, Perez-Guillen V, et al. Clinical subgroups in bilateral Meniere disease. Front Neurol. 2016;7:1–10. https://doi.org/10.3389/fneur.2016.00182. This study was able to identify clinical predictors for 5 subgroups of patients with bilateral Meniere disease by cluster analysis. CrossRefGoogle Scholar
- 25.• Frejo L, Martin-Sanz E, Teggi R, Trinidad G, Soto-Varela A, Santos-Perez S, et al. Extended phenotype and clinical subgroups in unilateral Meniere disease: a cross-sectional study with cluster analysis. Clin Otolaryngol. 2017;42(6):1–9. https://doi.org/10.1111/coa.12844. The second study performed in unilateral Meniere disease confirmed the clinical subgroups found in patients with bilateral involvement, including familial and autoimmune Meniere disease. CrossRefGoogle Scholar
- 30.Lopez-Escamez JA, Saenz-Lopez P, Acosta L, Moreno A, Gazquez I, Perez-Garrigues H, et al. Association of a functional polymorphism of PTPN22 encoding a lymphoid protein phosphatase in bilateral Meniere’s disease. Laryngoscope. 2010;120:103–7. https://doi.org/10.1002/lary.20650.CrossRefPubMedGoogle Scholar
- 33.Gázquez I, Moreno A, Requena T, Ohmen J, Santos-Perez S, Aran I, et al. Functional variants of MIF, INFG and TFNA genes are not associated with disease susceptibility or hearing loss progression in patients with Mèniére’s disease. Eur Arch Otorhinolaryngol. 2013;270(4):1521–9. https://doi.org/10.1007/s00405-012-2268-0.CrossRefPubMedGoogle Scholar
- 37.Cabrera S, Sanchez E, Requena T, Martinez-Bueno M, Benitez J, Perez N, et al. Intronic variants in the NFKB1 gene may influence hearing forecast in patients with unilateral sensorineural hearing loss in meniere’s disease. PLoS One. 2014;9(11):e112171. https://doi.org/10.1371/journal.pone.0112171.CrossRefPubMedPubMedCentralGoogle Scholar
- 39.Teranishi M, Uchida Y, Nishio N, Kato K, Otake H, Yoshida T, et al. Polymorphisms in genes involved in oxidative stress response in patients with sudden sensorineural hearing loss and Ménière’s disease in a Japanese population. DNA Cell Biol. 2012;31(10):1555–62. https://doi.org/10.1089/dna.2012.1631.CrossRefPubMedPubMedCentralGoogle Scholar
- 40.• Requena T, Cabrera S, Martín-Sierra C, Price SD, Lysakowski A, Lopez-Escamez JA. Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere’s disease. Hum Mol Genet. 2015;24(4):1119–26. https://doi.org/10.1093/hmg/ddu524. This was the first family with autosomal dominant Meniere disease in three generation segragating ultrarare variants in coding regions of DTNA and FAM136A genes. CrossRefPubMedGoogle Scholar
- 41.Martín-Sierra C, Requena T, Frejo L, Price SD, Gallego-Martinez A, Batuecas-Caletrio A, et al. A novel missense variant in PRKCB segregates low-frequency hearing loss in an autosomal dominant family with Meniere’s disease. Hum Mol Genet. 2016;25(16):3407–15. https://doi.org/10.1093/hmg/ddw183.CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Martín-Sierra C, Gallego-Martinez A, Requena T, Frejo L, Batuecas-Caletrío A, Lopez-Escamez JA. Variable expressivity and genetic heterogeneity involving DPT and SEMA3D genes in autosomal dominant familial Meniere’s disease. Eur J Hum Genet. 2017;25(2):200–7. https://doi.org/10.1038/ejhg.2016.154.CrossRefPubMedGoogle Scholar
- 45.Kim SH, Kim JY, Lee HJ, Gi M, Kim BG, Choi JY. Autoimmunity as a candidate for the etiopathogenesis of Meniere’s disease: detection of autoimmune reactions and diagnostic biomarker candidate. PLoS One. 2014;9(10):e111039. https://doi.org/10.1371/journal.pone.0111039.CrossRefPubMedPubMedCentralGoogle Scholar
- 47.Lopez-Escamez JA, Saenz-Lopez P, Gazquez I, Moreno A, Gonzalez-Oller C, Soto-Varela A, et al. Polymorphisms of CD16A and CD32 Fcγ receptors and circulating immune complexes in Ménière’s disease: a case-control study. BMC Med Genet. BioMed Central. 2011;12:2. https://doi.org/10.1186/1471-2350-12-2.CrossRefPubMedPubMedCentralGoogle Scholar
- 51.•• Nakanishi H, Kawashima Y, Kurima K, Chae JJ, Ross AM, Pinto-Patarroyo G, et al. NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy. Proc Natl Acad Sci U S A. 2017;114(37):E7766–75. This study describes NLRP3-mediated inflammation pathway as a potential mechanism for autoinflammatory inner ear diseease associated with sensorineural hearing loss and elevated IL1-β. https://doi.org/10.1073/pnas.1702946114.CrossRefPubMedPubMedCentralGoogle Scholar
- 54.Ruckenstein MJ. Autoimmune inner ear disease. Curr Opin Otolaryngol Head Neck Surg. 2004;12(5):426–30. https://doi.org/10.1097/01.moo.0000136101.95662.aa.CrossRefPubMedGoogle Scholar
- 55.• Pathak S, Goldofsky E, Vivas EX, Bonagura VR, Vambutas A. IL-1β is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease. J Immunol. 2011;186:1870–9. https://doi.org/10.4049/jimmunol.1002275. This study describes the mechanism of resistence to oral steroids. CrossRefPubMedPubMedCentralGoogle Scholar
- 68.Dagli M, Goksu N, Eryilmaz A, Mocan Kuzey G, Bayazit Y, Gun BD, et al. Expression of histamine receptors (H1, H2, and H3) in the rabbit endolymphatic sac: an immunohistochemical study. Am J Otolaryngol - Head Neck Med Surg. 2008;29(1):20–3. https://doi.org/10.1016/j.amjoto.2006.12.003.Google Scholar
- 71.•• Adrion C, Fischer CS, Wagner J, Gürkov R, Mansmann U, Strupp M. Efficacy and safety of betahistine treatment in patients with Meniere’s disease: primary results of a long term, multicentre, double blind, randomised, placebo controlled, dose defining trial (BEMED trial). BMJ. 2016;352:h6816. https://doi.org/10.1136/bmj.h6816. BMJ Publishing Group. This multicentre randomized clinical trial showed that betahistine at low or high dosage has no benefit compared to placebo. CrossRefPubMedPubMedCentralGoogle Scholar