Fertility and apparent genetic anticipation in Lynch syndrome

Genetic anticipation is the phenomenon in which age of onset of an inherited disorder decreases in successive generations. Inconsistent evidence suggests that this occurs in Lynch syndrome. A possible cause for apparent anticipation is fecundity bias, which occurs if the disease adversely affects fertility. The purpose of this study was to determine the effect of age of diagnosis of colorectal cancer (CRC) on lifetime fertility in Lynch syndrome, and whether this can falsely create the appearance of genetic anticipation. A computer model simulated age of diagnosis of CRC in hypothetical Lynch syndrome carriers and their offspring. The model assumed similar age distribution of CRC across generations (i.e. that there was no true anticipation). Age distribution of CRC diagnosis, and lifetime fertility rates (grouped by age of diagnosis of CRC) were determined from the Australasian Colorectal Cancer Family Registry (ACCFR). Apparent anticipation was calculated by comparing ages of diagnosis of CRC in affected parent-child pairs. A total of 1,088 patients with CRC were identified from the ACCFR. Total lifetime (cohort) fertility was related to age of diagnosis of CRC (correlation coefficient 0.13, P = 0.0001). In the simulation, apparent anticipation was 1.8 ± 0.54 years (P = 0.0044). Observed apparent anticipation in the ACCFR cohort was 4.8 ± 1.73 years (P = 0.0064). There was no difference in apparent anticipation between the simulate d and observed parent-child pairs (P = 0.89). The appearance of genetic anticipation in Lynch syndrome can be falsely created due to changes in fertility.

No evidence of genetic anticipation in a large family with Lynch syndrome.

Lynch syndrome is the commonest inherited cause of colorectal cancer (CRC). Genetic anticipation occurs when the age of onset of a disorder decreases in successive generations. It is controversial whether this occurs in Lynch syndrome. Previous studies have included heterogenous groups of subjects from multiple families, including subjects with a clinical diagnosis (based on family history) as well as those with proven germline mismatch repair gene mutations. The purpose of this study was to determine whether genetic anticipation occurs in mismatch repair gene carriers from a single Lynch syndrome family. This study includes members of a single family known to carry an MLH1 gene mutation who are proven germline mutation carriers or obligate carriers (based on their offspring's mutation status). Evidence of genetic anticipation (determined by age of onset of first CRC) was sought in two ways: Firstly, subjects were grouped as parent-child pairs and individuals were compared with their own offspring; secondly they were grouped by generation within the family tree. The Kaplan-Meier technique was used to adjust for variable follow up times. The family tree consisted of 714 subjects. Ninety-two subjects over five generations were included in the study. There was no evidence of genetic anticipation over the generations. (P = 0.37). Similarly, in the 75 parent-child pairs identified, age of onset of CRC was similar for parents and children (P = 0.51). We could not identify any evidence of genetic anticipation in mutation carriers from a single family with Lynch syndrome.

Fertility after young-onset colorectal cancer: a study of subjects with Lynch syndrome

AIM: Infertility is a concern for young survivors of colorectal cancer (CRC), but this risk is not well quantified. Carriers of mismatch repair (MMR) mutations are a useful cohort for studying fertility after CRC as they commonly develop CRC when young, and unaffected family members provide demographically similar controls. The aim of this study was to determine the effect of CRC on fertility in a large cohort of MMR mutation carriers. METHOD: Mismatch repair mutation carriers identified from the Australasian Colorectal Cancer Family Registry were included. For each year of life within the fertile age range (15-49), the number of living individuals and the number of children born to them were determined. Individuals were grouped by whether or not they had had a diagnosis of CRC by that age. Age-specific and total fertility rates were calculated. RESULTS: We identified 1068 subjects (611 women and 457 men), of whom 467 were diagnosed with CRC. There were 1192 births during 18 674 person-years of follow-up to the women and 814 births during 14 013 person-years of follow-up to the men. The total fertility rate was decreased in women after a diagnosis of CRC compared with those who did not have CRC (1.3 vs 2.2; P = 0.0011), but age-specific fertility was only reduced in the 20-24-year age group. In men the total fertility rate was similar for both groups (2.0 vs 1.8; P = 0.27). CONCLUSION: Age-specific fertility was decreased in female CRC survivors with Lynch syndrome aged 20-24, but not in older women or in men.

Lynch syndrome: natural history and colonoscopic surveillance

Lynch syndrome is the commonest inherited cause of bowel cancer. This thesis explores the natural history and cancer risk in Lynch syndrome and documents the effect of colorectal cancer on fertility. It also demonstrates that colonoscopic surveillance can prevent colorectal cancers and thus improve survival in these subjects.

