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      Genetics of vestibular disorders: pathophysiological insights

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          Abstract

          The two most common vestibular disorders are motion sickness and vestibular migraine, affecting 30 and 1–2 % of the population respectively. Both are related to migraine and show a familial trend. Bilateral vestibular hypofunction is a rare condition, and some of patients also present cerebellar ataxia and neuropathy. We present recent advances in the genetics of vestibular disorders with familial aggregation. The clinical heterogeneity observed in different relatives of the same families suggests a variable penetrance and the interaction of several genes in each family. Some Mendelian sensorineural hearing loss also exhibits vestibular dysfunction, including DFNA9, DFNA11, DFNA15 and DFNA28. However, the most relevant finding during the past years is the familial clustering observed in Meniere’s disease. By using whole exome sequencing and combining bioinformatics tools, novel variants in DTNA and FAM136A genes have been identified in familial Meniere’s disease, and this genomic strategy will facilitate the discovery of the genetic basis of familial vestibular disorders.

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          Most cited references68

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          Vestibular migraine: diagnostic criteria.

          This paper presents diagnostic criteria for vestibular migraine, jointly formulated by the Committee for Classification of Vestibular Disorders of the Bárány Society and the Migraine Classification Subcommittee of the International Headache Society (IHS). The classification includes vestibular migraine and probable vestibular migraine. Vestibular migraine will appear in an appendix of the third edition of the International Classification of Headache Disorders (ICHD) as a first step for new entities, in accordance with the usual IHS procedures. Probable vestibular migraine may be included in a later version of the ICHD, when further evidence has been accumulated. The diagnosis of vestibular migraine is based on recurrent vestibular symptoms, a history of migraine, a temporal association between vestibular symptoms and migraine symptoms and exclusion of other causes of vestibular symptoms. Symptoms that qualify for a diagnosis of vestibular migraine include various types of vertigo as well as head motion-induced dizziness with nausea. Symptoms must be of moderate or severe intensity. Duration of acute episodes is limited to a window of between 5 minutes and 72 hours.
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            Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2.

            Headache attacks and autonomic dysfunctions characterize migraine, a very common, disabling disorder with a prevalence of 12% in the general population of Western countries. About 20% of individuals affected with migraine experience aura, a visual or sensory-motor neurological dysfunction that usually precedes or accompanies the headache. Although the mode of transmission is controversial, population-based and twin studies have implicated genetic factors, especially in migraine with aura. Familial hemiplegic migraine is a hereditary form of migraine characterized by aura and some hemiparesis. Here we show that mutations in the gene ATP1A2 that encodes the alpha2 subunit of the Na+/K+ pump are associated with familial hemiplegic migraine type 2 (FHM2) linked to chromosome 1q23 (OMIM 602481). Functional data indicate that the putative pathogenetic mechanism is triggered by a loss of function of a single allele of ATP1A2. This is the first report associating mutations of Na+K+ pump subunits to genetic diseases.
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              Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine.

              Familial hemiplegic migraine is an autosomal dominant severe subtype of migraine with aura characterised by some degree of hemiparesis during the attacks. So far, mutations in two genes regulating ion translocation-CACNA1A and ATP1A2-have been identified in pedigrees with this disease. To identify additional genes for familial hemiplegic migraine, we did a genome-wide linkage analysis of two disease pedigrees without mutations in CACNA1A and ATP1A2. Ion channel genes in the candidate interval were analysed for mutations, and the functional consequences of the recorded sequence alteration were determined. We identified a novel locus for familial hemiplegic migraine on chromosome 2q24. Sequencing of candidate genes in this region revealed a heterozygous missense mutation (Gln1489Lys) in the neuronal voltage-gated sodium channel gene SCN1A, mutations of which have been associated with epilepsy. This same mutation was present in three families with familial hemiplegic migraine. It results in a charge-altering aminoacid exchange in the so-called hinged-lid domain of the protein, which is critical for fast inactivation of the channel. Whole-cell recordings in transiently transfected tsA201 cells expressing the highly homologous SCN5A sodium channel showed that the mutation induces a two-fold to four-fold accelerated recovery from fast inactivation without altering any of the other channel parameters investigated. Dysfunction of the neuronal sodium channel SCN1A can cause familial hemiplegic migraine. Our findings have implications for the understanding of migraine aura. Moreover, our study reinforces the molecular links between migraine and epilepsy, two common paroxysmal disorders.
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                Author and article information

                Contributors
                +34 958 715 500-160 , antonio.lopezescamez@genyo.es
                Journal
                J Neurol
                J. Neurol
                Journal of Neurology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0340-5354
                1432-1459
                15 April 2016
                15 April 2016
                2016
                : 263
                : 45-53
                Affiliations
                [ ]Otology and Neurotology Group CTS495, Department of Genomic Medicine, GENYO - Centre for Genomics and Oncological Research – Pfizer/University of Granada/Junta de Andalucía, PTS, 18016 Granada, Spain
                [ ]German Center for Vertigo and Balance Disorders, Munich, Germany
                [ ]Department of Otolaryngology, San Raffaelle Scientific Institute, Milan, Italy
                [ ]Department of Otolaryngology, Granada University Hospital, 18012 Granada, Spain
                Article
                7988
                10.1007/s00415-015-7988-9
                4833787
                27083884
                19a37a20-0d52-4ae4-96b6-9c0b2d9c70ab
                © The Author(s) 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 20 July 2015
                : 1 November 2015
                : 29 November 2015
                Funding
                Funded by: Meniere's Society
                Funded by: FundRef http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III (ES);
                Funded by: Fondazione Italiana Cefalee
                Categories
                Review
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2016

                Neurology
                vestibular disorders,whole exome sequencing,vestibular migraine,motion sickness,meniere disease

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