Poulton Joanna, Finsterer Josef, Yu-Wai-Man Patrick
Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK.
Krankenanstalt Rudolfstiftung, Postfach 20, 1180, Vienna, Austria.
Mol Diagn Ther. 2017 Aug;21(4):419-429. doi: 10.1007/s40291-017-0279-7.
The aim of this review was to provide an evidence-based approach to frequently asked questions relating to the risk of transmitting a maternally inherited mitochondrial disorder (MID). We do not address disorders linked with disturbed mitochondrial DNA (mtDNA) maintenance, causing mtDNA depletion or multiple mtDNA deletions, as these are autosomally inherited. The review addresses questions regarding prognosis, recurrence risks and the strategies available to prevent disease transmission. The clinical and genetic complexity of maternally inherited MIDs represent a major challenge for patients, their relatives and health professionals. Since many of the genetic and pathophysiological aspects of MIDs remain unknown, counselling of affected patients and at-risk family members remains difficult. MtDNA mutations are maternally transmitted or, more rarely, they are sporadic, occurring de novo (25%). Females carrying homoplasmic mtDNA mutations will transmit the mutant species to all of their offspring, who may or may not exhibit a similar phenotype depending on modifying, secondary factors. Females carrying heteroplasmic mtDNA mutations will transmit a variable amount of mutant mtDNA to their offspring, which can result in considerable phenotypic heterogeneity among siblings. The majority of mtDNA rearrangements, such as single large-scale deletions, are sporadic, but there is a small risk of recurrence (4%) among the offspring of affected women. The range and suitability of reproductive choices for prospective mothers is a complex area of mitochondrial medicine that needs to be managed by experienced healthcare professionals as part of a multidisciplinary team. Genetic counselling is facilitated by the identification of the underlying causative genetic defect. To provide more precise genetic counselling, further research is needed to clarify the secondary factors that account for the variable penetrance and the often marked differential expressivity of pathogenic mtDNA mutations both within and between families.
本综述的目的是为与母系遗传线粒体疾病（MID）传播风险相关的常见问题提供基于证据的方法。我们不涉及与线粒体DNA（mtDNA）维持紊乱相关的疾病，这些疾病会导致mtDNA耗竭或多个mtDNA缺失，因为它们是常染色体遗传的。本综述探讨了有关预后、复发风险以及可用于预防疾病传播的策略等问题。母系遗传MID的临床和遗传复杂性对患者及其亲属以及医疗专业人员构成了重大挑战。由于MID的许多遗传和病理生理方面仍不清楚，因此对受影响患者和高危家庭成员的咨询仍然很困难。mtDNA突变是母系遗传的，或者更罕见的是，它们是散发的，即从头发生（约25%）。携带纯质mtDNA突变的女性会将突变型传递给所有后代，这些后代可能会或可能不会根据修饰性的次要因素表现出相似的表型。携带异质mtDNA突变的女性会将可变数量的突变mtDNA传递给后代，这可能导致兄弟姐妹之间出现相当大的表型异质性。大多数mtDNA重排，如单个大规模缺失，是散发的，但受影响女性的后代中有较小的复发风险（约4%）。未来母亲的生殖选择范围和适用性是线粒体医学中一个复杂的领域，需要由经验丰富的医疗专业人员作为多学科团队的一部分来管理。确定潜在的致病基因缺陷有助于进行遗传咨询。为了提供更精确的遗传咨询，需要进一步研究以阐明导致家族内和家族间致病mtDNA突变外显率可变和表达差异往往明显的次要因素。
