Genetics and the Individualized Therapy of Vestibular Disorders

Abstract

Background: Vestibular disorders (VDs) are a clinically divergent group of conditions that stem from pathology at the level of the inner ear, vestibulocochlear nerve, or central vestibular pathway. No etiology can be identified in the majority of patients with VDs. Relatively few families have been reported with VD, and so far, no causative genes have been identified despite the fact that more than 100 genes have been identified for inherited hearing loss. Inherited VDs, similar to deafness, are genetically heterogeneous and follow Mendelian inheritance patterns with all modes of transmission, as well as multifactorial inheritance. With advances in genetic sequencing, evidence of familial clustering in VD has begun to highlight the genetic causes of these disorders, potentially opening up new avenues of treatment, particularly in Meniere's disease and disorders with comorbid hearing loss, such as Usher syndrome. In this review, we aim to present recent findings on the genetics of VDs, review the role of genetic sequencing tools, and explore the potential for individualized medicine in the treatment of these disorders.Methods: A search of the PubMed database was performed for English language studies relevant to the genetic basis of and therapies for vestibular disorders, using search terms including but not limited to: “genetics,” “genomics,” “vestibular disorders,” “hearing loss with vestibular dysfunction,” “individualized medicine,” “genome-wide association studies,” “precision medicine,” and “Meniere's syndrome.”Results: Increasing numbers of studies on vestibular disorder genetics have been published in recent years. Next-generation sequencing and new genetic tools are being utilized to unearth the significance of the genomic findings in terms of understanding disease etiology and clinical utility, with growing research interest being shown for individualized gene therapy for some disorders.Conclusions: The genetic knowledge base for vestibular disorders is still in its infancy. Identifying the genetic causes of balance problems is imperative in our understanding of the biology of normal function of the vestibule and the disease etiology and process. There is an increasing effort to use new and efficient genetic sequencing tools to discover the genetic causes for these diseases, leading to the hope for precise and personalized treatment for these patients.

Vestibular Deficits in Deafness: Clinical Presentation, Animal Modeling, and Treatment Solutions

“…Gene therapy tools have progressed considerably [improved AAVs, new delivery strategies, emerging gene editing tools; see ( 49 , 89 , 239 – 241 )] and there is an urgent need for their clinical application to hearing and balance disorders. Consistent with the considerable phylogenetic gap between vestibular and cochlear organs, the intermediate step toward successful gene therapies for the inner ear is now being achieved, at least in preclinical animal models presenting balance deficits.…”

“…Like hearing loss ( 49 , 88 ), vestibular disorders may have multiple causes, including genetics, aging, drugs, immune and environmental factors (e.g., infections, noise exposure) ( 89 ). The prevalence of vestibular impairment is high in children and adults with sensorineural hearing loss (SNHL), between 20 and 70% ( 90 , 91 ).…”

“…The first applications of gene therapy focused on gene replacement (or gene supplementation) therapy, in which a healthy copy of a defective gene is introduced into cells bearing the mutation. These studies essentially targeted key deafness genes small enough to be delivered with adeno-associated virus (AAV) vectors (maximum capacity of 4.7 kb for a single AAV) ( 49 , 89 , 239 – 241 ) (see Table 1 ). In recent years, new generations of AAVs with higher transduction rates for inner ear hair cells have been tested ( 139 , 141 , 146 , 240 , 242 ).…”

Case Report: Ménière's Disease-Like Symptoms in 22q11.2 Deletion Syndrome

“…A recent study found that non-coding variants in CRKL were significantly associated with risk for conotruncal heart defects in individuals with 22q11.2DS (12). Many genes have been related to hereditary non-syndromic hearing loss and Ménière's disease (13)(14)(15)(16). It is therefore possible that rare variants in these genes could modify audiovestibular phenotype by interacting with TBX1 in 22q11.2DS.…”

Cation Permeability of Voltage-Gated Hair Cell Ca2+ Channels of the Vertebrate Labyrinth

“…For instance, mutations in the subunits of the Ca V 1.3 channel type and in its modulator protein CaBP2 originate the autosomal recessive deafness, while many mutations in Ca V 1.4 channels and in their modulator protein CaBP4 are associated with autosomal recessive congenital stationary night blindness (reviewed in [ 4 ]). Vestibular disorders such as type 2 episodic ataxia are caused by mutations in the P/Q-type channel [ 6 ], possibly at the level of the vestibular hair cells [ 7 ]. Therefore, it is of paramount importance to investigate the biophysical properties of these channels: a convenient model is the hair cells isolated from the rana esculenta labyrinth, because they are particularly large and robust, yet they are very similar to the other vertebrate hair cells, and this comestible species can be easily supplied by local dealers.…”