No description available.

The number of known monogenic rare diseases (~7000) exceeds the number of effective treatments (~500) by more than an order of magnitude underlining the pressing need for generalizable therapeutic approaches for this class of conditions. In this regard, the majority of recessive and x-linked recessive disorders are caused by missense mutations encoding proteins that frequently have residual function but are rapidly degraded by the 26S proteasome. Bortezomib is a small molecule that inhibits the 26S proteasome and has been approved for use in patients for an unrelated condition; multiple myeloma. Previous work has shown that, for a small number of disorders, bortezomib can inhibit the degradation of the mutant protein, thereby increasing the protein level and activity, holding out the promise of a beneficial therapeutic effect by the repurposing of this agent. We present here a high level western blot based survey of nine recessive disorders to characterize the general effectiveness of such an approach. Thirteen patient fibroblast cell lines comprising 9 different diseases with 19 known mutations were selected on the basis of missense mutations protein expression data when available. The cell lines were incubated with bortezomib (10 nM and 50 nM; 24 hrs) and levels of the mutated protein were quantified by western blot. Unfortunately, no consistent, appreciable increase was observed for any of the conditions tested. The general therapeutic value of re-purposing bortezomib for recessive and x-linked diseases appears limited at best. The few reported cases of bortezomib successfully working in increasing mutated protein levels appear to be the exceptions and not the norm. Moreover successes are more often limited to cell lines carrying a transgene expressing the mutated protein rather than endogenous mutated protein in patient cell lines.

Yes / Currently there is no consensus regarding services required to help families with consanguineous marriages manage their increased genetic reproductive risk. Genetic services for communities with a preference for consanguineous marriage in the UK remain patchy, often poor. Receiving two disparate explanations of the cause of recessive disorders (cousin marriage and recessive inheritance) leads to confusion among families. Further, the realisation that couples in non-consanguineous relationships have affected children leads to mistrust of professional advice. British Pakistani families at-risk for recessive disorders lack an understanding of recessive disorders and their inheritance. Such an understanding is empowering and can be shared within the extended family to enable informed choice. In a three-site qualitative study of British Pakistanis, we explored family and health professional perspectives on recessively inherited conditions. Our findings suggest, first, that family networks hold strong potential for cascading genetic information, making the adoption of a family centred approach an efficient strategy for this community. However, this is dependent on provision of high quality and timely information from health care providers. Secondly, families’ experience was of ill-coordinated and time-starved services, with few having access to specialist provision from Regional Genetics Services; these perspectives were consistent with health professionals’ views of services. Thirdly, we confirm previous findings that genetic information is difficult to communicate and comprehend, further complicated by the need to communicate the relationship between cousin marriage and recessive disorders. A communication tool we developed and piloted is described and offered as a useful resource for communicating complex genetic information. / Department of Health