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Clinical Review

Meniere’s disease

BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g6544 (Published 12 November 2014) Cite this as: BMJ 2014;349:g6544

Genetics and autoimmunity in Meniere disease

Dear Editor,

We have read with great interest the excellent clinical review on Meniere’s disease (MD) by Harcourt et al. (1), and we strongly support the conservative approach based on the risk of bilateral involvement and chronic dizziness. MD is a clinically heterogeneous disorder. Probably the current clinical definition is too broad and patients with different etiologies are being included under the umbrella of MD’s symptoms. Furthermore, a considerable overlap of accompanying symptoms during the attacks is found between MD and vestibular migraine, such as headache in MD or auditory symptoms in vestibular migraine (2).
Since this review selected systematic reviews published from 1966-2013, we have missed some relevant studies for a better understanding of MD published during 2014. So, Tyrrell et al. have described the prevalence and comorbid conditions in the largest cross-sectional study of 1376 UK patients with MD compared with data from 500.000 individuals from UK Biobank (3). The estimated prevalence in UK is 0.24% and the study demonstrates robust associations between allergy, autoimmune conditions, or migraine and MD. Several autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondilytis or psoriasis are more commonly found in MD (3, 4). Two recent proteomic studies has found several candidate antigens in patient serum that could be used as potential biological markers (5, 6). These studies indicate an autoimmune mechanism for MD.
Several lines of evidence support a genetic susceptibility in MD. The white ethnicity has been consistently reported (3, 7). Recently, two independent studies in Finland and Spain have clearly demonstrated a strong familial aggregation in MD (8, 9). The familial history of hearing loss or episodic vertigo is frequently observed in these families, suggesting an incomplete phenotype in some relatives. The prevalence of familial MD is 8-10% and the estimated sibling recurrence risk ratio is 48 compared to the general population (9), suggesting that MD has a significant genetic background. Most of the families have an autosomal dominant pattern of inheritance, but genetic heterogeneity is observed, and recessive and de novo mutation are expected (9). Our group has been able to find 76 multi-case families with MD and combined whole-exome sequencing with linkage analysis to search for rare deleterious mutations causing MD. So, we have recently identified rare single nucleotide variants in the FAM136A and DTNA genes in an autosomal dominant pedigree affecting three women in consecutive generations (10). Bioinformatics analysis and functional in vitro studies have confirmed these genes as causal for autosomal dominant MD.
For clinical practice, familial MD is currently underdiagnosed and the identification of new multicase families will facilitate the identification of novel causal genes by genomic studies, opening the door for a potential personalized medicine.

References
1. Harcourt J, Barraclough K, Bronstein A. Meniere’s Disease. BMJ. 349:1-36, 24-27. Nov 2014.
2. Lopez-Escamez JA, Dlugaiczyk J, Jacobs J, Lempert T, Teggi R, von Brevern M, Bisdorff A. Accompanying symptoms overlap during attacks in Menière's Disease and Vestibular Migraine. Frontiers in Neurology 2014 (in press).
3. Tyrrell JS, Whinney DJD, Ukoumunne OC, Fleming LE, Osborne NJ. Prevalence, associated factors, and comorbid conditions for Ménière's disease. Ear Hear. 2014 Jul;35(4):e162–9.
4. Gazquez I, Soto-Varela A, Aran I, Santos S, Batuecas A, Trinidad G, et al. High Prevalence of Systemic Autoimmune Diseases in Patients with Menière's Disease. Means RE, editor. PLoS ONE. 2011 Oct 28;6(10):e26759.
5. 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. Sokolowski B, editor. PLoS ONE. 2014 Oct 17;9(10):e111039.
6. Chiarella G, Di Domenico M, Petrolo C, Saccomanno M, Rothenberger R, Giordano A, et al. A Proteomics-Driven Assay Defines Specific Plasma Protein Signatures in Different Stages of Ménière's Disease. J Cell Biochem. 2014 Apr 15;115(6):1097–100.
7. Ohmen JD, White CH, Li X, Wang J, Fisher LM, Zhang H, et al. Genetic evidence for an ethnic diversity in the susceptibility to Ménière's disease. Otol Neurotol. 2013 Sep;34(7):1336–41.
8. Hietikko E, Kotimäki J, Sorri M, Männikkö M. European Journal of Medical Genetics. Eur J Med Genetics 2013 Jun 1;56(6):279–85.
9. 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. Clinical Genetics. 2014 Mar;85(3):245–52.
10. Requena T, Cabrera S, Martin-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. Human Molecular Genetics. 2014 Oct 9.

Jose A Lopez-Escamez 1, 2, Juan Manuel Espinosa-Sanchez 3, Teresa Requena1
1 Otology & Neurotology Group CTS495, Department of Genomic Medicine, GENYO - Centre for Genomics and Oncological Research – Pfizer/University of Granada/ Junta de Andalucía, PTS, Granada, 18016 Spain. http://www.genyo.es/en/content/view-research-group?id=5
2 Department of Otolaryngology, Hospital de Poniente, El Ejido, Almería, 04700, Spain
3 Department of Otolaryngology, Hospital San Agustin, Linares, Jaén, Spain

Correspondence: antonio.lopezescamez@genyo.es

Competing interests: We have read and understood the BMJ policy on declaration of interest and declare the following interest: JALE has received funding for research from the Meniere’s Society and Instituto de Salud Carlos III PI13-1242 Grant. TR has received funding for research from Consejería de Salud y Bienestar Social 2012-0242 Grant.

Competing interests: We have read and understood the BMJ policy on declaration of interest and declare the following interest: JALE has received funding for research from the Meniere’s Society and Instituto de Salud Carlos III PI13-1242 Grant. TR has received funding for research from Consejería de Salud y Bienestar Social 2012-0242 Grant.

05 December 2014
Jose A. Lopez-Escamez
Clinical Otoneurology consultant and PI of Otology & Neurotology Group
Juan M. Espinosa-Sanchez, Teresa Requena
Otology & Neurotology Group CTS495, Department of Genomic Medicine, GENYO - Centre for Genomics and Oncological Research – Pfizer/University of Granada/ Junta de Andalucía,
Avda Ilustracion 114, PTS, Granada, 18016 Spain.