Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder generally presenting with intention tremor and gait ataxia, but with a growing list of co-morbid medical conditions including hypothyroidism, hypertension, peripheral neuropathy, and cognitive decline. The pathological hallmark of FXTAS is the presence of intranuclear inclusions in both neurons and astroglia. However, it is unknown to what extent such inclusions are present outside the central nervous system (CNS). To address this issue, we surveyed non-CNS organs in ten human cases with FXTAS and in a CGG repeat knock-in (CGG KI) mouse model known to possess neuronal and astroglial inclusions. We find inclusions in multiple tissues from FXTAS cases and CGG KI mice, including pancreas, thyroid, adrenal gland, gastrointestinal, pituitary gland, pineal gland, heart, and mitral valve, as well as throughout the associated autonomic ganglia. Inclusions were observed in the testes, epididymis, and kidney of FXTAS cases, but were not observed in mice. These observations demonstrate extensive involvement of the peripheral nervous system and systemic organs. The finding of intranuclear inclusions in non-CNS somaticorgan systems, throughout the PNS, and in the enteric nervous system of both FXTAS cases as well as CGG KI mice suggests that these tissues may serve as potential sites to evaluate early intervention strategies or be used as diagnostic factors.

SummaryBackground: The SF-6D is a new health state classification and utility scoring system based on 6 dimensions ('6D') of the Short Form 36, and permits a ''bridging'' transformation between SF-36 responses and utilities. The Health Utilities Index, mark 3 (HUI3) is a valid and reliable multi-attribute health utility scale that is widely used. We assessed within-subject agreement between SF-6D utilities and those from HUI3.Methods: Patients at increased risk of sudden cardiac death and participating in a randomized trial of implantable defibrillator therapy completed both instruments at baseline. Score distributions were inspected by scatterplot and histogram and mean score differences compared by paired t-test. Pearson correlation was computed between instrument scores and also between dimension scores within instruments. Between-instrument agreement was by intra-class correlation coefficient (ICC).Results: SF-6D and HUI3 forms were available from 246 patients. Mean scores for HUI3 and SF-6D were 0.61 (95% CI 0.60-0.63) and 0.58 (95% CI 0.54-0.62) respectively; a difference of 0.03 (p50.03). Score intervals for HUI3 and SF-6D were (-0.21 to 1.0) and (0.30-0.95). Correlation between the instrument scores was 0.58 (95% CI 0.48-0.68) and agreement by ICC was 0.42 (95% CI 0.31-0.52). Correlations between dimensions of SF-6D were higher than for HUI3.Conclusions: Our study casts doubt on the whether utilities and QALYs estimated via SF-6D are comparable with those from HUI3. Utility differences may be due to differences in underlying concepts of health being measured, or different measurement approaches, or both. No gold standard exists for utility measurement and the SF-6D is a valuable addition that permits SF-36 data to be transformed into utilities to estimate QALYs. The challenge is developing a better understanding as to why these classification-based utility instruments differ so markedly in their distributions and point estimates of derived utilities.

Introduction and hypothesisPelvic organ prolapse (POP) and other disorders, such as varicose veins and joint hypermobility, have been associated with changes in collagen strength and metabolism. We hypothesized that these various disorders were more prevalent in both POP patients and their family members.MethodsIn this study, the prevalence of various collagen-associated disorders, including POP, was compared between POP patients (n = 110) and control patients (n = 100) and their first and second degree family members.ResultsPOP patients reported a higher prevalence of varicose veins, joint hypermobility and rectal prolapse and were more likely to have family members with POP as compared to the control group (p < 0.01). In contrast, the family members of the POP group did not report a higher prevalence of collagen-associated disorders compared to the family members of the control group (p = 0.82).ConclusionsPOP and other collagen-associated disorders may have a common aetiology, originating at the molecular level of the collagens.

PURPOSE Women who carry a FMR1 premutation are at risk for fragile X-associated primary ovarian insufficiency (FXPOI) and should be counseled for a potentially reduced fertility. Multiple factors can affect the age of onset and severity of FXPOI. Here, we assessed the predictive power of several factors with menopausal age, a surrogate measure of onset of FXPOI. METHODS Genetic, environmental and reproductive factors were analysed by Cox proportional hazard models in 1,068 women, 385 of fragile X families ascertained through the Nijmegen study and 683 of fragile X families or general population families ascertained through the Atlanta study. RESULTS The highest association with menopausal age among FMR1 premutation carriers was found for risk index by CGG repeat size (HR 1.43) and smoking (HR 1.34). Women from the Nijmegen cohort showed an overall lower age at menopause onset, for which a correction was made. A prediction model based on these two parameters, mean menopausal age of first degree relatives with the same mutation status and the correction for ascertainment site, estimated the probability of becoming postmenopausal for premutation carriers, with a margin of 7-10%. CONCLUSION We conclude that this model serves as a first step towards clinical application of FXPOI prediction.