New Genetic Variants in CYP2B6 and SLC6A Support the Role of Oxidative Stress in Familial Ménière's Disease.

The objective was to study the genetic etiology of Ménière's disease (MD) using next-generation sequencing in three families with three cases of MD. Whole exome sequencing was used to identify rare genetic variants co-segregating with MD in Finnish families. In silico estimations and population databases were used to estimate the frequency and pathogenicity of the variants. Variants were validated and genotyped from additional family members using capillary sequencing. A geneMANIA analysis was conducted to investigate the functional pathways and protein interactions of candidate genes. Seven rare variants were identified to co-segregate with MD in the three families: one variant in the CYP2B6 gene in family I, one variant in GUSB and EPB42 in family II, and one variant in each of the SLC6A, ASPM, KNTC1, and OVCH1 genes in family III. Four of these genes were linked to the same co-expression network with previous familial MD candidate genes. Dysfunction of CYP2B6 and SLC6A could predispose to MD via the oxidative stress pathway. Identification of ASPM and KNTC1 as candidate genes for MD suggests dysregulation of mitotic spindle formation in familial MD. The genetic etiology of familial MD is heterogenic. Our findings suggest a role for genes acting on oxidative stress and mitotic spindle formation in MD but also highlight the genetic complexity of MD.

Autosomal recessive nonsyndromic hearing impairment in two Finnish families due to the population enriched CABP2 c.637+1G>T variant.

BACKGROUND: The genetic architecture of hearing impairment in Finland is largely unknown. Here, we investigated two Finnish families with autosomal recessive nonsyndromic symmetrical moderate-to-severe hearing impairment. METHODS: Exome and custom capture next-generation sequencing were used to detect the underlying cause of hearing impairment. RESULTS: In both Finnish families, we identified a homozygous pathogenic splice site variant c.637+1G>T in CAPB2 that is known to cause autosomal recessive nonsyndromic hearing impairment. Four CABP2 variants have been reported to underlie autosomal recessive nonsyndromic hearing impairment in eight families from Iran, Turkey, Pakistan, Italy, and Denmark. Of these variants, the pathogenic splice site variant c.637+1G>T is the most prevalent. The c.637+1G>T variant is enriched in the Finnish population, which has undergone multiple bottlenecks that can lead to the higher frequency of certain variants including those involved in disease. CONCLUSION: We report two Finnish families with hearing impairment due to the CABP2 splice site variant c.637+1G>T.

Whole-exome sequencing suggests multiallelic inheritance for childhood-onset Ménière's disease.

The genetic background of Ménière's disease (MD) was studied in one patient with childhood-onset MD and his grandfather affected with middle age-onset MD. Whole-exome sequencing was performed and the data were compared to 76 exomes from unrelated subjects without MD. Thirteen rare inner ear expressed variants with pathogenic estimations were observed in the case of childhood-onset MD. These variants were in genes involved in the formation of cell membranes or the cytoskeleton and in genes participating in cell death or gene-regulation pathways. His grandfather shared two of the variants: p.Y273N in HMX2 and p.L229F in TMEM55B. HMX2 p.Y273N was considered the more likely candidate for MD, as the gene is known to affect both hearing and vestibular function. The variant in the HMX2 gene may affect inner ear development and structural integrity and thus might predispose to the onset of MD. As there was a significant difference in onset between the patients, an accumulation of defects in several pathways is probably responsible for the exceptionally early onset of the disease, and the genetic etiology of childhood-onset MD is most likely multifactorial. This is the first molecular genetic study of childhood-onset MD.

Concomitant diseases and their effect on disease prognosis in Meniere's disease: diabetes mellitus identified as a negative prognostic factor.

OBJECTIVE: To study comorbidities and their effect on the disease progression in Meniere's disease (MD). METHODS: Retrospective study on 350 definite MD patients diagnosed according to AAO-HNS 1995 criteria using hospital records and postal questionnaire. RESULTS: The prevalence of migraine, hypothyroidism, allergies, coronary heart disease and autoimmune diseases was more common in MD patients than reported in the general population of Finland. Diabetes mellitus was associated with both more severe hearing impairment (p = .033) and more frequent vertigo (p = .028) in MD patients. The number of concomitant diseases was associated with more frequent vertigo (p = .021). CONCLUSIONS: A patient's concomitant diseases, especially diabetes, should be treated effectively because they might affect the progression of MD. Further studies on the effects of concomitant diseases on MD prognosis are needed.

[Kikuchi disease in a young Finnish man]. / Kikuchin tauti nuorella suomalaismiehellä.

Kikuchi disease is a lymphadenitis becoming manifest with flu-like symptoms and occurring particularly in Southeast Asian women. The disease is characterized by recurrent febrile episodes with enlarged and tender lymph nodes occurring most commonly in the neck region. With the exception of leukopenia, laboratory findings may be scarce. Diagnosis of the disease is based on necrotizing inflammation found upon histological examination of the lymph node, typical clinical picture and exclusion of other causes. There is no specific treatment, but the course of the disease is usually benign with spontaneously recovery within a couple of months.

Higher prevalence of autoimmune diseases and longer spells of vertigo in patients affected with familial Ménière's disease: A clinical comparison of familial and sporadic Ménière's disease.

