Juan M. Espinosa-Sanchez

Familial clustering and genetic heterogeneity in Meniere's disease

The aims of this study were to estimate the prevalence of familial cases in patients with Menieres disease (MD) and to identify clinical differences between sporadic and familial MD. We recruited 1375 patients with definite MD according to the American Academy of Otolaryngology‐Head and Neck Surgery criteria, obtaining the familial history of hearing loss or episodic vertigo by direct interview or a postal survey in 1245 cases in a multicenter study. Familial clustering was estimated by the recurrence risk ratio in siblings (λs) and offspring (λo) using intermediate and high prevalence values for MD in European population. A total of 431 patients (34%) reported a familial history of hearing loss or recurrent vertigo and 133 patients had a relative with possible MD. After clinical reevaluation, 93 relatives in 76 families were diagnosed of definite MD (8.4%), including three pairs of monozygotic twins. λs and λo were 16–48 and 4–12, respectively. We observed genetic heterogeneity, but most families had an autosomal dominant inheritance with anticipation. No clinical differences were found between sporadic and familial MD, except for an early onset in familial cases. We may conclude that MD has a strong familial aggregation and that sporadic and familial MDs are clinically identical.

Genetics of dizziness: cerebellar and vestibular disorders.

PURPOSE OF REVIEW Recent advances in next generation sequencing techniques (NGS) are increasing the number of novel genes associated with cerebellar and vestibular disorders. We have summarized clinical and molecular genetics findings in neuro-otolology during the last 2 years. RECENT FINDINGS Whole-exome and targeted sequencing have defined the genetic basis of dizziness including new genes causing ataxia: GBA2, TGM6, ANO10 and SYT14. Novel mutations in KCNA1 and CACNA1A genes are associated with episodic ataxia type 1 and type 2, respectively. Moreover, new variants in genes such as COCH, MYO7A and POU4F3 are associated with nonsyndromic deafness and vestibular dysfunction. Several susceptibility loci have been linked to familial vestibular migraine, suggesting genetic heterogeneity, but no specific gene has been identified. Finally, loci for complex and heterogeneous diseases such as bilateral vestibular hypofunction or familial Ménière disease have not been identified yet, despite their strong familial aggregation. SUMMARY Cerebellar and vestibular disorders leading to dizziness or episodic vertigo may show overlapping clinical features. A deep phenotyping including a complete familial history is a key step in performing a reliable molecular genetic diagnosis using NGS. Personalized molecular medicine will be essential to understand disease mechanisms as well as to improve their diagnosis and treatment.

New insights into pathophysiology of vestibular migraine

Vestibular migraine (VM) is a common disorder in which genetic, epigenetic, and environmental factors probably contribute to its development. The pathophysiology of VM is unknown; nevertheless in the last few years, several studies are contributing to understand the neurophysiological pathways involved in VM. The current hypotheses are mostly based on the knowledge of migraine itself. The evidence of trigeminal innervation of the labyrinth vessels and the localization of vasoactive neuropeptides in the perivascular afferent terminals of these trigeminal fibers support the involvement of the trigemino-vascular system. The neurogenic inflammation triggered by activation of the trigeminal-vestibulocochlear reflex, with the subsequent inner ear plasma protein extravasation and the release of inflammatory mediators, can contribute to a sustained activation and sensitization of the trigeminal primary afferent neurons explaining VM symptoms. The reciprocal connections between brainstem vestibular nuclei and the structures that modulate trigeminal nociceptive inputs (rostral ventromedial medulla, ventrolateral periaqueductal gray, locus coeruleus, and nucleus raphe magnus) are critical to understand the pathophysiology of VM. Although cortical spreading depression can affect cortical areas involved in processing vestibular information, functional neuroimaging techniques suggest a dysmodulation in the multimodal sensory integration and processing of vestibular and nociceptive information, resulting from a vestibulo-thalamo-cortical dysfunction, as the pathogenic mechanism underlying VM. The elevated prevalence of VM suggests that multiple functional variants may confer a genetic susceptibility leading to a dysregulation of excitatory–inhibitory balance in brain structures involved in the processing of sensory information, vestibular inputs, and pain. The interactions among several functional and structural neural networks could explain the pathogenic mechanisms of VM.

