The Laryngoscope C 2015 The American Laryngological, V
Rhinological and Otological Society, Inc.
Genetic Aspects and Clinical Characteristics of Familial Meniere’s Disease in a South Korean Population Jeon Mi Lee, MD; Mi Joo Kim, MD; Jinsei Jung, MD; Hyun Ji Kim, MD; Young Joon Seo, MD; Sung Huhn Kim, MD, PhD Objectives/Hypothesis: This study was undertaken to investigate the prevalence, inheritance patterns, and clinical characteristics of familial Meniere’s disease (MD) in a South Korean population. Study Design: Direct interviews, telephone interviews, and reviews of the medical records of definite Meniere’s disease patients and their families. Methods: Direct and telephone interviews were performed for 286 definite MD patients and their family members who were suspected of having MD. The diagnosis of MD in family members was made by obtaining a detailed history, performing basic neurotological examinations and reviewing hearing test results. The clinical characteristics as well as the prevalence and inheritance patterns of familial MD were analyzed. Results: The prevalence of familial Meniere-like syndrome (at least one family member with definite MD and other members with probable MD) and definite familial MD (two or more family members with definite Meniere’s disease) were 9.8% and 6.3%, respectively, and the most common inheritance pattern was autosomal dominant with incomplete penetrance. The significant clinical characteristics of familial cases were an early disease onset and a higher prevalence of migraines. Conclusions: This is the first report describing the genetic aspects of MD in a single large Asian population. The prevalence of definite familial MD was 6.3% with an incomplete autosomal dominant inheritance pattern in most cases. Earlyonset age and a high prevalence of migraines were significant clinical features of familial MD in this South Korean population. These data could provide a basis for the analysis of the genetic mechanism of familial MD in Asian populations. Key Words: Meniere’s disease, familial, inheritance, autosomal dominant, migraine. Level of Evidence: 4 Laryngoscope, 125:2175–2180, 2015
INTRODUCTION Meniere’s disease (MD) is a syndrome characterized by fluctuating vertigo, sensorineural hearing loss mostly confined to low frequencies, tinnitus, and aural fullness. A main pathologic finding of MD has been thought to be endolymphatic hydrops, which is an enlargement of the endolymphatic compartment of the inner ear due to excessive accumulation of endolymph.1 Endolymphatic
Additional Supporting Information may be found in the online version of this article. From the Department of Otorhinolaryngology (J.M.L., J.J., H.J.K., Y.J.S., S.H.K.), Yonsei University College of Medicine, Seoul, Korea; and the Department of Otorhinolaryngology (M.J.K.), Catholic Kwandong University College of Medicine, Incheon, Korea. Editor’s Note: This Manuscript was accepted for publication January 20, 2015. This study was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (NRF-2012R1A1A1042980) to S.H.K. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Jeon Mi Lee, MD, and Mi Joo Kim, MD, contributed equally to this work. Send correspondence to Sung Huhn Kim, MD, PhD, Department of Otorhinolaryngology, Yonsei University College of Medicine, 50 Yonsei-Ro, Seodaemun-Gu, 120-752 Seoul, Korea. E-mail: [email protected] DOI: 10.1002/lary.25207
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hydrops has been proposed to have autoimmune, genetic, traumatic, viral, and allergic etiologies; however, no single cause has been validated.2–6 This may imply that endolymphatic hydrops is an epiphenomenon caused by an insult to inner ear homeostasis due to various etiologies. Recently, genetic factors have been suggested as one of the causes of MD. After first reports by Brown about MD in two brothers in a family,7 many studies presented evidence of genetic causes for MD. Among the studies, there were several reports using the diagnostic criteria of the 1995 American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS).8 In a Finnish study, the prevalence of definite familial MD was reported to be 9.3%, and the prevalence increased up to 23.4% if probable MD was included in familial MD.4 Autosomal dominant (AD) inheritance with incomplete penetrance was identified in 87.5% of definite familial MD in this study. In a study of a UK population, 5% of MD cases were reported to be familial.9 The inheritance pattern was also mostly incomplete AD, with mother-todaughter transmission patterns being most common. In a German population, a 19.2% incidence of familial MD with a predominant AD inheritance pattern and a high prevalence of migraine (48.1%) in these families were reported.10 In a Spanish population, the frequency of familial MD was identified to be 8%, with an AD inheritance pattern with anticipation. The only clinical Lee et al.: Familial Meniere’s Disease in South Korea
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difference between sporadic and familial MD in this study was early onset of disease in familial cases.11 Several chromosomal loci and variants of several genes have been suggested to contribute to familial MD in recent studies, although corresponding genes for the loci and definite pathologic mechanisms caused by the variant genes were not identified. The proposed chromosomal loci and genes were chromosome 5q14-15, chromosome 12, chromosome 12p12.3, and FAM136A and DTNA genes.10,12,13 Notably, these studies were mostly performed in Caucasian populations, and no study has investigated the frequency and inheritance patterns of familial MD in an Asian population. The prevalence of MD is reported to differ among races,1 and as such, there are likely to be differences in the genetic and clinical characteristics of MD among races. Therefore, studies of familial MD and its related clinical characteristics in an Asian population are needed to elucidate the genetic mechanism of MD. In this study, we investigated the frequency, inheritance patterns, and clinical characteristics of familial MD in a South Korean population. The results of this study can provide the basis for further genetic studies aimed at analyzing genetic mutations and mechanisms of MD in Asian populations.
asked him/her to visit our outpatient clinic. If the relative visited us, we performed a full neurotological examination and pure tone audiometry to confirm the MD diagnosis. If an individual could not visit our outpatient clinic, we considered the individual as having probable MD if they had no previous history of noise exposure or middle ear problems. After confirming the possibility of MD in all family members, a pedigree of each family was created. Familial Meniere-like syndrome (MLS) was considered if at least one family member was diagnosed as definite MD and if he/she had more than one relative with probable MD. Definite familial MD was considered if more than two family members were diagnosed as having definite MD. Based on the data, we analyzed the prevalence of familial MLS, definite familial MD, and the inheritance pattern of the disease.