PURPOSE This study compared clinical features, predisposing factors, and concomitant diseases between sporadic and familial Ménière's disease (MD). METHOD Retrospective chart review and postal questionnaire were used. Participants were 250 definite patients with MD (sporadic, n =149; familial, n = 101) who fulfilled the American Academy of Otorhinolaryngology-Head and Neck Surgery (1995) criteria. RESULTS On average, familial patients were affected 5.6 years earlier than sporadic patients, and they suffered from significantly longer spells of vertigo (p = .007). The prevalence of rheumatoid arthritis (p = .002) and other autoimmune diseases (p = .046) was higher among the familial patients, who also had more migraine (p = .036) and hearing impairment (p = .002) in their families. CONCLUSION The clinical features of familial and sporadic MD are very similar in general, but some differences do exist. Familial MD patients are affected earlier and suffer from longer spells of vertigo.

High incidence of Meniere-like symptoms in relatives of Meniere patients in the areas of Oulu University Hospital and Kainuu Central Hospital in Finland.

Objective of this study was to systematically investigate the family histories of a large set of patients affected with Meniere's disease to determine the prevalence of familial MD and Meniere-like symptoms in their families. All 640 patients treated at the Oulu University Hospital and Kainuu Central Hospitals during 2005-2010 for Meniere's disease were selected as the initial study population. A postal family history survey was sent to all subjects. Hospital records of all patients were studied to confirm diagnosis and sufficient differential diagnosis. All patients that revealed a positive family history of Meniere's disease or Meniere-like symptoms were phone interviewed and the probability of Meniere's disease in a relative was estimated on a three level scale: probable, possible or unlikely. Affected family members of the patients were recruited to the study if possible. Familial Meniere's disease could be confirmed in 9.3% of patients, but 32.7% patients reported Meniere-like symptoms in their family. It was not possible to confirm all cases, but a family history of Meniere's disease was convincing (confirmed or probable) in 23.4% of the patients. Genetic factors are significant in the development of Meniere's disease.

A replication study on proposed candidate genes in Ménière's disease, and a review of the current status of genetic studies.

OBJECTIVE: Multiple candidate genes have been presented for Ménière's disease (MD), but to date no positive replications have been reported. We review here all the previously proposed candidate genes for MD and report our results on the analysis of six such genes, AQP2, KCNE1, KCNE3, HCFC1, COCH, and ADD1. STUDY SAMPLE: A well-defined sample set of 38 sporadic and 21 familial Finnish MD patients. DESIGN: Mutation analysis, case-control study, and review of literature. RESULTS: A polymorphism rs1805127 in the potassium channel gene, KCNE1, was associated with MD in sporadic (p = 0.011), but not familial patients (p = 0.62). In addition, we identified four novel unique variations in the KCNE1 gene. PolyPhen and Mutation Taster analyses indicated that at least one of the variations c.259T > C; p.Trp87Arg is probably damaging to the coded protein. CONCLUSIONS: Our review of the reported candidate genes shows that the current understanding of the genetic factors contributing to the development of MD is limited, and that the study of its etiology would benefit greatly from more comprehensive genetic knowledge.

[When external otitis does not heal]. / Kun korvakäytävätulehdus ei paranekaan.

An illness initially started as external otitis in a healthy and physically fit middle-aged person turned out to be a difficult-to-manage Langerhans cell histiocytosis. The disease occurs mostly in children, and international clinical guidelines have accordingly been devised mainly for juvenile patients. Treatment of adult patients is thus essentially empirical. The disease may affect several organs, as in our case report, in which the disease after progression to a multisystemic disease led to secondary leukemia and death of the patient.

[Treatment of recurrent dislocation of the temporomandibular joint with botulinum toxin: an alternative approach]. / Toistuvan leukaluksaation hoito botuliinitoksiinilla: vaihtoehtoinen lähestymistapa.

Repeated injections of botulinum toxin carried out at regular intervals are an effective means to treat otherwise treatment-resistant recurrent dislocation of the temporomandibular joint. The treatment can be performed simply and safely without electromyography (EMG) or imaging control by a specialist having expertise in the anatomy of the region. In a patient described by us, a previously treatment-resistant condition has been successfully treated in this way for three years.

Finnish familial Meniere disease is not linked to chromosome 12p12.3, and anticipation and cosegregation with migraine are not common findings.

PURPOSE: To study the inheritance and characteristics of familial Meniere disease in Finland and genetic linkage to the previously proposed locus on chromosome 12p12.3. METHODS: Sixteen Meniere families recruited from Kainuu Central Hospital and Helsinki and Oulu University Hospitals in the period 2001-2004 were reevaluated in 2009 using hospital records and mailed questionnaire forms. Ten highly polymorphic microsatellite markers were selected from the area of chromosome 12p12.3 and studied for linkage using the GENEHUNTER protocol. RESULTS: The families showed autosomal dominant inheritance without cosegregation with migraine. Anticipation was seen only in one family, and in the rest of the families, the age of onset varied randomly among generations and individuals. The severity of the disease was not related to descending generations. None of the maximum logarithm of odds (LOD)/heterogeneity LOD scores in the analysis of chromosome 12p12.3 in Finnish Meniere families reached a significant value of 3.0 (maximum cumulative LOD score: -7.29, heterogeneity LOD: -0.95, α = 0.4). CONCLUSIONS: Families affected by Meniere disease are highly heterogeneous. Migraine, age at onset, anticipation, or penetrance was not a shared feature. The findings support the multifactorial nature of the disease and indicate that genetic heterogeneity exists within familial Meniere disease.