Not just carriers: experiences of X-linked female heterozygotes.

PURPOSE: To better understand the needs and experiences of the X-linked carrier community to improve future recognition, diagnosis, and treatment by bringing X-linked carrier voices together. METHODS: An anonymous survey link was distributed to members of Remember the Girls, a non-profit organization for female (XX) carriers of X-linked conditions, through its website, Facebook group, Instagram, and Twitter. The survey was developed to gather data on XX carriers of numerous X-linked conditions. RESULTS: One hundred and fifty individuals participated in the study. The majority (81/150) of individuals learned about their carrier status by giving birth to a son diagnosed with an X-linked condition. However, over 80% (120/145) believed that they should learn this information before the age of 18. Over 80% of participants (124/148) felt that they either have or may have symptoms attributable to their X-linked condition. Yet, only 10.1% (15/148) felt that they had sufficient access to knowledgeable healthcare providers and/or medical information. Additionally, 46.7% (70/150) of participants reported that healthcare providers did not discuss reproductive options with them. Improving carrier access to medical information, research studies, new treatments, and reproductive methods was found to be the top priority. CONCLUSION: Limited information exists on X-linked carriers' risk for symptoms and there is a lack of available treatments. This study demonstrates the need for more knowledgeable healthcare providers and medical information within the X-linked carrier community.

A combination of cyclophosphamide and interleukin-2 allows CD4+ T cells converted to Tregs to control scurfy syndrome.

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by mutations in forkhead box P3 (FOXP3), which lead to the loss of function of regulatory T cells (Tregs) and the development of autoimmune manifestations early in life. The selective induction of a Treg program in autologous CD4+ T cells by FOXP3 gene transfer is a promising approach for curing IPEX. We have established a novel in vivo assay of Treg functionality, based on adoptive transfer of these cells into scurfy mice (an animal model of IPEX) and a combination of cyclophosphamide (Cy) conditioning and interleukin-2 (IL-2) treatment. This model highlighted the possibility of rescuing scurfy disease after the latter's onset. By using this in vivo model and an optimized lentiviral vector expressing human Foxp3 and, as a reporter, a truncated form of the low-affinity nerve growth factor receptor (ΔLNGFR), we demonstrated that the adoptive transfer of FOXP3-transduced scurfy CD4+ T cells enabled the long-term rescue of scurfy autoimmune disease. The efficiency was similar to that seen with wild-type Tregs. After in vivo expansion, the converted CD4FOXP3 cells recapitulated the transcriptomic core signature for Tregs. These findings demonstrate that FOXP3 expression converts CD4+ T cells into functional Tregs capable of controlling severe autoimmune disease.

Preimplantation genetic diagnosis of X-linked diseases examined by indirect linkage analysis.

BACKGROUND: Many centers of assisted reproduction in the Czech Republic offer preimplantation genetic diagnosis with fluorescent in situ hybridization (FISH) to couples requiring preimplantation genetic diagnosis (PGD) of X-linked diseases. However, this process results in discarding all male embryos and is not able to distinguish a carrier or healthy female embryo in X-linked recessive disorders. OBJECTIVES: The main aim of this study was to summarize a six-year period of PGD of X-linked monogenic diseases using indirect linkage analysis. METHODS AND RESULTS: We wanted to accentuate the advantage indirect analysis of PGD using multiple displacement amplification (MDA) followed by short tandem repeat (STR) analysis. We present forty-six PGD cycles, including pre-case haplotyping (PGH) panel, for fifteen X-linked diseases. Embryo transfer was made thirty-eight times and gravidity was confirmed in thirteen female probands with a success rate of pregnancy calculated at 42 %. CONCLUSIONS: PGD procedure using MDA amplification followed by STR analysis provides help in identifying genetic defects within embryos prior to implantation. The reliability of the method was also supported by high pregnancy rate compared to other publications, which commonly achieved a 30-35 % success rate (Tab. 2, Fig. 1, Ref. 33).

[Pre-conception sex selection]. / A születendo gyermek nemének megválasztása.

According to Article 14 of the Oviedo Convention on Human Rights and Biomedicine of the Council of Europe, the use of techniques of medically assisted procreation shall not be allowed for the purpose of choosing the sex of a future child, unless serious hereditary sex-related disease is to be avoided. In Israel and the United States of America, pre-conception sex selection for the purpose of family balancing is legal. The European health culture does not regard reproductive justice as part of social justice. From this aspect, the situation is very similar in China and India. Reproductive liberty is opposed by the Catholic Church, too. According to the Catholic Church, medical grounds may not justify pre-conception sex selection, though being bioethically less harmful than family balancing for social reasons. In Hungary, according to Section 170 of the Criminal Code, pre-conception sex selection for the purpose of family balancing constitutes a crime. At present, the Hungarian legislation is in full harmony with the Oviedo Convention, enacted in Hungary in 2002.

Ethical arguments for and against sperm sorting for non-medical sex selection: a review.

Much has been written about the ethics of sex selection. This article thoroughly explores the ethical arguments put forth in the literature both for and against non-medical sex selection using sperm sorting. While most of these arguments come from philosophers, feminist scholars, social scientists and members of the healthcare community, they are often echoed in empirical studies that have explored community values. This review is timely because the first efficacious method for sex selection via sperm sorting, MicroSort, is currently in clinical trials and moving closer to FDA approval for marketing in the USA. While the clinical trials are currently focused on the use of MicroSort to avoid X-linked genetic diseases, MicroSort can also be used to satisfy parental preferences.

Genetic counseling in mitochondrial disease.