MATERIALS AND METHODS
Analysis of Clinical Characteristics
Selection of Patients A total of 331 consecutive patients diagnosed with definite MD according to the diagnostic criteria from the 1995 AAOHNS guidelines8 and their families were enrolled in this study. Basic neurotological examinations of the tympanic membrane, spontaneous nystagmus, head shaking nystagmus, and positional/positioning testing were performed on all patients. The patients underwent pure-tone/speech audiometry and bithermal caloric tests. Patients revealed to have acoustic tumors or central lesions were excluded from the study.
Clinical Evaluations of the Patients and Interviews Regarding Family Histories of MD The medical records of the 331 patients were carefully reviewed, and the patients were interviewed at an outpatient clinic on a follow-up date. Telephone interviews were performed for patients who were unable to come to the outpatient clinic for personal interviews. The patients’ family histories were obtained in the interview; they were asked about any history of hearing loss and vertigo in their children and siblings for three generations. If there was a history of hearing loss or vertigo, individual telephone interviews were performed with each child and sibling. If the patient did not remember or know the history of hearing loss or vertigo among their relatives, telephone interviews with the relatives were performed. During those telephone interviews, we asked if the individual had been diagnosed with MD at an otolaryngology clinic. If he or she was diagnosed with MD, we contacted a medical professional at that clinic and asked about the classification of the disease (definite, probable, possible MD). If the relative had not visited an otolaryngology clinic, we asked if his/her vertigo spells persisted for more than 20 minutes with symptoms such as aural fullness and tinnitus, if the vertigo spells were recurrent, and if he/she had hearing loss. If the relative met all of the criteria, then we
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Analysis of Inheritance Patterns We determined the mode of inheritance based on several criteria. First, if the probability of being affected is more than 25%, the mode of inheritance is AD. Second, if expression of the disease is successive, it has a greater chance of being AD than autosomal recessive (AR). Third, if we suppose that the variant allele frequency is low in South Korea, it is less likely that an affected family member will have an affected spouse. Based on these criteria, we classified the mode of inheritance as AD or AR. X-linked inheritance and mitochondrial mutation could not be confirmed in this study, as confirmations could only be made with pedigrees of three generations.
The following clinical features of family members with probable/definite MD were assessed: onset age, gender, hearing threshold, canal paresis values in bithermal caloric testing, bilaterality, coexistence of migraines, delayed hydrops, and prognosis. These features were compared with those of sporadic cases. Hearing thresholds and caloric test results obtained from the medical records of family members with definite and probable MD were analyzed. Hearing thresholds were calculated by averaging the thresholds at 500, 1,000, 2,000, and 3,000 Hz, and the canal paresis values were calculated using Jongkee’s formula. For the diagnosis of migraines, we used the criteria proposed by the Barany Society and the International Headache Society,14 and we included patients with definite vestibular migraines. The prognosis of patients was analyzed using the 1995 AAO-HNS guidelines (Table I).8 Patients whose follow-up periods were longer than 2 years were assigned to classes A, B, C, D, and E. Patients who did not respond to medical treatment and who underwent invasive procedures, such as endolymphatic sac surgery, chemical labyrinthectomy, and vestibular neurectomy, were assigned to class F.
Statistical Analysis Values are presented as the mean 6 standard deviation. Differences in age, hearing thresholds, and canal paresis values between the patients with familial MLS (or definite familial MD) and sporadic MD were analyzed using Mann-Whitney rank sum tests. Differences in the distribution of gender, bilaterality, migraines, and prognosis classes between the two groups were analyzed using the Fisher exact test or v2 test. Differences were considered to be significant at P 120
E
Secondary treatment initiated due to disability from vertigo
F
Numerical value 5 (x/y) 3 100, rounded to the nearest whole number, where x is the average number of definitive spells per month for the 6 months 18 to 24 months after therapy, and y is the average number of definitive spells per month for the 6 months before therapy.
RESULTS Prevalence of Familial MLS and Definite Familial MD Among the 331 definite MD patients, interviews were conducted with 286 patients and their family members (Fig. 1). Familial MLS was identified in 28 out of the 286 families (9.8%, Fig. 1). Of the 28 families with familial MLS, 18 families were defined as having definite familial MD (6.3%, Fig. 1). The total number of family members in the 28 families with familial MLS was 64. The number of family members with definite MD was 51, 33 of whom were diagnosed at the authors’ institute and 18 of whom were diagnosed at a local hospital. The number of family members with probable MD was 13; of these individuals, four were diagnosed at the authors’ institute, four were diagnosed at a local hospital, and five were diagnosed only by information obtained from their telephone interview based on a history of recurrent vertigo persisting for more than 20 minutes with aural fullness or tinnitus and hearing loss without a documented audiogram.
Inheritance Patterns The pedigree analysis showed that the most frequent inheritance pattern was AD with incomplete penetrance (26/28 [92.9%] for familial MLS and 17/19 [89.5%] for definite familial MD) (Fig. 2A; see Supporting Figures 1 and 2 in the online version of this article). There is a possibility that the inheritance did not follow a Mendelian pattern and could instead be a result of polygenic inheritance. There was also an AR inheritance pattern, but the proportion of that inheritance pattern was relatively small (2/28 [7.1%] for familial MLS and 2/19 [10.5%] for definite familial MD) (Fig. 2B). However, mitochondrial mutation could not be ruled out in some families (15/28 [53.6%] for familial MLS and 8/19 [42.1%] for definite familial MD; see Supporting Figures 1 and 2 in the online version of this article). The preponderance of females within the families was significant Laryngoscope 125: September 2015
Fig. 1. Selection of patients with definite familial Meniere’s disease and familial Meniere-like syndrome. Eighteen families with definite familial Meniere’s disease and 28 families with Meniere-like syndrome were identified through direct or telephone interviews, neurotological examinations, reviews of medical records, and hearing test results.
(50/64 [78.1%] for familial MLS and 39/51 [76.5%] for definite familial MD). Furthermore, maternal transmission was predominant; mother-to-daughter transmission and mother-to-son transmission was detected in 12 and three cases of familial MLS, respectively, and six and three cases of definite familial MD, respectively. However, father-to-daughter and father-to-son transmission patterns were only detected in one and three cases of familial MLS, respectively, and in zero and two cases of definite familial MD, respectively (Table II).
