Transmission of Mitochondrial DNA Diseases and Ways to Prevent Them

Recent reports of strong selection of mitochondrial DNA (mtDNA) during transmission in animal models of mtDNA disease, and of nuclear transfer in both animal models and humans, have important scientific implications. These are directly applicable to the genetic management of mtDNA disease. The risk that a mitochondrial disorder will be transmitted is difficult to estimate due to heteroplasmy—the existence of normal and mutant mtDNA in the same individual, tissue, or cell. In addition, the mtDNA bottleneck during oogenesis frequently results in dramatic and unpredictable inter-generational fluctuations in the proportions of mutant and wild-type mtDNA. Pre-implantation genetic diagnosis (PGD) for mtDNA disease enables embryos produced by in vitro fertilization (IVF) to be screened for mtDNA mutations. Embryos determined to be at low risk (i.e., those having low mutant mtDNA load) can be preferentially transferred to the uterus with the aim of initiating unaffected pregnancies. New evidence that some types of deleterious mtDNA mutations are eliminated within a few generations suggests that women undergoing PGD have a reasonable chance of generating embryos with a lower mutant load than their own. While nuclear transfer may become an alternative approach in future, there might be more difficulties, ethical as well as technical. This Review outlines the implications of recent advances for genetic management of these potentially devastating disorders

Effect of electromagnetic-navigated shunt placement on failure rates: a prospective multicenter study.

Contains fulltext : 88738.pdf (publisher's version ) (Open Access)OBJECT: As many as 40% of shunts fail in the first year, mainly due to proximal obstruction. The role of catheter position on failure rates has not been clearly demonstrated. The authors conducted a prospective cohort study of navigated shunt placement compared with standard blind shunt placement at 3 European centers to assess the effect on shunt failure rates. METHODS: All adult and pediatric patients undergoing de novo ventriculoperitoneal shunt placement were included (patients with slit ventricles were excluded). The first cohort underwent standard shunt placement using anatomical landmarks. All centers subsequently adopted electromagnetic (EM) navigation for routine shunt placements, forming the second cohort. Catheter position was graded on postoperative CT in both groups using a 3-point scale developed for this study: (1) optimal position free-floating in CSF; (2) touching choroid or ventricular wall; or (3) intraparenchymal. Episodes and type of shunt revision were recorded. Early shunt failure was defined as that occurring within 30 days of surgery. Patients with shunts were followed-up for 12 months in the standard group, for a median of 6 months in the EM-navigated group, or until shunt failure. RESULTS: A total of 75 patients were included in the study, 41 with standard shunts and 34 with EM-navigated shunts. Seventy-four percent of navigated shunts were Grade 1 compared with 37% of the standard shunts (p=0.001, chi-square test). There were no Grade 3 placements in the navigated group, but 8 in the standard group, and 75% of these failed. Early shunt failure occurred in 9 patients in the standard group and in 2 in the navigated group, reducing the early revision rate from 22 to 5.9% (p=0.048, Fisher exact test). Early shunt failures were due to proximal obstruction in 78% of standard shunts (7 of 9) and in 50% of EM-navigated shunts (1 of 2). CONCLUSIONS: Noninvasive EM image guidance in shunt surgery reduces poor shunt placement, resulting in a significant decrease in the early shunt revision rate.01 december 201