Earlier life leisure-time physical activity in relation to age-related frailty syndrome.

BACKGROUND: frailty syndrome is common amongst older people. Low physical activity is part of frailty, but long-term prospective studies investigating leisure-time physical activity (LTPA) during the life course as a predictor of frailty are still warranted. The aim of this study is to investigate whether earlier life LTPA predicts frailty in older age. METHODS: the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) included older adults (aged 60-77 years) from the general population who were at increased risk of cognitive decline. Frailty was assessed for 1,137 participants at a baseline visit using a modified version of Fried's phenotype, including five criteria: weight loss, exhaustion, weakness, slowness and low physical activity. Self-reported data on earlier life LTPA were available from previous population-based studies (average follow-up time 13.6 years). A binomial logistic regression analysis was used to investigate the association between earlier life LTPA and pre-frailty/frailty in older age. RESULTS: the prevalence of frailty and pre-frailty was 0.8% and 27.3%, respectively. In the analyses, pre-frail and frail groups were combined. People who had been physically very active (OR 0.37, 95% CI 0.23-0.60) or moderately active (OR 0.45, 95% CI 0.32-0.65) earlier in life had lower odds of becoming pre-frail/frail than individuals who had been sedentary. CONCLUSIONS: frailty was rare in this relatively healthy study population, but almost a third of the participants were pre-frail. Earlier life LTPA was associated with lower levels of pre-frailty/frailty. The results highlight the importance of physical activity when aiming to promote healthy old age.

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.

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.

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.

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.

The theory of autoimmunity in Meniere's disease is lacking evidence.

The role of immunological factors in the pathophysiology of Meniere's disease (MD) has been hypothesized. In order to evaluate the current level of evidence on autoimmunity in MD, original articles relevant to the matter (1970-2016) were reviewed. The following has been considered to support the theory of autoimmunity in MD (1) the increased prevalence of autoimmune diseases among MD patients, (2) the elevated levels of antibodies and immunocomplexes in MD patients, (3) the association of MD with HLA-types and genetic polymorphisms and (4) the positive corticosteroid-responsiveness detected in some MD patients. However, all studies have been small and lack positive replication. Studies concerning antibodies, HLA types and genetic polymorphisms have produced conflicting results and no single antibody, HLA type or polymorphism has been found in all or even in a significant subpopulation of MD patients. No convincing basic research evidence of autoimmunity in MD exists hence the field needs further study.

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.

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.