Build your own life : a self-help guide for individuals with Asperger`s syndrome

As someone with Asperger's Syndrome, Wendy Lawson knows all about the social difficulties that accompany the condition. In this book, she guides others on the autism spectrum through the confusing map of life, tackling the building bricks of social existence one by one with humour, insight and practical suggestions. Exploring what it is like to be an adult in an alien world, she looks at the concepts of 'self' and 'other' and talks about the people in our lives -- how to relate to them, how we can use their support and how we can protect ourselves in the process. Using poetry and illustrations, she goes on to explain the difficult notion of putting on a face, looks at how to assess personal skills in order to develop them into a suitable career and how to deal with unwelcome changes in life. This book is essential reading for all those on the higher-functioning end of the autism spectrum, helping them to get the best out of a world that is often confusing and aiding those close to them to understand their perspective. Book jacket.

The dying town syndrome : a survey of urban development in the Western District of Victoria,1890-1930

The experience of urban settlement in the Western District of Victoria suggests that the pattern of growth and decline in small towns is tied to the pattern of land use. This, in turn, is determined by the economic and technological factors which influence farm management and practices. At times, these factors have encouraged urban development and small towns have flourished. For the most part, however, these forces have not been conducive to sustaining long-term growth and prosperity and small towns, have been trapped in a cycle of growth and decline.

Cognitive functioning in chronic fatigue syndrome and the role of depression, anxiety and fatigue

Objective: This study was designed to investigate the role of depression, anxiety, and fatigue in Chronic Fatigue Syndrome (CFS) sufferers' objective and subjective cognitive performance. Methods: Twenty-three CFS sufferers and 23 healthy control participants were compared on objective and subjective assessments of cognitive performance. Depression, anxiety, and fatigue were also evaluated. Results: CFS sufferers did not demonstrate any impairment in objective cognitive functioning compared to the control group, and objective performance was not related to their higher levels of depression or their level of fatigue. Depression scores only accounted for a small amount of the variance in CFS sufferers' lower subjective assessment of their cognitive performance compared to control participants. There were no differences between the groups on anxiety scores. Conclusion: The results are discussed in terms of the heterogeneity of the CFS population and the complex interaction of symptomatological factors that characterise CFS.

A contested disease state : chronic fatigue syndrome

This paper aims firstly to look at characteristics of the condition, and current issues related to the symptomatology and presentation of ME-CFS. Secondly, it identifies methodological problems in researching ME/CFS and demonstrates that the experimental approach to researching the condition can be informed by more qualitative, constructivist approaches. Thirdly, it argues that ME-CFS is a contested state whose acceptance by the medical profession requires the legitimation of a demonstrated biomedical basis

Association of genetic vatiation within UBL5 with phenotypes of metabolic syndrome

The BEACON gene was initially identified using the differential display polymerase chain reaction on hypothalamic mRNA samples collected from lean and obese Psammomys obesus, a polygenic animal model of obesity. Hypothalamic BEACON gene expression was positively correlated with percentage of body fat, and intracerebroventricular infusion of the Beacon protein resulted in a dose-dependent increase in food intake and body weight. The human homolog of BEACON, UBL5, is located on chromosome 19p in a region previously linked to quantitative traits related to obesity. Our previous studies showed a statistically significant association between UBL5 sequence variation and several obesity- and diabetes-related quantitative physiological measures in Asian Indian and Micronesian cohorts. Here we undertake a replication study in a Mexican American cohort where the original linkage signal was first detected. We exhaustively resequenced the complete gene plus the putative promoter region for genetic variation in 55 individuals and identified five single nucleotide polymorphisms (SNPs), one of which was novel. These SNPs were genotyped in a Mexican American cohort of 900 individuals from 40 families. Using a quantitative trait linkage disequilibrium test, we found significant associations between UBL5 genetic variants and waist-to-hip ratio (p = 0.027), and the circulating concentrations of insulin (p = 0.018) and total cholesterol (p = 0.023) in fasted individuals. These data are consistent with our earlier published studies and further support a functional role for the UBL5 gene in influencing physiological traits that underpin the development of metabolic syndrome.

The limits of medicine and the social consequences for sufferers of chronic fatigue syndrome

Chronic fatigue syndrome (CFS) appears to be made up of several clusters of illness categories acting alone or in tandem to cause the decline of health through; fatigue/exhaustion, sensitivity/allergies, pain, general muscle and joint pains, cognitive impairment and gastrointestinal problems. This study investigated how patients interpret, evaluate and respond to the complex and varied symptoms of chronic fatigue syndrome. Data were collected from persons with CFS using a survey (n=90) and an interview (n=45). The researchers investigated how chronic fatigue syndrome is diagnosed by medical practitioners, how the label of CFS is determined and the social consequences for the patient. The results confirm the limited ability of the biomedical paradigm to diagnose adequately and treat effectively 'socially constructed' and medically ambiguous illnesses like CFS. In the absence of a legitimated regime of medical treatment for CFS, a range of often expensive treatments are employed by CFS sufferers, from formal use of pharmaceutical drugs through to 'alternative' therapies, including herbal, vitamin, homeopathic, esoteric meditative techniques, spiritual healing and general counselling are taken in no particular order.