Journal of Neurology

, Volume 265, Supplement 1, pp 29–34 | Cite as

Genetic contribution to vestibular diseases

  • Alvaro Gallego-Martinez
  • Juan Manuel Espinosa-Sanchez
  • Jose Antonio Lopez-Escamez


Growing evidence supports the contribution of allelic variation to vestibular disorders. Heritability attributed to rare allelic variants is found in familial vestibular syndromes such as enlarged vestibular aqueduct syndrome or familial Meniere disease. However, the involvement of common allelic variants as key regulators of physiological processes in common and rare vestibular diseases is starting to be deciphered, including motion sickness or sporadic Meniere disease. The genetic contribution to most of the vestibular disorders is still largely unknown. This review will outline the role of common and rare variants in human genome to episodic vestibular syndromes, progressive vestibular syndrome, and hereditary sensorineural hearing loss associated with vestibular phenotype. Future genomic studies and network analyses of omic data will clarify the pathway towards a personalized stratification of treatments.


Dizziness Vestibular disorders Genetics Meniere disease Vestibular migraine 



The authors are supported by Grants from Meniere’s Society, UK (MS-2016-17 Grant), PI17/01644 Grant from ISCIII by FEDER Funds from EU, H2020-MSCA-ITN-2016-722046 from EU and Luxembourg National Research Fund (INTER/Mobility/17/11772209).

Compliance with ethical standards

Conflicts of interest

The authors declare no competing conflict of interest.