Mitochondrial diseases are a genetically and clinically diverse group of disorders that arise as a result of dysfunction of the mitochondria. Mitochondrial disorders can be caused by alterations in nuclear DNA and/or mitochondrial DNA. Although some mitochondrial syndromes have been described clearly in the literature many others present as challenging clinical cases with multisystemic involvement at variable ages of onset. Given the clinical variability and genetic heterogeneity of these conditions, patients and their families often experience a lengthy and complicated diagnostic process. The diagnostic journey may be characterized by heightened levels of uncertainty due to the delayed diagnosis and the absence of a clear prognosis, among other factors. Uncertainty surrounding issues of family planning and genetic testing may also affect the patient. The role of the genetic counselor is particularly important to help explain these complexities and support the patient and family's ability to achieve effective coping strategies in dealing with increased levels of uncertainty.

Attitudes about preconception sex selection: a focus group study with Americans.

BACKGROUND: MicroSort, a sperm-sorting technology for sex selection, may eventually be approved by the Food and Drug Administration and marketed to the public. Data on US public attitudes about the morally appropriate uses and regulation of this technology are lacking. METHODS: We conducted 20 focus groups in April 2003 with participants from five major US cities to identify the values that shape Americans' attitudes about the use and regulation of preconception sex selection (PSS) technology. One hundred and seventy-six individuals between the ages of 18 and 68 were assigned to groups ranging from 6 to 11 participants based on their location, sex, race/ethnicity, religion, age, education and parental status. Qualitative analysis of focus group transcripts was conducted using NVivo 2.0 software to determine beliefs and values that shape participants' opinions about the appropriate use and regulation of PSS. RESULTS: Most participants strongly favor using PSS to avoid X-linked genetic diseases. Although some participants were uncomfortable with the use of PSS for non-medical sex selection, believing it to be 'selfish' and inconsistent with parental love, they did not perceive the potential harms to be significant enough to warrant governmental intrusion into reproductive decisions. CONCLUSIONS: PSS should face little public opposition in the US if widely marketed.

[Preimplantation genetic diagnosis]. / Preimplantatorisk genetisk diagnostikk.

BACKGROUND: The revised Norwegian biotechnology law implies restrictive use of preimplantation genetic diagnostics--a highly specialised procedure, which is still in an early phase of development. MATERIAL AND METHOD: The paper is based on more than 10 years of clinical experience in preimplantation genetic diagnostics and on literature retrieved through PubMed/Medline. RESULTS: According to the biotechnology law, preimplantation genetic diagnostics can only be carried out when strict medical indications are present. Genetic counselling and a fertility work-up are compulsory for couples who wish to receive preimplantation genetic diagnostics. INTERPRETATION: Few disorders have an indication for preimplantation genetic diagnostics. It will therefore take time to build up adequate national expertise. For couples with a known risk of serious hereditary disease, preimplantation genetic diagnosis is useful in achieving an uncomplicated pregnancy and a healthy child.

Five years' experience of preimplantation genetic diagnosis in the Parisian Center: outcome of the first 441 started cycles.

OBJECTIVE: To investigate the evolution of techniques and strategies and to evaluate the results of preimplantation genetic diagnosis (PGD) from January 2000 to December 2004 in chromosomal, monogenic and mitochondrial DNA disorders treated at our institution. DESIGN: Retrospective study. SETTING: Single French Parisian PGD center. PATIENT(S): Patients at risk of transmitting a serious genetic disorder to their offspring. INTERVENTION(S): 171 couples enrolled in the program undergoing stimulated and frozen embryo replacement cycles with PGD. MAIN OUTCOME MEASURE(S): Results of the 441 first PGD cycles performed for various genetic conditions. RESULT(S): During 5 years, 416 stimulation and 25 frozen embryo replacement cycles were started, among which 52 clinical and 47 ongoing pregnancies occurred. In stimulation cycles, the overall ongoing pregnancy rate was 24% per embryo transfer, 11% per started cycle, and 27% per couple. The implantation rate was 16%. CONCLUSION(S): These encouraging results demonstrate that PGD might be considered as a valid alternative to prenatal diagnosis. Nevertheless, couples referred for PGD must be selected and counseled appropriately, considering the complexity of the treatment and the relatively low take-home baby rate.

Is any form of gender selection ethical?

In later years, sex selection has become of importance for prevention of X-linked diseases in families at risk. There is today a potential to perform sperm selection before fertilization by taking advantage of the chromosomal heterogamy of spermatozoa, and before implantation by preimplantation genetic diagnosis (PGD). The methods of sex determination by separating sperrmatozoa are, in our opinion, still not safe enough for routine clinical use. Apart from the technical problems and possible associated risks, which first must be better evaluated, the most critical questions are ethical or legal. We support the use of sex selection by PGD in X-linked severe disease, but due to the potential risks of misuse, we are not prepared to support a more liberal attitude as long as the discriminated sex in nearly all parts of the world are women.

Analysis of sex chromosomes in preimplantation genetic diagnosis for X-chromosome-linked disorders.

Preimplantation genetic diagnosis (PGD) is diagnostic tool to avoid inheritance of genetic disease by transferring unaffected embryos. Recently, PCR and FISH have been mainly applied to the diagnosis of single gene disorders and chromosomal abnormalities, respectively. Since with PGD, only a few cells are available for genetic tests, both gene and chromosomes analysis have to be obtained from the same, limited material. Cell recycling makes it possible to obtain the information on genes as well as chromosomes from the same cells. Therefore cell recycling is an acceptable strategy where in PGD targets large proportions of embryos severe chromosomal abnormalities. The responsible genes of the X-linked disorder and numerical abnormalities of sex chromosomes should be analyzed simultaneously. Gender information is definitely useful because only male affected embryos should be avoided for transfer.