Meniere’s disease remains a disorder of unknown origin despite the collective efforts to determine the pathogenesis, although experts have long recognized that disease development likely has some heritable component. Although genetic studies of Meniere’s disease have been inconclusive, increasing knowledge of human genetic structure and mutation and investigative techniques have potential to further understanding of this disorder.
Definition
Meniere’s disease (MD) is a clinical disorder defined by the symptom complex of fluctuating sensorineural hearing loss, vertigo, tinnitus, and aural pressure. In an effort to develop uniform reporting criteria for MD, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) Committee on Hearing and Equilibrium published guidelines for diagnosing this entity in 1995. To be diagnosed with definite MD, a patient must display two or more episodes of characteristic vertigo (each episode lasting longer than 20 minutes), documented hearing loss (typically fluctuating low-frequency sensorineural loss seen on serial audiograms), and presence of aural pressure or tinnitus in the affected ear, and other causes of vertigo must be excluded. The effort to include only definite cases in clinical studies of MD is intended to allow reliable comparisons among different institutions. Not all patients presenting to specialty clinics will satisfy diagnostic criteria for definite MD, because isolated hearing symptoms are common. In general, approximately two-thirds of patients with symptoms of MD will be classified as definite, whereas the remainder are usually classified as possible MD.
The natural history of MD has been documented in several studies. The mean age of onset is between 45 and 55 years. Sensorineural hearing loss typically begins in low frequencies, and will show fluctuation early in the disease. With time, fluctuation ceases and most patients develop a progressive moderate to severe hearing loss. The hearing tends to stabilize 8 to 10 years after onset. Vertigo symptoms are dramatic at onset, but also tend to diminish in frequency and severity over time. Vestibular function usually remains compromised in the affected ear. The disorder is unilateral at onset in most cases, but with extended follow-up, symptoms may develop in the opposite ear in up to 30% of patients. The list of treatment options is extensive. The general tendency toward diminished vertigo attacks, reports of similar efficacy for widely varying treatment modalities, paucity of controlled studies, and inability to alter the progression of hearing loss casts doubt on the ultimate value of medical management. Clearly, greater understanding of the pathophysiology of this disorder would enhance clinical management.
Etiology/Pathogenesis
Endolymphatic hydrops has been consistently identified as a histologic feature of temporal bone specimens from patients with MD. Historically, great significance was attached to this finding, resulting in speculation that hydrops produced the characteristic symptoms of MD. More recent analysis of temporal bone specimens by Merchant and colleagues described similar degrees of endolymphatic hydrops in specimens from people with and without the characteristic symptoms of MD. However, patients with MD who did not have hydrops on histologic examination have also been reported, and therefore the presence of hydrops is neither essential nor specific to MD. The event that triggers development of hydrops remains undefined, although disruption of Na+/K+ homeostasis may be an important contributing factor.
Numerous theories regarding MD pathogenesis exist, with it being broadly categorized as caused by metabolic, autonomic, or endocrine dysfunction; allergy; autoimmunity; trauma; infectious disease; or vascular disease. Each theory has varying degrees of supportive evidence. Some preliminary observations have not been replicated in subsequent studies, illustrated by the ambiguity of the role of autoimmunity in MD. The relative contributions of each potential theory may be predicted based partially on clinical history. Trauma and acute infectious events are rarely associated with the development of symptoms. The typically unilateral symptoms are difficult to explain based on a theory of systemic metabolic, endocrine, allergic, immune, or vascular disorders. Finally, little epidemiologic evidence shows that other comorbid diseases exceed the expected population prevalence in patients with MD, with the possible exception of migraine. Although none of the proposed theories can be categorically rejected, two interesting possibilities that do account for the unilateral nature of the disease are migraine and recrudescent viral infection.
