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Familial Meniere's disease in five generations
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Ear-Nose-Throat)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Earn-Nose-Throat)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2006 (English)In: Otology and Neurotology, ISSN 1531-7129, E-ISSN 1537-4505, Vol. 27, no 5, 681-686 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Clinical characterization of a Swedish family followed for five generations. Several members of each generation had Meniere's disease (MD). Possible modes of genetic transmission were assessed.

Study Design: Retrospective family survey.

Setting: University hospital. Tertiary referral center.

Patients: Members of a large family in which several members in each generation were affected by MD.

Interventions: Hearing levels were assessed, and the patients were asked to complete a questionnaire regarding age at onset, hearing loss, tinnitus, aural fullness, vertigo, and if MD was unilateral or bilateral. Glycerol tests were performed in a few cases. For deceased relatives, information was obtained from patient charts and interviews with relatives. Genetic studies with linkage analysis was performed for the loci DFNA 1, DFNA6/14, DFNA9, and DFNA 15.

Results: One member of Generation I and, according to patient charts, two members of Generation 11 could have suffered from MD. In Generations III to V, 9 of 25 members developed inner ear dysfunction. Six of these individuals developed MD that was strictly in accordance with American Academy of Otolaryngology and Head and Neck Surgery, 1995 guidelines criteria, whereas three individuals had unilateral or bilateral hearing impairment, one in combination with benign paroxysmal positioning vertigo, which could represent an incomplete expression of the disease. ne mean age at disease onset was 64.5 years in Generation 111, 43 years in Generation W, and 25 years in Generation V. In the genetic studies, none of the regions investigated showed linkage to the disease gene with a significant calculated log of odds ratio (LOD) score above three.

Conclusion: The pattern of inheritance suggested that familial MD was autosomal dominant and exhibited incomplete expression of inner ear symptoms in some affected members. The decreasing age at onset of disease with succeeding generations could indicate anticipation. None of the hitherto-known DFNA loci, which has phenotypes hearing some resemblance to MD, had haplotypes in common with this large family affected by MD.

Place, publisher, year, edition, pages
2006. Vol. 27, no 5, 681-686 p.
Keyword [en]
anticipation, cochleovestibular dysfunction, familial, Meniere's disease
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96366DOI: 10.1097/01.mao.0000226315.27811.c8ISI: 000239528500019PubMedID: 16868516OAI: oai:DiVA.org:uu-96366DiVA: diva2:170919
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Clinical and Genetic Studies of Hearing Impairment
Open this publication in new window or tab >>Clinical and Genetic Studies of Hearing Impairment
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Monogenic disorders offer a possibility for studies of genetic disturbances in hearing impairment—a knowledge which could be essential for development of future treatment options. In this thesis, the underlying genetic disturbances in neurofibromatosis 2 (NF2) and familial Meniere’s disease (FMD) were evaluated, and familial X-linked hearing impairment was described from a clinical point of view.

In paper I, constitutional DNA from 116 individuals with NF2 of variable severity was studied using the array-CGH method focusing on a 7.6-Mb area surrounding the NF2 gene on chromosome 22q. Deletions were found in 20.7% of samples. In mild NF2, the deletions were small, but variable sizes of deletions were found in cases that were moderately or severely affected. Disease phenotype could not be predicted from the size of the deletions.

In papers II and III, a single five-generation family with autosomal dominant FMD was described. Anticipation concerning age of onset was observed. Genome scan revealed five candidate gene regions with a LOD score of > 1. Two additional families with autosomal dominant MD were analyzed for linkage to these five regions. A cumulative Zmax of 3.46 was obtained for a single 463-kb region on chromosome 12p12.3, containing only one known gene: PIK3C2G. This encodes a protein with a proposed role in hair cell regeneration in mammalian ears. No mutations were found in protein-coding sequences or exon-intron borders. In two of the three families, a shared haplotype, suggested common ancestry, was found to extend over 1.7 Mb, which could be a genomic region of importance for FMD.

In paper IV, a family in which five males displayed progressive low- and mid-frequency hearing impairment from the first or second decade was described. Female carriers were affected by a high-frequency hearing impairment from the fourth decade. The family could represent a novel X-linked dominant audiophenotype.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 286
Keyword
Otorhinolaryngology, NF2, array-CGH, Meniere’s disease, PIK3C2G, X-linked, progressive, hearing impairment, Otorhinolaryngologi
Identifiers
urn:nbn:se:uu:diva-8290 (URN)978-91-554-7006-7 (ISBN)
Public defence
2007-11-23, Skoogsalen, 78.79, Öronkliniken, Akademiska Sjukhuset, 751 85, Uppsala, 09:00
Opponent
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Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2011-06-28Bibliographically approved

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Frykholm, CarinaDahl, NiklasFriberg, Ulla

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