Clinical Characteristics of Familial MLS and Definite Familial MD Among the clinical characteristics, gender (familial MLS, female:male 5 51:14; definite familial MD, female: male 5 39:12; sporadic MD, female:male 5 168:90), affected side (familial MLS, left:right 5 29:28; definite familial MD, left:right 5 25:21; sporadic MD, left:right 5 112:140), bilaterality (five in familial MLS, five in familial MD, and six in sporadic MD), hearing threshold (familial MLS, 43.1 6 22.3 dB HL; familial MD, 44.4 6 23.2 dB HL; sporadic MD, 43.5 6 26.3 dB HL), canal paresis value (familial MLS, 25.5 6 20.1%; familial MD, 26.1 6 22.0%; sporadic MD, 29.2 6 25.3%), and incidence of delayed hydrops (none in familial MLS and MD, 13 in sporadic MD) were not significantly different between sporadic MD and definite familial MD or between sporadic MD and familial MLS (P >.05; Table III). One of the significant differences in the above parameters between a South Korean population and Caucasian population was the low incidence of bilaterality. The incidence of bilateral MD in this study totaled 3.8% (11/286), with 2.3% (6/258) and 9.8% (5/51) occurring in patients with sporadic and definite familial MD, respectively, whereas the prevalence of bilateral MD in Lee et al.: Familial Meniere’s Disease in South Korea
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Fig. 2. Representative pedigrees of familial Meniere-like syndrome and definite familial Meniere’s disease. (A) Families with an autosomal dominant inheritance pattern with incomplete penetrance. (B) Families with an autosomal recessive inheritance pattern. Numbers indicate the age of onset of Meniere’s disease. With regard to the affected side, R, L, and B indicate right, left, and both sides, respectively. M indicates the coexistence of migraine. Mitochondrial mutations could not be completely ruled out in family 13.
the Caucasian population was reported to be 25% to 40%.15 The mean interval from unilateral to bilateral MD was 68 6 60 months as a whole, 71 6 58 months for sporadic cases, and 65 6 62 months for familial cases. It was difficult to determine the difference in disease progression from unilateral to bilateral between the sporadic and definite familial MD groups due to the small number of patients in each group. Prognostic differences were analyzed only in the definite MD patients with follow-up periods greater than 2 years (50 definite familial MD and 258 sporadic MD patients). There were no significant prognostic differences between sporadic and definite familial MD; 152
TABLE II. Transmission of Meniere’s Disease Phenotypes From Parents to Their Children.
(58.9%) sporadic MD and 33 (66%) definite familial MD patients were categorized into classes A and B (P >.05). Two clinical factors were significantly different between familial and sporadic cases: the disease onset age and the prevalence of migraines. Disease onset occurred earlier in patients with definite familial MD (42.2 6 14.2 years) than in patients with sporadic MD (46.9 6 13.9 years) (P 5.042). However, the onset age was not different between familial MLS (42.5 6 14.2 years) and sporadic MD (46.9 6 13.9 years) (P 5.05; Table III). The prevalence of migraines was significantly higher in familial MLS (29/64 [45.3%]) and definite familial MD (28/51 [54.9%]) than in sporadic cases (54/286 [18.9%]) (P 5.026 and .001, respectively). An association between the mode of inheritance and clinical characteristics could not be identified due to the small number of cases with an AR inheritance pattern and the uncertainty of the inheritance pattern of mitochondrial mutations.
Transmitting Parents Gender of Children
Mother
Father
Female
12 (6)
1 (0)
Male
3 (3)
3 (2)
The number without parentheses indicates the number of definite and probable Meniere’s disease patients, and the number in parentheses indicates the number of definite Meniere’s disease patients.
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DISCUSSION The prevalence of familial MLS was 9.8% (28/286), and the prevalence of definite familial MD was 6.3% (18/ 286) in this study, which is similar to the results of other studies examining Caucasian populations (5%– 20%).9–11,16 We attempted to avoid overestimations by defining the diagnosis based on a detailed history Lee et al.: Familial Meniere’s Disease in South Korea
TABLE III. Clinical Characteristics of Familial Meniere-Like Syndrome and Definite Familial Meniere’s Disease. Variables
Familial MLS
Definite Familial MD
Sporadic MD
51
39
168
Gender Female Male Age of onset, yr
14 12 90 42.5 6 14.2* 42.2 6 14.2† 46.9 6 13.9
Affected ear Left Right Bilateral
29 28
25 21
112 140
5
5
6
Undetermined Hearing threshold, dB HL
2 43.1 6 22.3
0 44.4 6 23.2
0 43.5 6 26.3
Canal paresis, %
25.5 6 20.1
26.1 6 22.0
29.2 6 25.3
0 29‡
0 28§
13 54
A B
— —
26 7
109 43
C
—
4
9
D E
— —
1 2
19 8
F
—
10
70
Delayed hydrops Migraine coexistence Treatment response
Prognostic differences were analyzed only in definite MD patients with follow-up periods >2 years (50 definite familial MD and 258 sporadic MD patients). *P 5.05. † P 5.042. ‡ P 5.026. § P 5.001. MD 5 Meniere’s disease; MLS 5 Meniere-like syndrome.