Clinical Subgroups in Bilateral Meniere Disease

Meniere disease (MD) is a heterogeneous clinical condition characterized by sensorineural hearing loss, episodic vestibular symptoms, and tinnitus associated with several comorbidities, such as migraine or autoimmune disorders (AD). The frequency of bilateral involvement may range from 5 to 50%, and it depends on the duration of the disease. We have performed a two-step cluster analysis in 398 patients with bilateral MD (BMD) to identify the best predictors to define clinical subgroups with a potential different etiology to improve the phenotyping of BMD and to develop new treatments. We have defined five clinical variants in BMD. Group 1 is the most frequently found, includes 46% of patients, and is defined by metachronic hearing loss without migraine and without AD. Group 2 is found in 17% of patients, and it is defined by synchronic hearing loss without migraine or AD. Group 3, with 13% of patients, is characterized by familial MD, while group 4, that includes 12% of patients, is associated by the presence of migraine in all cases. Group 5 is found in 11% of patients and is defined by AD. This approach can be helpful in selecting patients for genetic and clinical research. However, further studies will be required to improve the phenotyping in these clinical variants for a better understanding of the diverse etiological factors contributing to BMD.

Intronic variants in the NFKB1 gene may influence hearing forecast in patients with unilateral sensorineural hearing loss in Meniere's disease.

Menieres disease is an episodic vestibular syndrome associated with sensorineural hearing loss (SNHL) and tinnitus. Patients with MD have an elevated prevalence of several autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and psoriasis), which suggests a shared autoimmune background. Functional variants of several genes involved in the NF-κB pathway, such as REL, TNFAIP3, NFKB1 and TNIP1, have been associated with two or more immune-mediated diseases and allelic variations in the TLR10 gene may influence bilateral affectation and clinical course in MD. We have genotyped 716 cases of MD and 1628 controls by using the ImmunoChip, a high-density genotyping array containing 186 autoimmune loci, to explore the association of immune system related-loci with sporadic MD. Although no single nucleotide polymorphism (SNP) reached a genome-wide significant association (p<10−8), we selected allelic variants in the NF-kB pathway for further analyses to evaluate the impact of these SNPs in the clinical outcome of MD in our cohort. None of the selected SNPs increased susceptibility for MD in patients with uni or bilateral SNHL. However, two potential regulatory variants in the NFKB1 gene (rs3774937 and rs4648011) were associated with a faster hearing loss progression in patients with unilateral SNHL. So, individuals with unilateral MD carrying the C allele in rs3774937 or G allele in rs4648011 had a shorter mean time to reach hearing stage 3 (>40 dB HL) (log-rank test, corrected p values were p = 0.009 for rs3774937 and p = 0.003 for rs4648011, respectively). No variants influenced hearing in bilateral MD. Our data support that the allelic variants rs3774937 and rs4648011 can modify hearing outcome in patients with MD and unilateral SNHL.

Extended phenotype and clinical subgroups in unilateral Meniere disease: A cross-sectional study with cluster analysis

To define clinical subgroups by cluster analysis in patients with unilateral Meniere disease (MD) and to compare them with the clinical subgroups found in bilateral MD.

