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Towards personalized medicine in Ménière's disease
Jose Antonio Lopez-Escamez1,2,3, Angel Batuecas-Caletrio4, Alexandre Bisdorff5
1Otology & Neurotology Group CTS495, Department of Genomic Medicine, Centro de Genómica e Investigación Oncológica, Pfizer/Universidad de Granada/Junta de Andalucía (GENYO), Granada, Spain.
Abstract:
Ménière's disease (MD) represents a heterogeneous group of relatively rare disorders with three core symptoms: episodic vertigo, tinnitus, and sensorineural hearing loss involving 125 to 2,000 Hz frequencies. The majority of cases are considered sporadic, although familial aggregation has been recognized in European and Korean populations, and the search for familial MD genes has been elusive until the last few years. Detailed phenotyping and cluster analyses have found several clinical predictors for different subgroups of patients, which may indicate different mechanisms, including genetic and immune factors. The genes associated with familial MD are COCH, FAM136A, DTNA, PRKCB, SEMA3D, and DPT. At least two mechanisms have been involved in MD: (a) a pro-inflammatory immune response mediated by interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNFα), and IL-6, and (b) a nuclear factor-kappa B (NF-κB)-mediated inflammation in the carriers of the single-nucleotide variant rs4947296. It is conceivable that microbial antigens trigger inflammation with release of pro-inflammatory cytokines at different sites within the cochlea, such as the endolymphatic sac, the stria vascularis, or the spiral ligament, leading to fluid imbalance with an accumulation of endolymph. Computational integration of clinical and "omics" data eventually should transform the management of MD from "one pill fits all" to precise patient stratification and a personalized approach. This article lays out a proposal for an algorithm for the genetic diagnosis of MD. This approach will facilitate the identification of new molecular targets for individualized treatment, including immunosuppressant and gene therapy, in the near future.
Insights
Ménière's disease (MD) involves vertigo, tinnitus, and hearing loss. Genetic and immune factors are implicated, with specific genes and inflammatory pathways identified, paving the way for personalized treatments.
Area of Science:
- Otolaryngology
- Genetics
- Immunology
Background:
- Ménière's disease (MD) is a rare, heterogeneous disorder characterized by episodic vertigo, tinnitus, and sensorineural hearing loss.
- While often sporadic, familial aggregation suggests a genetic component, with several genes now linked to familial MD.
- Understanding underlying genetic and immune mechanisms is crucial for advancing MD management.
Purpose of the Study:
- To review current knowledge on the genetic and immune factors contributing to Ménière's disease.
- To propose an algorithm for the genetic diagnosis of MD.
- To highlight the potential for personalized treatment strategies in MD.
Main Methods:
- Review of literature on familial Ménière's disease genetics and immune pathways.
- Analysis of clinical predictors and genetic associations.
- Proposal of a diagnostic algorithm integrating genetic information.
Main Results:
- Identified genes associated with familial MD: COCH, FAM136A, DTNA, PRKCB, SEMA3D, and DPT.
- Elucidated two key mechanisms: pro-inflammatory cytokine response (IL-1β, TNFα, IL-6) and NF-κB-mediated inflammation.
- Linked inflammation to microbial antigens and cochlear site involvement, leading to endolymphatic hydrops.
Conclusions:
- MD pathogenesis involves complex genetic and immune interactions.
- A proposed genetic diagnostic algorithm can aid in patient stratification.
- Future directions include developing individualized treatments like immunosuppressants and gene therapy for MD.