obtained from direct interviews, neurotological examinations, medical records, and reported sensorineural hearing loss in patients suspected of having familial MD. We included definite and probable MD in the analysis; possible MD was excluded because the diagnosis was too vague for the disease to be defined as familial. As a result, 59 patients were accurately diagnosed; five patients were suspected of having definite MD based on their telephone interviews, but they were classified as having probable MD due to the absence of documented sensorineural hearing loss. Consequently, the prevalence of familial MLS and definite familial MD are not likely to be overestimated; however, a small amount of underestimation is possible. The mode of inheritance observed for familial MD in this study was similar to that observed in other studies examining Caucasian populations.9–11,16 All of the families except families 27 and 28 (AR) were classified as exhibiting AD inheritance with incomplete penetrance. Incomplete penetrance of familial MD has been explained by several mechanisms: de novo somatic mutations in the inner ear, multiple mutations at different loci, and/or the existence of mutant heteroplasmic mitochondrial DNA with normal mitochondrial DNA.11 However, none of these mechanisms were confirmed because Laryngoscope 125: September 2015
the genetic causes of MD varied from study to study. The female preponderance and frequent mother-todaughter transmission were also similar to the results obtained in other studies.9,16 Based on the data regarding the frequency of maternal transmission, mitochondrial inheritance can be suspected. However, we could not confirm the mitochondrial inheritance due to the incomplete penetrance pattern and the fact that the pedigrees were limited to, at most, three generations of family members. If we could obtain more information regarding individuals older than the first generation family members, the inheritance patterns could be more accurately determined. However, this was impossible because older-generation family members were usually deceased, and we could not obtain any information from their medical records due to the poor medical infrastructure that was in place in South Korea in the past. In addition, a higher frequency of mother-to-daughter transmission could be caused by the female preponderance of familial MLS and definite familial MD, which could bias the analysis of inheritance patterns. We could not hypothesize the chromosomal loci or genes for familial MD only by pedigrees and phenotypes. The chromosomal loci and genes such as chromosome 5q14–15, chromosome 12p12.3, FAM136A gene at chromosome 2, and DTNA gene at chromosome 18 were identified in the families with AD inheritance, but they were variable among studies.10,12,13 The relationship between candidate genes (or chromosomal loci) and phenotypes of MD was not identified as there were not enough related studies. To identify the causative mutation in the families of this study, whole-exome sequencing with appropriate numbers of MD and control family members should be performed. This may enable the identification of similar or new causative mutational loci of familial MD in the Asian population. The clinical features that were significantly different between the sporadic and familial MD in this study were the age of onset and prevalence of migraines. These findings are also common in Caucasian populations, as reported in other studies.10,11,17 Although the age of onset was significantly earlier in definite familial MD patients than in sporadic cases, it was not significantly different between familial MLS and sporadic cases (P 5.05). However, the P value for significance was borderline, but may have been significant if a larger patient pool were enrolled. Despite the early onset of the disease, hearing thresholds, disease stages, and responses to medical treatments were not significantly different between the sporadic and definite familial MD groups, which is also a common finding in Caucasian populations.11 A close relationship between migraines and MD has been suggested; however, these two conditions cannot be fully differentiated by the current symptom-based diagnostic criteria in certain cases. Migraine headaches can sometimes be replaced by vertigo attacks, especially in women around menopause, which mimics the symptoms of MD.15 Vestibular migraine showed female preponderance (1.5–5 to 1) and not infrequently showed familial occurrence with an incomplete AD inheritance pattern.15 A genome-wide Lee et al.: Familial Meniere’s Disease in South Korea
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screen for chromosomal loci in a four-generation family with vestibular migraine identified a suspected disease gene located between rs244895 and D5S2073 in chromosome 5q35.18 Candidate genes in this area were genes for ion transport, such as KCNMB1, KCNIP1, ATP6V0E, and SLC34A1, and neurotransmitter receptor genes, such as GABRP, DRD1, and HRH2.18 Although the identified chromosomal loci were different from those of familial MD identified so far, these candidate genes are also likely to cause MD, as there are many ion channels, transporters, and neurotransmitters receptors in the inner ear. The deterioration of certain ion channels and neurotransmitter receptor function can cause disruption of inner ear homeostasis, which can ultimately cause endolymphatic hydrops. Given that a higher prevalence of migraines was identified in the familial MD population, mutations in particular loci may affect both migraines and MD. If a genetic mutation that affects both migraines and MD is identified, it may be responsible for the close relationship between the two disease entities. In such a situation, headaches could be an incomplete phenotype of familial MD or vice versa. This study is the first and largest study to analyze the prevalence, inheritance patterns, and clinical characteristics of familial MD in an Asian population in the English literature. Because the patients enrolled in this study are of the same ethnicity, data from this study can be used as a basis for future investigations of the genetic causes of MD in Asian populations. Future studies regarding mutated genes and loci will help to elucidate the common and dissimilar aspects of the genetic causes of MD among different races.
CONCLUSION This is the first report describing the genetic aspects of MD in an Asian population. The prevalence of familial MLS and definite familial MD were 9.8% and 6.3%, respectively, and the most common inheritance pattern was AD with incomplete penetrance. Early-onset age and a high prevalence of migraines were significant clinical characteristics of familial MD in the South
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Korean population. These data could provide a basis for the analysis of the genetic mechanism of familial MD in Asian populations.
Acknowledgments The authors acknowledge the English editing support from Soo Ah Choi.
BIBLIOGRAPHY 1. Sajjadi H, Paparella MM. Meniere’s disease. Lancet 2008;372:406–414. 2. Banks C, McGinness S, Harvey R, Sacks R. Is allergy related to Meniere’s disease? Curr Allergy Asthma Rep 2012;12:255–260. 3. Fife TD, Giza C. Posttraumatic vertigo and dizziness. Semin Neurol 2013; 33:238–243. 4. Hietikko E, Kotimaki J, Sorri M, Mannikko M. High incidence of Menierelike symptoms in relatives of Meniere patients in the areas of Oulu University Hospital and Kainuu Central Hospital in Finland. Eur J Med Genet 2013;56:279–285. 5. Minor LB, Schessel DA, Carey JP. Meniere’s disease. Curr Opin Neurol 2004;17:9–16. 6. Wackym PA, Sando I. Molecular and cellular pathology of Meniere’s disease. Otolaryngol Clin North Am 1997;30:947–960. 7. Brown MR. Meniere’s syndrome. Arch Neurol Psychiatry 1941;46:1. 8. Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Meniere’s disease. American Academy of Otolaryngology-Head and Neck Foundation, Inc. Otolaryngol Head Neck Surg 1995;113:181–185. 9. Morrison AW, Bailey ME, Morrison GA. Familial Meniere’s disease: clinical and genetic aspects. J Laryngol Otol 2009;123:29–37. 10. Arweiler-Harbeck D, Horsthemke B, Jahnke K, Hennies HC. Genetic aspects of familial Meniere’s disease. Otol Neurotol 2011;32:695–700. 11. Requena T, Espinosa-Sanchez JM, Cabrera S, et al. Familial clustering and genetic heterogeneity in Meniere’s disease. Clin Genet 2014; 85: 245–252. 12. Klar J, Frykholm C, Friberg U, Dahl N. A Meniere’s disease gene linked to chromosome 12p12.3. Am J Med Genet B Neuropsychiatr Genet 2006; 141B:463–467. 13. Requena T, Cabrera S, Martin-Sierra C, Price SD, Lysakowski A, LopezEscamez JA. Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere’s disease. Hum Mol Genet 2015;24:1119–1126. 14. Lempert T, Olesen J, Furman J, et al. Vestibular migraine: diagnostic criteria. Consensus document of the Barany Society and the International headache society. Rev Neurol (Paris) 2014;170:401–406. 15. Huppert D, Strupp M, Brandt T. Long-term course of Meniere’s disease revisited. Acta Otolaryngol 2010;130:644–651. 16. Klockars T, Kentala E. Inheritance of Meniere’s disease in the Finnish population. Arch Otolaryngol Head Neck Surg 2007;133:73–77. 17. Hietikko E, Sorri M, Mannikko M, Kotimaki J. Higher prevalence of autoimmune diseases and longer spells of vertigo in patients affected with familial Meniere’s disease: a clinical comparison of familial and sporadic Meniere’s disease. Am J Audiol 2014;23:232–237. 18. Bahmad F Jr, DePalma SR, Merchant SN, et al. Locus for familial migrainous vertigo disease maps to chromosome 5q35. Ann Otol Rhinol Laryngol 2009;118:670–676.