  1. 1.
    Lopez-Escamez JA, Dlugaiczyk J, Jacobs J, Lempert T, Teggi R, von Brevern M, Bisdorff A (2014) Accompanying symptoms overlap during attacks in Meniere’s disease and vestibular migraine. Front Neurol 5:265CrossRefGoogle Scholar
  2. 2.
    Teggi R, Colombo B, Albera R, Asprella Libonati G, Balzanelli C, Batuecas Caletrio A, Casani A, Espinoza-Sanchez JM, Gamba P, Lopez-Escamez JA et al (2017) Clinical features, familial history, and migraine precursors in patients with definite vestibular migraine: the VM-phenotypes projects. Headache. CrossRefPubMedGoogle Scholar
  3. 3.
    Bisdorff AR, Staab JP (2015) Overview of the International Classification of Vestibular Disorders. Neurol Clin 33:541–550CrossRefGoogle Scholar
  4. 4.
    Frejo L, Giegling I, Teggi R, Lopez-Escamez JA, Rujescu D (2016) Genetics of vestibular disorders: pathophysiological insights. J Neurol 263:45–53CrossRefGoogle Scholar
  5. 5.
    Roman-Naranjo P, Gallego-Martinez A, Lopez Escamez JA (2017) Genetics of vestibular syndromes. Curr Opin Neurol 31:1CrossRefGoogle Scholar
  6. 6.
    Requena T, Espinosa-Sanchez JM, Lopez-Escamez JA (2014) Genetics of dizziness: cerebellar and vestibular disorders. Curr Opin Neurol 27:98–104CrossRefGoogle Scholar
  7. 7.
    Martín-Sierra C, Gallego-Martinez A, Requena T, Frejo L, Batuecas-Caletrío A, Lopez-Escamez JA (2017) Variable expressivity and genetic heterogeneity involving DPT and SEMA3D genes in autosomal dominant familial Meniere’s disease. Eur J Hum Genet 25:200–207CrossRefGoogle Scholar
  8. 8.
    Hromatka BS, Tung JY, Kiefer AK, Do CB, Hinds DA, Eriksson N (2015) Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis. Hum Mol Genet 24:2700–2708CrossRefGoogle Scholar
  9. 9.
    Espinosa-Sanchez JM, Lopez-Escamez JA (2015) New insights into pathophysiology of vestibular migraine. Front Neurol 6:12CrossRefGoogle Scholar
  10. 10.
    Lempert T, Olesen J, Furman J, Waterston J, Seemungal B, Carey J, Bisdorff A, Versino M, Evers S, Newman-Toker D (2012) Vestibular migraine: diagnostic criteria. J Vestib Res Equilib Orientat 22:167–172Google Scholar
  11. 11.
    Oh AK, Lee H, Jen JC, Corona S, Jacobson KM, Baloh RW (2001) Familial benign recurrent vertigo. Am J Med Genet 100:287–291CrossRefGoogle Scholar
  12. 12.
    Evans DGR, Moran A, King A, Saeed S, Gurusinghe N, Ramsden R (2005) Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period: higher incidence than previously thought. Otol Neurotol 26:93–97CrossRefGoogle Scholar
  13. 13.
    Li SL, Ma XH, Ji JF, Li H, Liu W, Lu FZ, Wu ST, Zhang Y (2016) miR-1 association with cell proliferation inhibition and apoptosis in vestibular schwannoma by targeting VEGFA. Genet Mol Res 15:1–8. CrossRefGoogle Scholar
  14. 14.
    Håvik AL, Bruland O, Myrseth E, Miletic H, Aarhus M, Knappskog P-M, Lund-Johansen M (2018) Genetic landscape of sporadic vestibular schwannoma. J Neurosurg 128:911–922. CrossRefPubMedGoogle Scholar
  15. 15.
    Jen JC, Wang H, Lee H, Sabatti C, Trent R, Hannigan I, Brantberg K, Halmagyi GM, Nelson SF, Baloh RW (2004) Suggestive linkage to chromosome 6q in families with bilateral vestibulopathy. Neurology 63:2376–2379CrossRefGoogle Scholar
  16. 16.
    Szmulewicz DJ, Roberts L, McLean CA, MacDougall HG, Halmagyi GM, Storey E (2016) Proposed diagnostic criteria for cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Neurol Clin Pract 6:61–68CrossRefGoogle Scholar
  17. 17.
    Szmulewicz DJ, McLean CA, MacDougall HG, Roberts L, Storey E, Halmagyi GM (2014) CANVAS an update: clinical presentation, investigation and management. J Vestib Res 24:465–474PubMedGoogle Scholar
  18. 18.
    Ahmad H, Requena T, Frejo L, Cobo M, Gallego-Martinez A, Martin F, Lopez-Escamez JA, Bronstein AM (2018) Clinical and functional characterization of a missense ELF2 variant in a CANVAS family. Front Genet 9:85. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Robertson NG, Lu L, Heller S, Merchant SN, Eavey RD, McKenna M, Nadol JB, Miyamoto RT, Linthicum FH, Lubianca Neto JF et al (1998) Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction. Nat Genet 20:299–303CrossRefGoogle Scholar
  20. 20.
    Robertson NG, Cremers CWRJ, Huygen PLM, Ikezono T, Krastins B, Kremer H, Kuo SF, Liberman MC, Merchant SN, Miller CE et al (2006) Cochlin immunostaining of inner ear pathologic deposits and proteomic analysis in DFNA9 deafness and vestibular dysfunction. Hum Mol Genet 15:1071–1085CrossRefGoogle Scholar
  21. 21.
    Tamagawa Y, Ishikawa K, Ishikawa K, Ishida T, Kitamura K, Makino S, Tsuru T, Ichimura K (2002) Phenotype of DFNA11: a nonsyndromic hearing loss caused by a myosin VIIA mutation. Laryngoscope 112:292–297CrossRefGoogle Scholar
  22. 22.
    Van Drunen FJW, Pauw RJ, Collin RWJ, Kremer H, Huygen PLM, Cremers CWRJ (2009) Vestibular impairment in a Dutch DFNA15 family with an L289F mutation in POU4F3. Audiol Neurotol 14:303–307CrossRefGoogle Scholar
  23. 23.
    Seco CZ, Oonk AMM, Domínguez-Ruiz M, Draaisma JMT, Gandía M, Oostrik J, Neveling K, Kunst HPM, Hoefsloot LH, del Castillo I et al (2015) Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5. Eur J Hum Genet 23:189–194CrossRefGoogle Scholar
  24. 24.
    Requena T, Espinosa-Sanchez JM, Cabrera S, Trinidad G, Soto-Varela A, Santos-Perez S, Teggi R, Perez P, Batuecas-Caletrio A, Fraile J et al (2014) Familial clustering and genetic heterogeneity in Meniere’s disease. Clin Genet 85:245–252CrossRefGoogle Scholar
  25. 25.
    Requena T, Cabrera S, Martín-Sierra C, Price SD, Lysakowski A, Lopez-Escamez JA (2015) Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere’s disease. Hum Mol Genet 24:1119–1126CrossRefGoogle Scholar
  26. 26.
    Martín-Sierra C, Requena T, Frejo L, Price SD, Gallego-Martinez Á, Batuecas-Caletrio Á, Santos-Perez S, Soto-Varela A, Lysakowski A, Lopez-Escamez JA (2016) A novel missense variant in PRKCB segregates low-frequency hearing loss in an autosomal dominant family with Meniere’s disease. Hum Mol Genet 25:3407–3415CrossRefGoogle Scholar
  27. 27.
    Frejo L, Requena T, Okawa S, Gallego-Martinez A, Martinez-Bueno M, Aran I, Batuecas-Caletrio A, Benitez-Rosario J, Espinosa-Sanchez JM, Fraile-Rodrigo JJ et al (2017) Regulation of Fn14 receptor and NF-κB underlies inflammation in Meniere’s disease. Front Immunol 8:1739. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Heidenreich KD, Kileny PR, Ahmed S, El-Kashlan HK, Melendez TL, Basura GJ, Lesperance MM (2017) Superior canal dehiscence syndrome affecting 3 families. JAMA Otolaryngol Head Neck Surg 143:656–662CrossRefGoogle Scholar
  29. 29.
    Noonan KY, Russo J, Shen J, Rehm H, Halbach S, Hopp E, Noon S, Hoover J, Eskey C, Saunders JE (2016) CDH23 related hearing loss. Otol Neurotol 37:1583–1588CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Otology and Neurotology Group CTS495, Department of Genomic MedicineCentre for Genomics and Oncological Research-Pfizer/University of Granada/Andalusian Regional Government (GENYO)GranadaSpain
  2. 2.Luxembourg Centre for Systems Biomedicine (LCSB)University of LuxembourgEsch-sur-AlzetteLuxembourg
  3. 3.Department of Otolaryngology, Instituto de Investigación Biosanitaria ibs.GRANADAHospital Universitario Virgen de las NievesGranadaSpain

Personalised recommendations