Vestibular symptoms are frequently described in individuals with migraine. The diagnostic criteria for migraine-associated dizziness are fulfillment of International Headache Society (IHS) criteria for migraine headache with concurrent vestibular symptoms. These individuals rarely have any associated hearing loss. Other experts have observed that the prevalence of migraine in patients with MD exceeds that of the expected population prevalence. The highest percentage of concomitant MD and migraine is reported to be 56% of all patients with MD. This finding suggests that MD attacks and migraine headache share a common pathway for symptom development. Additional support is provided by the clinical observation that agents for migraine prophylaxis have shown benefit in some patients with MD.
The genetic component of migraine is clinically evident and partially defined at the molecular level. At least nine loci exist for common migraine with or without aura, and three for familial hemiplegic migraine (FHM). Mutations in three different genes are described for different pedigrees of FHM. All of these, CACNA1A , ATP1A2, and SCN1A , code for intracellular ion channels. Rapid changes in intracellular electrolyte concentrations are suspected to take place in the presence of a dysfunctional ion channel. This mechanism remains appealing as a potential explanation for the episodic vertigo and fluctuating hearing loss characteristic of MD.
The possibility of a viral infection is considered because of the ubiquitous presence and ease of transmission of the potential infectious agents. However, the inaccessibility of the labyrinth for routine culture and variable systemic immune response make clinical confirmation of a viral infection difficult. The recurrent nature of symptoms in patients with MD favors a virus that is capable of recrudescence, rather than repeated inoculation of virus from an external source.
Herpes viruses, including herpes simplex virus (HSV) and varicella zoster virus (VZV), are neurotrophic DNA viruses capable of establishing a latent infection in sensory nerve ganglia. Reactivation of the virus and resulting viral replication induces an inflammatory response with clinical symptoms depending on the specific nerve involved. Intermittent symptoms interspersed within periods of quiescence, recurrence provoked by stress, variable severity, and a tendency for symptoms to decrease with extended follow-up are all characteristic of both MD and HSV reactivation.
Etiology/Pathogenesis
Endolymphatic hydrops has been consistently identified as a histologic feature of temporal bone specimens from patients with MD. Historically, great significance was attached to this finding, resulting in speculation that hydrops produced the characteristic symptoms of MD. More recent analysis of temporal bone specimens by Merchant and colleagues described similar degrees of endolymphatic hydrops in specimens from people with and without the characteristic symptoms of MD. However, patients with MD who did not have hydrops on histologic examination have also been reported, and therefore the presence of hydrops is neither essential nor specific to MD. The event that triggers development of hydrops remains undefined, although disruption of Na+/K+ homeostasis may be an important contributing factor.
Numerous theories regarding MD pathogenesis exist, with it being broadly categorized as caused by metabolic, autonomic, or endocrine dysfunction; allergy; autoimmunity; trauma; infectious disease; or vascular disease. Each theory has varying degrees of supportive evidence. Some preliminary observations have not been replicated in subsequent studies, illustrated by the ambiguity of the role of autoimmunity in MD. The relative contributions of each potential theory may be predicted based partially on clinical history. Trauma and acute infectious events are rarely associated with the development of symptoms. The typically unilateral symptoms are difficult to explain based on a theory of systemic metabolic, endocrine, allergic, immune, or vascular disorders. Finally, little epidemiologic evidence shows that other comorbid diseases exceed the expected population prevalence in patients with MD, with the possible exception of migraine. Although none of the proposed theories can be categorically rejected, two interesting possibilities that do account for the unilateral nature of the disease are migraine and recrudescent viral infection.
Vestibular symptoms are frequently described in individuals with migraine. The diagnostic criteria for migraine-associated dizziness are fulfillment of International Headache Society (IHS) criteria for migraine headache with concurrent vestibular symptoms. These individuals rarely have any associated hearing loss. Other experts have observed that the prevalence of migraine in patients with MD exceeds that of the expected population prevalence. The highest percentage of concomitant MD and migraine is reported to be 56% of all patients with MD. This finding suggests that MD attacks and migraine headache share a common pathway for symptom development. Additional support is provided by the clinical observation that agents for migraine prophylaxis have shown benefit in some patients with MD.