Lee et al.: Familial Meniere’s Disease in South Korea
Rhinological and Otological Society, Inc.
Genetic Aspects and Clinical Characteristics of Familial Meniere’s Disease in a South Korean Population Jeon Mi Lee, MD; Mi Joo Kim, MD; Jinsei Jung, MD; Hyun Ji Kim, MD; Young Joon Seo, MD; Sung Huhn Kim, MD, PhD Objectives/Hypothesis: This study was undertaken to investigate the prevalence, inheritance patterns, and clinical characteristics of familial Meniere’s disease (MD) in a South Korean population. Study Design: Direct interviews, telephone interviews, and reviews of the medical records of definite Meniere’s disease patients and their families. Methods: Direct and telephone interviews were performed for 286 definite MD patients and their family members who were suspected of having MD. The diagnosis of MD in family members was made by obtaining a detailed history, performing basic neurotological examinations and reviewing hearing test results. The clinical characteristics as well as the prevalence and inheritance patterns of familial MD were analyzed. Results: The prevalence of familial Meniere-like syndrome (at least one family member with definite MD and other members with probable MD) and definite familial MD (two or more family members with definite Meniere’s disease) were 9.8% and 6.3%, respectively, and the most common inheritance pattern was autosomal dominant with incomplete penetrance. The significant clinical characteristics of familial cases were an early disease onset and a higher prevalence of migraines. Conclusions: This is the first report describing the genetic aspects of MD in a single large Asian population. The prevalence of definite familial MD was 6.3% with an incomplete autosomal dominant inheritance pattern in most cases. Earlyonset age and a high prevalence of migraines were significant clinical features of familial MD in this South Korean population. These data could provide a basis for the analysis of the genetic mechanism of familial MD in Asian populations. Key Words: Meniere’s disease, familial, inheritance, autosomal dominant, migraine. Level of Evidence: 4 Laryngoscope, 125:2175–2180, 2015
INTRODUCTION Meniere’s disease (MD) is a syndrome characterized by fluctuating vertigo, sensorineural hearing loss mostly confined to low frequencies, tinnitus, and aural fullness. A main pathologic finding of MD has been thought to be endolymphatic hydrops, which is an enlargement of the endolymphatic compartment of the inner ear due to excessive accumulation of endolymph.1 Endolymphatic
Additional Supporting Information may be found in the online version of this article. From the Department of Otorhinolaryngology (J.M.L., J.J., H.J.K., Y.J.S., S.H.K.), Yonsei University College of Medicine, Seoul, Korea; and the Department of Otorhinolaryngology (M.J.K.), Catholic Kwandong University College of Medicine, Incheon, Korea. Editor’s Note: This Manuscript was accepted for publication January 20, 2015. This study was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (NRF-2012R1A1A1042980) to S.H.K. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Jeon Mi Lee, MD, and Mi Joo Kim, MD, contributed equally to this work. Send correspondence to Sung Huhn Kim, MD, PhD, Department of Otorhinolaryngology, Yonsei University College of Medicine, 50 Yonsei-Ro, Seodaemun-Gu, 120-752 Seoul, Korea. E-mail: [email protected] DOI: 10.1002/lary.25207
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hydrops has been proposed to have autoimmune, genetic, traumatic, viral, and allergic etiologies; however, no single cause has been validated.2–6 This may imply that endolymphatic hydrops is an epiphenomenon caused by an insult to inner ear homeostasis due to various etiologies. Recently, genetic factors have been suggested as one of the causes of MD. After first reports by Brown about MD in two brothers in a family,7 many studies presented evidence of genetic causes for MD. Among the studies, there were several reports using the diagnostic criteria of the 1995 American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS).8 In a Finnish study, the prevalence of definite familial MD was reported to be 9.3%, and the prevalence increased up to 23.4% if probable MD was included in familial MD.4 Autosomal dominant (AD) inheritance with incomplete penetrance was identified in 87.5% of definite familial MD in this study. In a study of a UK population, 5% of MD cases were reported to be familial.9 The inheritance pattern was also mostly incomplete AD, with mother-todaughter transmission patterns being most common. In a German population, a 19.2% incidence of familial MD with a predominant AD inheritance pattern and a high prevalence of migraine (48.1%) in these families were reported.10 In a Spanish population, the frequency of familial MD was identified to be 8%, with an AD inheritance pattern with anticipation. The only clinical Lee et al.: Familial Meniere’s Disease in South Korea
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difference between sporadic and familial MD in this study was early onset of disease in familial cases.11 Several chromosomal loci and variants of several genes have been suggested to contribute to familial MD in recent studies, although corresponding genes for the loci and definite pathologic mechanisms caused by the variant genes were not identified. The proposed chromosomal loci and genes were chromosome 5q14-15, chromosome 12, chromosome 12p12.3, and FAM136A and DTNA genes.10,12,13 Notably, these studies were mostly performed in Caucasian populations, and no study has investigated the frequency and inheritance patterns of familial MD in an Asian population. The prevalence of MD is reported to differ among races,1 and as such, there are likely to be differences in the genetic and clinical characteristics of MD among races. Therefore, studies of familial MD and its related clinical characteristics in an Asian population are needed to elucidate the genetic mechanism of MD. In this study, we investigated the frequency, inheritance patterns, and clinical characteristics of familial MD in a South Korean population. The results of this study can provide the basis for further genetic studies aimed at analyzing genetic mutations and mechanisms of MD in Asian populations.