Migraine, sudden sensorineural hearing loss and autoimmune ear disease

We have read with attention the article entitled ‘‘Migraine is a risk factor for sudden sensorineural hearing loss: A nationwide population-based study’’ by Chu et al. (1). The authors have reported a welldesigned retrospective study in two cohorts of migraine and non-migrainous patients matching by age, sex and comorbidities such as diabetes, hypertension, dyslipidemia and atrial fibrillation. Although this matching has avoided a selection bias for vascular risk factors, the authors have not considered systemic autoimmune diseases, and they can be associated with sensorineural hearing loss. We have found a higher prevalence of rheumatoid arthritis, systemic lupus erythematous and ankylosing spondylitis in patients with Meniere’s disease (MD) and migraine than in patients with MD and tension-type headache (2). Interestingly, the authors have excluded MD as a cause of sudden onset sensorineural hearing loss (SSNHL), but they have not considered vestibular migraine (VM). The reported incidence rate of MD seems too high when compared to published rates (227 MD patients of a total of 13,532 migraine patients during the 10-year follow-up). It should also be noted that about 50% of patients with MD meet criteria for migraine (3). It is our opinion that several of the excluded MD patients were probably VM sufferers, and some migraine patients with SSNHL may correspond to VM patients. VM is probably the most common cause of recurrent spontaneous vertigo (4). The relation between migraine and MD is well known. An increased prevalence of migraine in MD patients has been reported in several studies; likewise migraine may predispose to develop MD. Vestibular migraine and MD overlap in presentation and may be misdiagnosed. It has been proposed that both conditions share a common pathophysiology and may even be inherited as a symptom cluster. The diagnostic criteria of VM will be included in the appendix of the next review of the International Headache Classification. This will contribute to elucidating the differential diagnosis. Cochlear symptoms are also present in VM. Although phonophobia is the most common auditory symptom, 50% of VM patients refer tinnitus and 34% report hearing loss (5). Hearing loss is usually episodic in VM, but permanent unilateral hearing loss and SSNHL has also been reported in vestibular migraine. We suggest that autoimmune inner ear disease may explain the differences in SSNHL between both groups. Regardless, these comments do not decrease the merit of the study.

Regulation of Fn14 Receptor and NF-κB Underlies Inflammation in Meniere’s Disease

Meniere’s disease (MD) is a rare disorder characterized by episodic vertigo, sensorineural hearing loss, tinnitus, and aural fullness. It is associated with a fluid imbalance between the secretion of endolymph in the cochlear duct and its reabsorption into the subarachnoid space, leading to an accumulation of endolymph in the inner ear. Epidemiological evidence, including familial aggregation, indicates a genetic contribution and a consistent association with autoimmune diseases (AD). We conducted a case–control study in two phases using an immune genotyping array in a total of 420 patients with bilateral MD and 1,630 controls. We have identified the first locus, at 6p21.33, suggesting an association with bilateral MD [meta-analysis leading signal rs4947296, OR = 2.089 (1.661–2.627); p = 1.39 × 10−09]. Gene expression profiles of homozygous genotype-selected peripheral blood mononuclear cells (PBMCs) demonstrated that this region is a trans-expression quantitative trait locus (eQTL) in PBMCs. Signaling analysis predicted several tumor necrosis factor-related pathways, the TWEAK/Fn14 pathway being the top candidate (p = 2.42 × 10−11). This pathway is involved in the modulation of inflammation in several human AD, including multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. In vitro studies with genotype-selected lymphoblastoid cells from patients with MD suggest that this trans-eQTL may regulate cellular proliferation in lymphoid cells through the TWEAK/Fn14 pathway by increasing the translation of NF-κB. Taken together; these findings suggest that the carriers of the risk genotype may develop an NF-κB-mediated inflammatory response in MD.

Genetic contribution to vestibular diseases

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.

Ménière's Syndrome and Migraine

Numerous studies have shown an increased frequency of Meniere’s disease (MD) in migraineurs and, conversely, a high prevalence of migraine in MD patients. Vestibular migraine (VM) and MD are common causes of spontaneous episodic vertigo, with a clear clinical overlap between both disorders. Furthermore, we have also demonstrated a higher prevalence of migraine in familial MD as compared with sporadic syndrome. All this suggests a common pathophysiological link between migraine and MD. Several mechanisms could explain this relation including an inherited alteration of brain excitability, the sensitization of the trigemino-vascular system, a neurogenic vasodilation of meningeal and labyrinth vessels, and a susceptibility to transient ischemic events.