Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening

Missense mutations to the TSC1 gene cause tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34 or the TSC2 gene on chromosome 16p13.3. The TSC1 and TSC2 gene products, TSC1 and TSC2, interact to form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). Here we investigate the effects of putative TSC1 missense mutations identified in individuals with signs and/or symptoms of TSC on TSC1–TSC2 complex formation and mTOR signalling. We show that specific amino-acid substitutions close to the N-terminal of TSC1 reduce steady-state levels of TSC1, resulting in the activation of mTOR signalling and leading to the symptoms of TSC

Correlation of internally deleted dystrophin and dystrophin-associated protein expression with clinical severity in Becker muscular dystrophy

Neurological Motor Disorder

Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials

Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aims to transform the Duchenne muscular dystrophy phenotype to that of the milder disorder, Becker muscular dystrophy, typically caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin. There is ongoing debate regarding the functional properties of the different internally deleted dystrophins produced by exon skipping for different mutations; more insight would be valuable to improve and better predict the outcome of exon skipping clinical trials. To this end, we have characterized the clinical phenotype of 17 patients with Becker muscular dystrophy harbouring in-frame deletions relevant to on-going or planned exon skipping clinical trials for Duchenne muscular dystrophy and correlated it to the levels of dystrophin, and dystrophin-associated protein expression. The cohort of 17 patients, selected exclusively on the basis of their genotype, included 4 asymptomatic, 12 mild and 1 severe patient. All patients had dystrophin levels of >40% of control and significantly higher dystrophin (P = 0.013), \u3b2-dystroglycan (P = 0.025) and neuronal nitric oxide synthase (P = 0.034) expression was observed in asymptomatic individuals versus symptomatic patients with Becker muscular dystrophy. Furthermore, grouping the patients by deletion, patients with Becker muscular dystrophy with deletions with an end-point of exon 51 (the skipping of which could rescue the largest group of Duchenne muscular dystrophy deletions) showed significantly higher dystrophin levels (P = 0.034) than those with deletions ending with exon 53. This is the first quantitative study on both dystrophin and dystrophin-associated protein expression in patients with Becker muscular dystrophy with deletions relevant for on-going exon skipping trials in Duchenne muscular dystrophy. Taken together, our results indicate that all varieties of internally deleted dystrophin assessed in this study have the functional capability to provide a substantial clinical benefit to patients with Duchenne muscular dystrophy

Mortality Risk Associated With Truncating Founder Mutations in Titin

BACKGROUND: Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy, found in METHODS: Haplotype and genealogical analyses were performed on 3 recurrent TTNtv. Subsequently, the family tree mortality ratio method was used to compare all-cause mortality of subjects at an a priori 50% risk of carrying TTNtv to the general Dutch population. SMRs were stratified for sex, age, and calendar period. Subgroups were compared with Poisson regression. Similarly, SMRs were calculated in parents of 128 present-day dilated cardiomyopathy probands with TTNtv using the reverse parent-offspring method. RESULTS: The TTNtv were established as founder mutations and traced to 18th century ancestors. In 20 522 person-years, overall mortality was not significantly increased (SMR, 1.06; 95% CI, 0.95-1.18; P=0.162). However, mortality was significantly increased in subjects living after 1965 (SMR, 1.27; 95% CI, 1.04-1.53; P=0.009) and aged =60 years (SMR, 1.17; 95% CI, 1.01-1.35; P=0.02). The reverse parent-offspring analysis showed overall excess mortality (SMR, 1.26; 95% CI, 1.07-1.48; P=0.003), driven by subjects aged =60 years. CONCLUSIONS: The natural history of the analyzed TTNtv shows a relatively mild disease course with significant excess mortality in elderly patients. With increasing life expectancy, TTNtv-associated morbidity and mortality will likely become more prevalent

Mortality Risk Associated With Truncating Founder Mutations in Titin

Background Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy, found in ≤25% of familial cases. Moreover, TTNtv associated with dilated cardiomyopathy are estimated to be present in 0.5% of the general population. The prognosis of asymptomatic carriers of TTNtv is poorly understood because TTNtv are associated with a highly variable phenotype. We aim to assess the natural history and clinical relevance of TTNtv by analyzing standardized mortality ratios (SMR) in multigenerational pedigrees and in close relatives of present-day patients. Methods Haplotype and genealogical analyses were performed on 3 recurrent TTNtv. Subsequently, the family tree mortality ratio method was used to compare all-cause mortality of subjects at an a priori 50% risk of carrying TTNtv to the general Dutch population. SMRs were stratified for sex, age, and calendar period. Subgroups were compared with Poisson regression. Similarly, SMRs were calculated in parents of 128 present-day dilated cardiomyopathy probands with TTNtv using the reverse parent-offspring method. Results The TTNtv were established as founder mutations and traced to 18th century ancestors. In 20 522 person-years, overall mortality was not significantly increased (SMR, 1.06; 95% CI, 0.95–1.18; P=0.162). However, mortality was significantly increased in subjects living after 1965 (SMR, 1.27; 95% CI, 1.04–1.53; P=0.009) and aged ≥60 years (SMR, 1.17; 95% CI, 1.01–1.35; P=0.02). The reverse parent-offspring analysis showed overall excess mortality (SMR, 1.26; 95% CI, 1.07–1.48; P=0.003), driven by subjects aged ≥60 years. Conclusions The natural history of the analyzed TTNtv shows a relatively mild disease course with significant excess mortality in elderly patients. With increasing life expectancy, TTNtv-associated morbidity and mortality will likely become more prevalent

Mortality Risk Associated With Truncating Founder Mutations in Titin

BACKGROUND: Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy, found in METHODS: Haplotype and genealogical analyses were performed on 3 recurrent TTNtv. Subsequently, the family tree mortality ratio method was used to compare all-cause mortality of subjects at an a priori 50% risk of carrying TTNtv to the general Dutch population. SMRs were stratified for sex, age, and calendar period. Subgroups were compared with Poisson regression. Similarly, SMRs were calculated in parents of 128 present-day dilated cardiomyopathy probands with TTNtv using the reverse parent-offspring method. RESULTS: The TTNtv were established as founder mutations and traced to 18th century ancestors. In 20 522 person-years, overall mortality was not significantly increased (SMR, 1.06; 95% CI, 0.95-1.18; P=0.162). However, mortality was significantly increased in subjects living after 1965 (SMR, 1.27; 95% CI, 1.04-1.53; P=0.009) and aged =60 years (SMR, 1.17; 95% CI, 1.01-1.35; P=0.02). The reverse parent-offspring analysis showed overall excess mortality (SMR, 1.26; 95% CI, 1.07-1.48; P=0.003), driven by subjects aged =60 years. CONCLUSIONS: The natural history of the analyzed TTNtv shows a relatively mild disease course with significant excess mortality in elderly patients. With increasing life expectancy, TTNtv-associated morbidity and mortality will likely become more prevalent