asked him/her to visit our outpatient clinic. If the relative visited us, we performed a full neurotological examination and pure tone audiometry to confirm the MD diagnosis. If an individual could not visit our outpatient clinic, we considered the individual as having probable MD if they had no previous history of noise exposure or middle ear problems. After confirming the possibility of MD in all family members, a pedigree of each family was created. Familial Meniere-like syndrome (MLS) was considered if at least one family member was diagnosed as definite MD and if he/she had more than one relative with probable MD. Definite familial MD was considered if more than two family members were diagnosed as having definite MD. Based on the data, we analyzed the prevalence of familial MLS, definite familial MD, and the inheritance pattern of the disease.
MATERIALS AND METHODS
Analysis of Clinical Characteristics
Selection of Patients A total of 331 consecutive patients diagnosed with definite MD according to the diagnostic criteria from the 1995 AAOHNS guidelines8 and their families were enrolled in this study. Basic neurotological examinations of the tympanic membrane, spontaneous nystagmus, head shaking nystagmus, and positional/positioning testing were performed on all patients. The patients underwent pure-tone/speech audiometry and bithermal caloric tests. Patients revealed to have acoustic tumors or central lesions were excluded from the study.
Clinical Evaluations of the Patients and Interviews Regarding Family Histories of MD The medical records of the 331 patients were carefully reviewed, and the patients were interviewed at an outpatient clinic on a follow-up date. Telephone interviews were performed for patients who were unable to come to the outpatient clinic for personal interviews. The patients’ family histories were obtained in the interview; they were asked about any history of hearing loss and vertigo in their children and siblings for three generations. If there was a history of hearing loss or vertigo, individual telephone interviews were performed with each child and sibling. If the patient did not remember or know the history of hearing loss or vertigo among their relatives, telephone interviews with the relatives were performed. During those telephone interviews, we asked if the individual had been diagnosed with MD at an otolaryngology clinic. If he or she was diagnosed with MD, we contacted a medical professional at that clinic and asked about the classification of the disease (definite, probable, possible MD). If the relative had not visited an otolaryngology clinic, we asked if his/her vertigo spells persisted for more than 20 minutes with symptoms such as aural fullness and tinnitus, if the vertigo spells were recurrent, and if he/she had hearing loss. If the relative met all of the criteria, then we
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Analysis of Inheritance Patterns We determined the mode of inheritance based on several criteria. First, if the probability of being affected is more than 25%, the mode of inheritance is AD. Second, if expression of the disease is successive, it has a greater chance of being AD than autosomal recessive (AR). Third, if we suppose that the variant allele frequency is low in South Korea, it is less likely that an affected family member will have an affected spouse. Based on these criteria, we classified the mode of inheritance as AD or AR. X-linked inheritance and mitochondrial mutation could not be confirmed in this study, as confirmations could only be made with pedigrees of three generations.
The following clinical features of family members with probable/definite MD were assessed: onset age, gender, hearing threshold, canal paresis values in bithermal caloric testing, bilaterality, coexistence of migraines, delayed hydrops, and prognosis. These features were compared with those of sporadic cases. Hearing thresholds and caloric test results obtained from the medical records of family members with definite and probable MD were analyzed. Hearing thresholds were calculated by averaging the thresholds at 500, 1,000, 2,000, and 3,000 Hz, and the canal paresis values were calculated using Jongkee’s formula. For the diagnosis of migraines, we used the criteria proposed by the Barany Society and the International Headache Society,14 and we included patients with definite vestibular migraines. The prognosis of patients was analyzed using the 1995 AAO-HNS guidelines (Table I).8 Patients whose follow-up periods were longer than 2 years were assigned to classes A, B, C, D, and E. Patients who did not respond to medical treatment and who underwent invasive procedures, such as endolymphatic sac surgery, chemical labyrinthectomy, and vestibular neurectomy, were assigned to class F.
Statistical Analysis Values are presented as the mean 6 standard deviation. Differences in age, hearing thresholds, and canal paresis values between the patients with familial MLS (or definite familial MD) and sporadic MD were analyzed using Mann-Whitney rank sum tests. Differences in the distribution of gender, bilaterality, migraines, and prognosis classes between the two groups were analyzed using the Fisher exact test or v2 test. Differences were considered to be significant at P 120
E
Secondary treatment initiated due to disability from vertigo
F
Numerical value 5 (x/y) 3 100, rounded to the nearest whole number, where x is the average number of definitive spells per month for the 6 months 18 to 24 months after therapy, and y is the average number of definitive spells per month for the 6 months before therapy.
RESULTS Prevalence of Familial MLS and Definite Familial MD Among the 331 definite MD patients, interviews were conducted with 286 patients and their family members (Fig. 1). Familial MLS was identified in 28 out of the 286 families (9.8%, Fig. 1). Of the 28 families with familial MLS, 18 families were defined as having definite familial MD (6.3%, Fig. 1). The total number of family members in the 28 families with familial MLS was 64. The number of family members with definite MD was 51, 33 of whom were diagnosed at the authors’ institute and 18 of whom were diagnosed at a local hospital. The number of family members with probable MD was 13; of these individuals, four were diagnosed at the authors’ institute, four were diagnosed at a local hospital, and five were diagnosed only by information obtained from their telephone interview based on a history of recurrent vertigo persisting for more than 20 minutes with aural fullness or tinnitus and hearing loss without a documented audiogram.
