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.

Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study.

BACKGROUND: tinnitus is a heterogeneous condition associated with audiological and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype. METHODS: for this extreme phenotype study, we used three different cohorts with European ancestry (Spanish with Meniere disease (MD), Swedes tinnitus and European generalized epilepsy). In addition, four independent control datasets were also used for comparisons. Whole-exome sequencing was performed for the MD and epilepsy cohorts and whole-genome sequencing was carried out in Swedes with tinnitus. FINDINGS: we found an enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort, the most significant being PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 (p < 2E-04), when they were compared with reference datasets. This burden was replicated for ANK2 gene in a Swedish cohort with 97 tinnitus individuals, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 genes (p < 2E-02). However, these associations were not significant in a third cohort of 701 generalized epilepsy individuals without tinnitus. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, including membrane trafficking and cytoskeletal protein binding in neurons. INTERPRETATION: a burden of rare variants in ANK2, AKAP9 and TSC2 is associated with severe tinnitus. ANK2, encodes a cytoskeleton scaffolding protein that coordinates the assembly of several proteins, drives axonal branching and influences connectivity in neurons.

Lorente de Nó: From Neuroanatomy to Neurophysiology.

Rafael Lorente de Nó (1902-1990) was the youngest and last of Santiago Ramón y Cajal's students. With Fernando de Castro, Lorente de Nó helped to transition the focus of Ramón y Cajal's School from neuroanatomy to neurophysiology. His main contributions to neuroscience concerned the cytoarchitecture of the cerebral isocortex and hippocampus, neural networks, central vestibular system anatomy, vestibulo-ocular reflex physiology, cochlear nuclei anatomy, and synaptic transmission mechanisms. This article pays tribute to the memory of Lorente de Nó by providing a comprehensive review of the life and work of this giant of neuroscience. Anat Rec, 303:1221-1231, 2020. © 2019 American Association for Anatomy.

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.

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.

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.

[Pharmacotherapy for tinnitus: much ado about nothing]. / Tratamiento farmacológico de los acúfenos: mucho ruido y pocas nueces.

INTRODUCTION: Chronic tinnitus affects 5-15% of the general population; in 1% of individuals with tinnitus this condition severely affects their quality of life. Pharmacological treatment is one of the options for the management of tinnitus patients, but their efficacy remains controversial. AIM. To evaluate the level of evidence to support the use of different drugs in reducing the severity of tinnitus. DEVELOPMENT: The pharmacological groups that have been investigated for the treatment of tinnitus include anesthetics, anticonvulsants, antidepressants, antihistamines, benzodiazepines, diuretics, corticosteroids, and of other substances. Intravenous lidocaine seems to be effective, but the short duration of the effect and the adverse reactions prevent its use. Compared with placebo, carbamazepine and gabapentine have not demonstrated effectiveness although they may be effective in some patients with auditory nerve vascular compression or myoclonus. Tricyclic antidepressants are no more effective than placebo at reducing tinnitus severity although they may improve comorbid depression. There is insufficient evidence to evaluate the effectiveness of selective serotonin reuptake inhibitors and benzodiazepines. Acamprosate may decrease the severity of tinnitus, but the level of evidence is low. There are no consistent results in the studies with intratympanic gentamicin or steroids in tinnitus associated with Meniere's disease. CONCLUSIONS: The use of pharmacotherapy in reducing the severity of tinnitus is not well supported by prospective, randomized, placebo-controlled clinical trials. Various drugs have been shown to be effective in some studies, but the clinical evidence is limited. Large randomized clinical trials are needed.