The genetic component of migraine is clinically evident and partially defined at the molecular level. At least nine loci exist for common migraine with or without aura, and three for familial hemiplegic migraine (FHM). Mutations in three different genes are described for different pedigrees of FHM. All of these, CACNA1A , ATP1A2, and SCN1A , code for intracellular ion channels. Rapid changes in intracellular electrolyte concentrations are suspected to take place in the presence of a dysfunctional ion channel. This mechanism remains appealing as a potential explanation for the episodic vertigo and fluctuating hearing loss characteristic of MD.
The possibility of a viral infection is considered because of the ubiquitous presence and ease of transmission of the potential infectious agents. However, the inaccessibility of the labyrinth for routine culture and variable systemic immune response make clinical confirmation of a viral infection difficult. The recurrent nature of symptoms in patients with MD favors a virus that is capable of recrudescence, rather than repeated inoculation of virus from an external source.
Herpes viruses, including herpes simplex virus (HSV) and varicella zoster virus (VZV), are neurotrophic DNA viruses capable of establishing a latent infection in sensory nerve ganglia. Reactivation of the virus and resulting viral replication induces an inflammatory response with clinical symptoms depending on the specific nerve involved. Intermittent symptoms interspersed within periods of quiescence, recurrence provoked by stress, variable severity, and a tendency for symptoms to decrease with extended follow-up are all characteristic of both MD and HSV reactivation.
Genetic basis for Meniere’s disease
An attractive method for corroborating any given theory of MD pathogenesis (autoimmune disease, migraine variant, herpes virus infection) is through genetic investigation. Defining a gene mutation that determines susceptibility would obviously support a given theory and refocus treatment efforts on a specific molecular pathway. The search for a genetic contribution to any disease process involves careful epidemiologic study of the target population. Clinical observations regarding the prevalence, age of onset, gender, race, socioeconomic status, familial tendency, and comorbid conditions help in formulating a hypothesis of disease susceptibility. Objective data that can be used to confirm the diagnosis enhance the ability to define affected individuals.
Several features of MD suggest a genetic component. A distinct racial predilection is recognized. The prevalence is highest in Caucasians, with an estimated 218 cases per 100,000 persons. Familial cases of MD were first reported by Brown in 1941, with an estimated 7% of all patients having affected family members. Siblings of patients display a 10-fold increased risk of developing the disease. Several MD pedigrees have been reported, mostly in Caucasians. Several Brazilian families with concurrent MD and migraine are also described. The larger series of patients indicate that familial MD is inherited in an autosomal dominant manner with an estimated penetrance of 60%.
Linkage studies
Classical genetic investigation focused on collecting a group of people with a similar genetic background, some of whom expressed a trait or disease of interest and some that did not. Analysis of an extended family pedigree allows geneticists to analyze methods of inheritance and penetrance of a given genetic disorder. With this information in hand, the genomes of the affected individuals are compared with the controls to assess for regions that are distinctly different in the disease group.
Analysis with sets of genomic markers that are progressively closer together improves the resolution of the region of interest, leading to identification of a candidate gene. Sequencing of the candidate gene ultimately identifies mutations that alter gene function, confirming the gene’s role in disease development. The method is particularly robust for single genes with large effect, in which mutation of a single gene product or function results in a readily discernable alteration in anatomy or function of a single or multiple organ systems. Pedigree studies have identified most of the currently recognized syndromes of hereditary hearing loss. In several of these examples, insight into disease mechanisms was gained after identification of the responsible gene.
Genetic markers of MD have not been identified precisely. Several reported linkage sites as shown in Table 1 . Early studies focused on analyzing human leukocyte antigens (HLAs), presuming dysfunction in immune function or autoimmunity as a factor in disease development. Among the earliest studies, an association was detected between the Cw7 antigen and MD. Multiple studies have been performed since, with different HLA associations or no association reported by the various authors. Both susceptibility and resistance antigens are purported. Only one study provides replication of the Cw7 association, with others contradicting this association. The finding of a significant association in the HLA complex led to increased scrutiny of chromosome 6p as a candidate gene, although none has been identified.
