Stability of the m.8993T->G mtDNA mutation load during human embryofetal development has implications for the feasibility of prenatal diagnosis in NARP syndrome

Background

Mitochondrial DNA (mtDNA) mutations cause a wide range of serious genetic diseases with maternal inheritance. Because of the high transmission risk and the absence of therapy in these disorders, at‐risk couples often ask for prenatal diagnosis (PND). However, because heteroplasmy load (coexistence of mutant and wild‐type mtDNA) may vary among tissues and with time, the possibility that a single fetal sample may not reflect the whole neonate impedes prenatal diagnosis of mtDNA diseases.

Methods

We performed 13 prenatal diagnoses for the NARP (neurogenic weakness, ataxia, retinitis pigmentosa) m.8993T→G mtDNA mutation (p.Leu156Arg) in the ATP synthase subunit 6 gene. Analyses were performed on chorionic villous (CVS) and/or amniocyte samples carried out at various stages of pregnancy, using a method enabling quantification of low DNA amounts.

Results

Maternal mutant loads ranged from 0 to 75% in blood and had no predictive value for the fetus status, except for women with no detectable mutant DNA, whose fetuses were consistently mutation‐free. In 8/13 PND, mutant load was <30%. These children are healthy at 2–7 years of age. In 5/13 PND, mutant load ranged from 65 to 100%, and parents preferred to terminate the pregnancies (15–22 weeks of gestation). Single‐cell analysis of 20 trophoblastic cells and 21 amniocytes isolated from two affected fetuses found an average mutant load close to the overall CVS and amniocyte mutant load, despite striking intercellular variation. The m.8993T→G mutant loads, assessed in 7, 17, 11, and 5 different tissues from 4 terminations, respectively, were identical in all tissues from a given individual (mean (SD) 78 (1.2)%, 91 (0.7)%, 74 (2)%, and 63 (1.6)% for the 4 fetuses, respectively).

Conclusions

Our results indicate that the placental/amniotic mutant loads do reflect the NARP mutant mtDNA load in the whole fetus, even when the sample amount is small, and suggest that heteroplasmy level remains stable during pregnancy, at least after 10 weeks of gestation. Although these data establish the feasibility of PND for this mutation, assessing more precisely the correlation between mutant load and disease severity should further help in interpreting PND results.     

超声诊断羊水过少与母子预后的临床分析

目的分析超声诊断晚期妊娠羊水过少对母子预后的影响。方法应用最大羊水暗区深度(AFD)和羊水指数(AFI)指标测定法，对诊断为羊水过少110例临床资料进行分析。结果绝对羊水过少组胎儿窘迫、低体重儿、新生儿窒息、羊水Ⅱ～Ⅲ度污染、过期妊娠、剖宫产发生率明显高于临界羊水过少组和正常羊水组。结论B超以AFD AFI方法结合诊断羊水过少准确率高，晚期妊娠羊水过少是引起围产儿预后不良的根本原因，以剖宫产终止妊娠是绝对羊水过少的必要措施。     

ELISA二种不同包被方法的原子力显微镜表征及活力比较

用原子力显微观察二种不同包被方法的ＥＬＩＳＡ聚苯乙烯板微孔，图象显示经醛化处理的聚苯乙烯板较常规物理吸附法包被致密，排列有序，有效结合位点增多。常规ＥＬＩＳＡ检测表明经醛化处理，板的灵敏度、特性及线性有较大的改善，提示ＥＬＩＳＡ的包被方法改进可以大大提高试剂检测水平。     

