Heteroplasmy and Copy Number in the Common m.3243A>G Mutation-A Post-Mortem Genotype-Phenotype Analysis
常见 m.3243A> G 突变中的异质性和拷贝数-死后基因型-表型分析
- 作者列表："Scholle LM","Zierz S","Mawrin C","Wickenhauser C","Urban DL
:Different mitochondrial DNA (mtDNA) mutations have been identified to cause mitochondrial encephalopathy, lactate acidosis and stroke-like episodes (MELAS). The underlying genetic cause leading to an enormous clinical heterogeneity associated with m.3243A>G-related mitochondrial diseases is still poorly understood. Genotype-phenotype correlation (heteroplasmy levels and clinical symptoms) was analysed in 16 patients (15 literature cases and one unreported case) harbouring the m.3243A>G mutation. mtDNA copy numbers were correlated to heteroplasmy levels in 30 different post-mortem tissue samples, including 14 brain samples of a 46-year-old female. In the central nervous system, higher levels of heteroplasmy correlated significantly with lower mtDNA copy numbers. Skeletal muscle levels of heteroplasmy correlated significantly with kidney and liver. There was no significant difference of heteroplasmy levels between clinically affected and unaffected patients. In the patient presented, we found >75% heteroplasmy levels in all central nervous system samples, without harbouring a MELAS phenotype. This underlines previous suggestions, that really high levels in tissues do not automatically lead to a specific phenotype. Missing significant differences of heteroplasmy levels between clinically affected and unaffected patients underline recent suggestions that there are additional factors such as mtDNA copy number and nuclear factors that may also influence disease severity.
: 不同的线粒体 DNA (mtDNA) 突变已被确定可引起线粒体脑病、乳酸酸中毒和卒中样发作 (MELAS)。导致与 m.3243A> G 相关的线粒体疾病相关的巨大临床异质性的潜在遗传原因仍知之甚少。分析了 16 例携带 m.3243A> G 突变的患者 (15 例文献病例和 1 例未报告病例) 的基因型-表型相关性 (异质性水平和临床症状)。MtDNA 拷贝数与 30 个不同死后组织样本的异源性水平相关，包括 14 个 46 岁女性的大脑样本。在中枢神经系统中，较高水平的异质性与较低的 mtDNA 拷贝数显著相关。骨骼肌异位水平与肾脏和肝脏显著相关。临床受累患者和未受累患者的异位血浆水平无显著差异。在呈现的患者中，我们在所有中枢神经系统样本中发现> 75% 的异位水平，没有携带 MELAS 表型。这强调了以前的建议，即组织中真正高水平的不会自动导致特定的表型。缺少临床受累患者和未受累患者之间的异质性水平的显著差异强调了最近的建议，即存在 mtDNA 拷贝数和核因子等其他因素也可能影响疾病严重程度。
METHODS:BACKGROUND:Ultrasound has been demonstrated to accurately diagnose rectal deep endometriosis (DE) and pouch of Douglas (POD) obliteration. The role of ultrasound in the assessment of patients who have undergone surgery for rectal DE and POD obliteration has not been evaluated. AIM:To describe the transvaginal ultrasound (TVS) findings of patients who have undergone rectal surgery for DE. MATERIALS AND METHODS:An observational cross-sectional study at a tertiary care centre in Sydney, Australia between January and April 2017. Patients previously treated for rectal DE (low anterior resection vs rectal shaving/disc excision) were recruited and asked to complete a questionnaire on their current symptoms. On TVS, POD state and rectal DE were assessed. Correlating recurrence of POD obliteration and/or rectal DE to surgery type and symptoms was done. RESULTS:Fifty-six patients were contacted; 22/56 (39.3%) attended for the study visit. Average interval of surgery to study visit was 52.8 ± 24.6 months. Surgery type breakdown was as follows: low anterior resection (56%) and rectal shaving/disc excision (44%). The prevalence of POD obliteration was 16/22 (72.7%) intraoperatively and 8/22 (36.4%) at study visit, as per the sliding sign. Nine patients (39.1%) had evidence on TVS of recurrent rectal DE. Recurrence of POD obliteration and rectal DE was not associated with surgery type or symptomatology. CONCLUSION:Despite surgery for rectal DE, many patients have a negative sliding sign on TVS, representing POD obliteration, and rectal DE. Our numbers are too small to correlate with the surgery type or their current symptoms.
METHODS::Minimally invasive surgery for complex endometriosis requires preoperative planning that intimately connects the gynecologic surgeon to the radiologist. Understanding the surgeon's perspective to endometriosis treatment facilitates a productive relationship that ultimately benefits the patient. We examine minimally invasive surgery for endometriosis and the key radiologic information which enable the surgeon to successfully negotiate patient counseling, preoperative planning, and an interdisciplinary approach to surgery.
METHODS:STUDY OBJECTIVE:Prior research collectively shows that endometriosis is inversely related to women's adiposity. The aim of this study was to assess whether this inverse relationship holds true by disease severity and typology. DESIGN:Cross sectional study among women with no prior diagnosis of endometriosis. SETTING:Fourteen clinical centers in Salt Lake City, Utah and San Francisco, California. PATIENTS:Four hundred and ninety five women, ages 18-44 years, were enrolled in the operative cohort of the Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) Study. INTERVENTIONS:Gynecologic laparoscopy/laparotomy, regardless of clinical indication. MEASUREMENTS AND MAIN RESULTS:Participants underwent anthropometric assessments, body composition, and body fat distribution ratios before surgery. Surgeons completed a standardized operative report immediately after surgery to capture revised ASRM staging (I to IV) and typology of disease (superficial [SE], ovarian endometrioma [OE], and deep infiltrating endometriosis [DIE]). Linear mixed models, taking into account within-clinical-center correlation were used to generate least square means (95% confidence intervals) to assess differences in adiposity measures by endometriosis stage (no endometriosis, I-IV) and typology (no endometriosis, SE, DIE, OE, OE + DIE) adjusting for age, race/ethnicity, and parity. While the majority of confidence intervals were wide and overlapping, three general impressions emerged: 1) women with versus without incident endometriosis had the lowest anthropometric/body composition indicators; 2) women with stage I or IV had lower indicators compared to women with stage II or III; and 3) women with OE and/or DIE tended to have the lowest indicators, while women with SE had the highest indicators. CONCLUSION:Our research highlights that the relationship between women's adiposity and endometriosis severity and typology may be more complicated than prior research indicates.