TITLE: Tratamiento farmacologico de los acufenos: mucho ruido y pocas nueces.Introduccion. El 5-15% de la poblacion general presenta acufenos cronicos, que afectan de manera grave a la calidad de vida del 1% de los casos. El tratamiento farmacologico es una de las opciones terapeuticas en el abordaje de pacientes con acufenos, aunque su eficacia es controvertida. Objetivo. Evaluar el nivel de evidencia que sustenta el uso de diferentes farmacos para reducir la intensidad de los acufenos. Desarrollo. Se han revisado varios grupos farmacologicos incluyendo anestesicos, antiepilepticos, antidepresivos, antihistaminicos, benzodiacepinas, diureticos, corticoides y otras sustancias. La lidocaina intravenosa parece ser eficaz aunque la breve duracion de su efecto y la aparicion de reacciones adversas han llevado a descartarla. La carbamacepina y la gabapentina no han mostrado eficacia frente a placebo, si bien podrian ser eficaces en algunos pacientes con compresion neurovascular o mioclonias. Los antidepresivos triciclicos no son mas eficaces que el placebo aunque pueden mejorar una depresion coexistente. La evidencia es insuficiente para evaluar la eficacia de los inhibidores selectivos de la recaptacion de serotonina y las benzodiacepinas. El acamprosato podria reducir la intensidad de los acufenos, aunque el nivel de evidencia es bajo. No disponemos de resultados consistentes para el tratamiento de los acufenos de la enfermedad de Meniere empleando gentamicina intratimpanica o corticoides. Conclusiones. La utilizacion de medicamentos para reducir la intensidad de los acufenos no esta bien apoyada por ensayos clinicos controlados, aleatorizados y prospectivos. Algunos farmacos son eficaces en algunos estudios, pero la evidencia es limitada. Se necesitan ensayos clinicos aleatorizados mas amplios.

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

Meniere's 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.

Tratamiento farmacológico de los acúfenos: mucho ruido y pocas nueces / Pharmacotherapy for tinnitus: much ado about nothing

Introducción. El 5-15% de la población general presenta acúfenos crónicos, que afectan de manera grave a la calidad de vida del 1% de los casos. El tratamiento farmacológico es una de las opciones terapéuticas en el abordaje de pacientes con acúfenos, aunque su eficacia es controvertida. Objetivo. Evaluar el nivel de evidencia que sustenta el uso de diferentes fármacos para reducir la intensidad de los acúfenos. Desarrollo. Se han revisado varios grupos farmacológicos incluyendo anestésicos, antiepilépticos, antidepresivos, antihistamínicos, benzodiacepinas, diuréticos, corticoides y otras sustancias. La lidocaína intravenosa parece ser eficaz aunque la breve duración de su efecto y la aparición de reacciones adversas han llevado a descartarla. La carbamacepina y la gabapentina no han mostrado eficacia frente a placebo, si bien podrían ser eficaces en algunos pacientes con compresión neurovascular o mioclonías. Los antidepresivos tricíclicos no son más eficaces que el placebo aunque pueden mejorar una depresión coexistente. La evidencia es insuficiente para evaluar la eficacia de los inhibidores selectivos de la recaptación de serotonina y las benzodiacepinas. El acamprosato podría reducir la intensidad de los acúfenos, aunque el nivel de evidencia es bajo. No disponemos de resultados consistentes para el tratamiento de los acúfenos de la enfermedad de Ménière empleando gentamicina intratimpánica o corticoides. Conclusiones. La utilización de medicamentos para reducir la intensidad de los acúfenos no está bien apoyada por ensayos clínicos controlados, aleatorizados y prospectivos. Algunos fármacos son eficaces en algunos estudios, pero la evidencia es limitada. Se necesitan ensayos clínicos aleatorizados más amplios (AU)

Introduction. Chronic tinnitus affects 5-15% of the general population; in 1% of individuals with tinnitus this condition severely affects their quality of life. Pharmacological treatment is one of the options for the management of tinnitus patients, but their efficacy remains controversial. Aim. To evaluate the level of evidence to support the use of different drugs in reducing the severity of tinnitus. Development. The pharmacological groups that have been investigated for the treatment of tinnitus include anesthetics, anticonvulsants, antidepressants, antihistamines, benzodiazepines, diuretics, corticosteroids, and of other substances. Intravenous lidocaine seems to be effective, but the short duration of the effect and the adverse reactions prevent its use. Compared with placebo, carbamazepine and gabapentine have not demonstrated effectiveness although they may be effective in some patients with auditory nerve vascular compression or myoclonus. Tricyclic antidepressants are no more effective than placebo at reducing tinnitus severity although they may improve comorbid depression. There is insufficient evidence to evaluate the effectiveness of selective serotonin reuptake inhibitors and benzodiazepines. Acamprosate may decrease the severity of tinnitus, but the level of evidence is low. There are no consistent results in the studies with intratympanic gentamicin or steroids in tinnitus associated with Ménière’s disease. Conclusions. The use of pharmacotherapy in reducing the severity of tinnitus is not well supported by prospective, randomized, placebo-controlled clinical trials. Various drugs have been shown to be effective in some studies, but the clinical evidence is limited. Large randomized clinical trials are needed (AU)

Migraña vestibular: un diagnóstico emergente / Vestibular migraine: An emerging diagnosis

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