Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Limburg, Netherlands.
J Med Genet. 2013 Feb;50(2):125-32. doi: 10.1136/jmedgenet-2012-101172.
Mitochondrial or oxidative phosphorylation diseases are relatively frequent, multisystem disorders; in about 15% of cases they are caused by maternally inherited mitochondrial DNA (mtDNA) mutations. Because of the possible severity of the phenotype, the lack of effective treatment, and the high recurrence risk for offspring of carrier females, couples wish to prevent the transmission of these mtDNA disorders to their offspring. Prenatal diagnosis is problematic for several reasons, and concern the often poor correlation between mutation percentages and disease severity and the uncertainties about the representativeness of a fetal sample. A new option for preventing transmission of mtDNA disorders is preimplantation genetic diagnosis (PGD), which circumvents these problems by transferring an embryo below the threshold of clinical expression.
We present the data on nine PGD cycles in four female carriers of mitochondrial diseases: three mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) (m.3243A>G), and one Leigh (m.8993T>G). Our threshold for transfer after PGD is 15% for the m.3243A>G mutation and 30% for the m.8993T>G mutation.
All four female carriers produced embryos eligible for transfer. The m.8993T>G mutation in oocytes/embryos showed more skewing than the m.3243A>G. In about 80% of the embryos the mutation load in the individual blastomeres was fairly constant (interblastomere differences <10%). However, in around 11% (in embryos with the m.3243A>G mutation only), the mutation load differed substantially (>15%) between blastomeres of a single embryo, mostly as a result of one outlier. The m.8993T>G carrier became pregnant and gave birth to a healthy son.
PGD provides carriers of mtDNA mutations the opportunity to conceive healthy offspring.
线粒体或氧化磷酸化疾病是相对常见的多系统疾病；大约 15%的病例是由母系遗传的线粒体 DNA（mtDNA）突变引起的。由于表型可能严重、缺乏有效治疗以及携带者女性后代的高复发风险，夫妇希望防止这些 mtDNA 疾病遗传给他们的后代。由于多种原因，产前诊断存在问题，包括突变百分比与疾病严重程度之间的相关性往往较差，以及对胎儿样本代表性的不确定性。预防 mtDNA 疾病传播的一个新选择是胚胎植入前遗传学诊断（PGD），它通过将胚胎转移到低于临床表达阈值来规避这些问题。
我们介绍了四名线粒体疾病携带者的九个 PGD 周期的数据：三名线粒体脑肌病、乳酸酸中毒和卒中样发作（MELAS）（m.3243A>G），以及一名 Leigh（m.8993T>G）。我们进行 PGD 后转移的阈值是 m.3243A>G 突变的 15%和 m.8993T>G 突变的 30%。
所有四名女性携带者都产生了符合转移条件的胚胎。卵母细胞/胚胎中的 m.8993T>G 突变比 m.3243A>G 更偏斜。在大约 80%的胚胎中，单个卵裂球的突变负荷相当稳定（卵裂球间差异<10%）。然而，在大约 11%（仅在 m.3243A>G 突变的胚胎中）的情况下，单个胚胎的卵裂球之间的突变负荷差异很大（>15%），主要是由于一个异常值。m.8993T>G 携带者怀孕并生下了一个健康的儿子。
PGD 为 mtDNA 突变携带者提供了生育健康后代的机会。