Inheritance Patterns The pedigree analysis showed that the most frequent inheritance pattern was AD with incomplete penetrance (26/28 [92.9%] for familial MLS and 17/19 [89.5%] for definite familial MD) (Fig. 2A; see Supporting Figures 1 and 2 in the online version of this article). There is a possibility that the inheritance did not follow a Mendelian pattern and could instead be a result of polygenic inheritance. There was also an AR inheritance pattern, but the proportion of that inheritance pattern was relatively small (2/28 [7.1%] for familial MLS and 2/19 [10.5%] for definite familial MD) (Fig. 2B). However, mitochondrial mutation could not be ruled out in some families (15/28 [53.6%] for familial MLS and 8/19 [42.1%] for definite familial MD; see Supporting Figures 1 and 2 in the online version of this article). The preponderance of females within the families was significant Laryngoscope 125: September 2015
Fig. 1. Selection of patients with definite familial Meniere’s disease and familial Meniere-like syndrome. Eighteen families with definite familial Meniere’s disease and 28 families with Meniere-like syndrome were identified through direct or telephone interviews, neurotological examinations, reviews of medical records, and hearing test results.
(50/64 [78.1%] for familial MLS and 39/51 [76.5%] for definite familial MD). Furthermore, maternal transmission was predominant; mother-to-daughter transmission and mother-to-son transmission was detected in 12 and three cases of familial MLS, respectively, and six and three cases of definite familial MD, respectively. However, father-to-daughter and father-to-son transmission patterns were only detected in one and three cases of familial MLS, respectively, and in zero and two cases of definite familial MD, respectively (Table II).
Clinical Characteristics of Familial MLS and Definite Familial MD Among the clinical characteristics, gender (familial MLS, female:male 5 51:14; definite familial MD, female: male 5 39:12; sporadic MD, female:male 5 168:90), affected side (familial MLS, left:right 5 29:28; definite familial MD, left:right 5 25:21; sporadic MD, left:right 5 112:140), bilaterality (five in familial MLS, five in familial MD, and six in sporadic MD), hearing threshold (familial MLS, 43.1 6 22.3 dB HL; familial MD, 44.4 6 23.2 dB HL; sporadic MD, 43.5 6 26.3 dB HL), canal paresis value (familial MLS, 25.5 6 20.1%; familial MD, 26.1 6 22.0%; sporadic MD, 29.2 6 25.3%), and incidence of delayed hydrops (none in familial MLS and MD, 13 in sporadic MD) were not significantly different between sporadic MD and definite familial MD or between sporadic MD and familial MLS (P >.05; Table III). One of the significant differences in the above parameters between a South Korean population and Caucasian population was the low incidence of bilaterality. The incidence of bilateral MD in this study totaled 3.8% (11/286), with 2.3% (6/258) and 9.8% (5/51) occurring in patients with sporadic and definite familial MD, respectively, whereas the prevalence of bilateral MD in Lee et al.: Familial Meniere’s Disease in South Korea
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Fig. 2. Representative pedigrees of familial Meniere-like syndrome and definite familial Meniere’s disease. (A) Families with an autosomal dominant inheritance pattern with incomplete penetrance. (B) Families with an autosomal recessive inheritance pattern. Numbers indicate the age of onset of Meniere’s disease. With regard to the affected side, R, L, and B indicate right, left, and both sides, respectively. M indicates the coexistence of migraine. Mitochondrial mutations could not be completely ruled out in family 13.
the Caucasian population was reported to be 25% to 40%.15 The mean interval from unilateral to bilateral MD was 68 6 60 months as a whole, 71 6 58 months for sporadic cases, and 65 6 62 months for familial cases. It was difficult to determine the difference in disease progression from unilateral to bilateral between the sporadic and definite familial MD groups due to the small number of patients in each group. Prognostic differences were analyzed only in the definite MD patients with follow-up periods greater than 2 years (50 definite familial MD and 258 sporadic MD patients). There were no significant prognostic differences between sporadic and definite familial MD; 152
TABLE II. Transmission of Meniere’s Disease Phenotypes From Parents to Their Children.
(58.9%) sporadic MD and 33 (66%) definite familial MD patients were categorized into classes A and B (P >.05). Two clinical factors were significantly different between familial and sporadic cases: the disease onset age and the prevalence of migraines. Disease onset occurred earlier in patients with definite familial MD (42.2 6 14.2 years) than in patients with sporadic MD (46.9 6 13.9 years) (P 5.042). However, the onset age was not different between familial MLS (42.5 6 14.2 years) and sporadic MD (46.9 6 13.9 years) (P 5.05; Table III). The prevalence of migraines was significantly higher in familial MLS (29/64 [45.3%]) and definite familial MD (28/51 [54.9%]) than in sporadic cases (54/286 [18.9%]) (P 5.026 and .001, respectively). An association between the mode of inheritance and clinical characteristics could not be identified due to the small number of cases with an AR inheritance pattern and the uncertainty of the inheritance pattern of mitochondrial mutations.
Transmitting Parents Gender of Children
Mother
Father
Female
12 (6)
1 (0)
Male
3 (3)
3 (2)
The number without parentheses indicates the number of definite and probable Meniere’s disease patients, and the number in parentheses indicates the number of definite Meniere’s disease patients.