| Location | Ethnic | Can Gene | Replication | Phenotype |
|---|---|---|---|---|
| 12p12.3 | Swedish | PIK3C2G | No | MD |
| 14q11–13 | UK | None | No | MD |
| COCH | Danish | COCH | No | Not MD |
| 6p | Multiple | Hla region | No | MD |
Fransen and colleagues recognized the presence of concurrent auditory and vestibular symptoms in a large Belgian family with hereditary hearing loss, designated DFNA9. The gene responsible for the disorder is cochlin ( COCH ). The presence of variable auditory and vestibular symptoms prompted the authors to suggest a relationship with MD. However, the clinical course of DFNA9 and MD are different. Some temporal bones from individuals with DFNA9 hearing loss have shown the presence of endolymphatic hydrops, but the characteristic finding in DFNA9 is microfibrillar deposits in the stria vascularis, a feature not detected in MD. Individuals with DFNA9 develop hearing loss at a young age, the hearing loss is more often high frequency, the vestibular symptoms include chronic disequilibrium and oscillopsia, and both auditory and vestibular deficits progress to severe loss of function with advancing age. Subsequent studies of sporadic MD cases have failed to confirm any association of COCH with MD. In addition, other familial cases of MD have not been associated with COCH mutations.
Morrison and Johnson propose a unique familial MD locus on chromosome 14q that is distinct from COCH . In their series, linkage data suggested a locus in a region overlapping COCH . However, mutation analysis did not detect any of the reported COCH mutations in DFNA9, or any novel mutations. They concluded that their familial locus is not in COCH but do not propose an alternative candidate gene.
A large Swedish family was studied for linkage to loci in known familial forms of cochleovestibular dysfunction, and using a genome wide set of microsatellite markers. The investigators did not find any association with hereditary hearing loss loci for DFNA1, DFNA6/14, DFNA9, or DFNA15. This family did show linkage for several markers on chromosome 12. When combined with additional families, the locus was narrowed to 12p12.3. Within this region only a single known gene is identified, phosphoinositide-3-kinase ( PIK3C2G ). Mutation analysis involving the coding regions of the gene did not detect any mutations.
Lynch and colleagues selected a candidate gene for mutation analysis from a series of familial MD cases. No preliminary linkage study was performed in this group of individuals; rather, the antiquin ( ATQ ) gene was selected based on a presumed effect in maintenance of fluid balance. Mhatre and colleagues reported a similar “mutation analysis first” approach in unrelated patients with the aquaporin-2 ( AQP2 ) gene. Proceeding straight to mutation analysis is inherently precarious, because it presupposes that the correct physiologic disruption producing the disease is known. Not surprisingly, no gene alterations unique to the patient group were identified in either study.
Animal models
No evidence shows that MD will occur spontaneously in animals. The hallmark symptoms of the disease—recurrent vertigo and fluctuating sensorineural hearing loss in animals—are also difficult to produce in animals. Therefore, animal models have been designed to replicate the histologic feature of endolymphatic hydrops. This feature is most reliably produced by occluding the endolymphatic duct in the guinea pig, but the effects of the procedure are not uniform across species. Multiple methods for inducing hydrops in animals are reported, although not as uniformly successful as the guinea pig model.
Although valuable for understanding changes in physiology caused by endolymphatic hydrops, therapeutic interventions are difficult to develop based on this model. Symptoms associated with the guinea pig hydrops model include some early fluctuating hearing loss, but minimal to no vestibular dysfunction is appreciated.
Several rodent models develop endolymphatic hydrops as a consequence of single gene mutations such as Slc26A4 , Foxi1 , Brn-4 , and Phex . All are related to hereditary human hearing loss; Pendred syndrome and DFNB4 for Slc26A4 and Foxi1 , DFN3 for Brn-4 ( POU3F4 ), and familial hypophosphatemic rickets for Phex . Onset of hydrops is very early in all except Phex , where a progressive hearing loss and hydrops is seen. The clinical features in humans parallel the findings in the animal models; however, all are distinctly different from the presentation of MD ( Table 2 ).