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DISCUSSION The prevalence of familial MLS was 9.8% (28/286), and the prevalence of definite familial MD was 6.3% (18/ 286) in this study, which is similar to the results of other studies examining Caucasian populations (5%– 20%).9–11,16 We attempted to avoid overestimations by defining the diagnosis based on a detailed history Lee et al.: Familial Meniere’s Disease in South Korea
TABLE III. Clinical Characteristics of Familial Meniere-Like Syndrome and Definite Familial Meniere’s Disease. Variables
Familial MLS
Definite Familial MD
Sporadic MD
51
39
168
Gender Female Male Age of onset, yr
14 12 90 42.5 6 14.2* 42.2 6 14.2† 46.9 6 13.9
Affected ear Left Right Bilateral
29 28
25 21
112 140
5
5
6
Undetermined Hearing threshold, dB HL
2 43.1 6 22.3
0 44.4 6 23.2
0 43.5 6 26.3
Canal paresis, %
25.5 6 20.1
26.1 6 22.0
29.2 6 25.3
0 29‡
0 28§
13 54
A B
— —
26 7
109 43
C
—
4
9
D E
— —
1 2
19 8
F
—
10
70
Delayed hydrops Migraine coexistence Treatment response
Prognostic differences were analyzed only in definite MD patients with follow-up periods >2 years (50 definite familial MD and 258 sporadic MD patients). *P 5.05. † P 5.042. ‡ P 5.026. § P 5.001. MD 5 Meniere’s disease; MLS 5 Meniere-like syndrome.
obtained from direct interviews, neurotological examinations, medical records, and reported sensorineural hearing loss in patients suspected of having familial MD. We included definite and probable MD in the analysis; possible MD was excluded because the diagnosis was too vague for the disease to be defined as familial. As a result, 59 patients were accurately diagnosed; five patients were suspected of having definite MD based on their telephone interviews, but they were classified as having probable MD due to the absence of documented sensorineural hearing loss. Consequently, the prevalence of familial MLS and definite familial MD are not likely to be overestimated; however, a small amount of underestimation is possible. The mode of inheritance observed for familial MD in this study was similar to that observed in other studies examining Caucasian populations.9–11,16 All of the families except families 27 and 28 (AR) were classified as exhibiting AD inheritance with incomplete penetrance. Incomplete penetrance of familial MD has been explained by several mechanisms: de novo somatic mutations in the inner ear, multiple mutations at different loci, and/or the existence of mutant heteroplasmic mitochondrial DNA with normal mitochondrial DNA.11 However, none of these mechanisms were confirmed because Laryngoscope 125: September 2015
the genetic causes of MD varied from study to study. The female preponderance and frequent mother-todaughter transmission were also similar to the results obtained in other studies.9,16 Based on the data regarding the frequency of maternal transmission, mitochondrial inheritance can be suspected. However, we could not confirm the mitochondrial inheritance due to the incomplete penetrance pattern and the fact that the pedigrees were limited to, at most, three generations of family members. If we could obtain more information regarding individuals older than the first generation family members, the inheritance patterns could be more accurately determined. However, this was impossible because older-generation family members were usually deceased, and we could not obtain any information from their medical records due to the poor medical infrastructure that was in place in South Korea in the past. In addition, a higher frequency of mother-to-daughter transmission could be caused by the female preponderance of familial MLS and definite familial MD, which could bias the analysis of inheritance patterns. We could not hypothesize the chromosomal loci or genes for familial MD only by pedigrees and phenotypes. The chromosomal loci and genes such as chromosome 5q14–15, chromosome 12p12.3, FAM136A gene at chromosome 2, and DTNA gene at chromosome 18 were identified in the families with AD inheritance, but they were variable among studies.10,12,13 The relationship between candidate genes (or chromosomal loci) and phenotypes of MD was not identified as there were not enough related studies. To identify the causative mutation in the families of this study, whole-exome sequencing with appropriate numbers of MD and control family members should be performed. This may enable the identification of similar or new causative mutational loci of familial MD in the Asian population. The clinical features that were significantly different between the sporadic and familial MD in this study were the age of onset and prevalence of migraines. These findings are also common in Caucasian populations, as reported in other studies.10,11,17 Although the age of onset was significantly earlier in definite familial MD patients than in sporadic cases, it was not significantly different between familial MLS and sporadic cases (P 5.05). However, the P value for significance was borderline, but may have been significant if a larger patient pool were enrolled. Despite the early onset of the disease, hearing thresholds, disease stages, and responses to medical treatments were not significantly different between the sporadic and definite familial MD groups, which is also a common finding in Caucasian populations.11 A close relationship between migraines and MD has been suggested; however, these two conditions cannot be fully differentiated by the current symptom-based diagnostic criteria in certain cases. Migraine headaches can sometimes be replaced by vertigo attacks, especially in women around menopause, which mimics the symptoms of MD.15 Vestibular migraine showed female preponderance (1.5–5 to 1) and not infrequently showed familial occurrence with an incomplete AD inheritance pattern.15 A genome-wide Lee et al.: Familial Meniere’s Disease in South Korea
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screen for chromosomal loci in a four-generation family with vestibular migraine identified a suspected disease gene located between rs244895 and D5S2073 in chromosome 5q35.18 Candidate genes in this area were genes for ion transport, such as KCNMB1, KCNIP1, ATP6V0E, and SLC34A1, and neurotransmitter receptor genes, such as GABRP, DRD1, and HRH2.18 Although the identified chromosomal loci were different from those of familial MD identified so far, these candidate genes are also likely to cause MD, as there are many ion channels, transporters, and neurotransmitters receptors in the inner ear. The deterioration of certain ion channels and neurotransmitter receptor function can cause disruption of inner ear homeostasis, which can ultimately cause endolymphatic hydrops. Given that a higher prevalence of migraines was identified in the familial MD population, mutations in particular loci may affect both migraines and MD. If a genetic mutation that affects both migraines and MD is identified, it may be responsible for the close relationship between the two disease entities. In such a situation, headaches could be an incomplete phenotype of familial MD or vice versa. This study is the first and largest study to analyze the prevalence, inheritance patterns, and clinical characteristics of familial MD in an Asian population in the English literature. Because the patients enrolled in this study are of the same ethnicity, data from this study can be used as a basis for future investigations of the genetic causes of MD in Asian populations. Future studies regarding mutated genes and loci will help to elucidate the common and dissimilar aspects of the genetic causes of MD among different races.
CONCLUSION This is the first report describing the genetic aspects of MD in an Asian population. The prevalence of familial MLS and definite familial MD were 9.8% and 6.3%, respectively, and the most common inheritance pattern was AD with incomplete penetrance. Early-onset age and a high prevalence of migraines were significant clinical characteristics of familial MD in the South
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Korean population. These data could provide a basis for the analysis of the genetic mechanism of familial MD in Asian populations.
Acknowledgments The authors acknowledge the English editing support from Soo Ah Choi.
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Lee et al.: Familial Meniere’s Disease in South Korea