产前超声与MRI对胎儿先天性肺囊腺瘤样畸形分型的鉴别诊断

目的分析产前超声与MRI对胎儿先天性肺囊腺瘤样畸形分型的鉴别诊断。方法选取2018年1月至2019年8月本院收治并已被确诊为先天性肺囊腺瘤样畸形的36例胎儿作为研究对象,采用奇偶分组法将其分成参照组(18例)和研究组(18例)。参照组行产前MRI诊断,研究组行产前超声诊断。比较两种诊断方式的准确率、漏诊率、误诊率、囊肿体积大小以及异常和病灶位置的检出情况。结果研究组胎儿接受产前超声诊断的准确率为94.44%,高于参照组胎儿接受MRI诊断的83.33%,但两组数据比较,差异无统计学意义(P>0.05);参照组胎儿的误诊率为5.56%,高于研究组的0.00%,但两组数据比较,差异无统计学意义(P>0.05)。两组胎儿囊肿体积平均值比较,差异无统计学意义(P>0.05)。MRI检查中,胎儿异常发生率为33.33%(6/18),双侧病灶1例、单侧病灶17例;产前超声检查中,胎儿异常发生率为22.22%(4/18),双侧病灶2例、单侧病灶16例,两组胎儿异常发生率比较,差异无统计学意义(P>0.05)。结论产前超声与产前MRI均可对胎儿先天性肺囊腺瘤样畸形作出准确的观察及诊断,对疾病的分型和预后具有十分重要的作用,其中产前超声检查具有操作简便、价格实惠的特点,值得临床推广。     

Doppler Ultrasound in Canine Pregnancy

Objective. The aim of this article is to review the current knowledge of Doppler ultrasound in canine pregnancy. A brief introduction of Doppler principles and their applications in human obstetrics is also included. Methods. A review of the peer‐reviewed published literature was conducted of the articles pertaining to the use of Doppler ultrasound in canine pregnancy, general Doppler principles, and Doppler applications in human obstetrics. Results. In bitches, Doppler ultrasound has been used to assess ovarian, uterine, umbilical, fetal aorta, common carotid artery, and fetal caudal vena cava blood flow during normal gestation. Most of these vessels increase their blood flow during normal pregnancy. The resistive index and systolic/diastolic ratio of the uterine arteries have been recently described in an experimental pharmacologically induced model of abnormal canine gestation. Both indices progressively increase up to abortion, probably because of progesterone deprivation. Moreover, resistive index abnormalities have been found in canine cases of spontaneous abnormal gestations as described in human medicine. Conclusions. Doppler ultrasound is a useful method for assessing development of the placental and fetal circulation during normal and abnormal canine pregnancy. Further studies are still necessary to widely use this technique in clinical practice.     

Prenatal diagnosis of fetal chest lymphangioma.

OBJECTIVE: Prenatally diagnosed cystic nuchal hygroma is often associated with chromosomal anomalies and hydrops fetalis. Chest lymphangioma diagnosed later in gestation appears to be a completely different disease, with a low incidence of chromosomal and structural anomalies. METHODS: Two chest cavernous lymphangiomas of the fetus are presented. The sonographic images, chromosomal analyses, and macroscopic and microscopic evaluations are described. RESULTS: Fetal chest cavernous lymphangiomas were identified at 15 and 22 weeks' gestation. In the first case, the couple decided to interrupt gestation. In the second case, prenatal sonography showed a multilocular, cystic lymphangioma external to the chest wall with no flow on Doppler sonography. Follow-up sonography revealed normal fetal growth and slow enlargement of the cystic mass surrounding the left chest cavity. The neonate was delivered without complications and was treated surgically. CONCLUSIONS: The chest lymphangioma appears to be a lesion usually not associated with other congenital abnormalities. The prenatal diagnosis of chest wall lymphangioma is relatively easy sonographically, and the treatment of choice is surgical excision. The outcome is relatively favorable, with a low incidence of chromosomal and structural anomalies.     

Correlation between the content of albumin and carotenoids in human vitreous body during prenatal development

The dynamics of the content albumin and carotenoids in human fetal vitreous body during weeks 16–31 of gestation was studied. The maximum values of total albumin (1.42 mg) and carotenoids (276 ng) during the studied period were recorded on weeks 20–22. Albumin concentration peaked during week 17 (2.11×10⁻⁴ mol/liter) and carotenoids during weeks 16–17 (about 0.045×10⁻⁴ mol/liter) of prenatal development. By week 31, the concentrations and total content of albumin and carotenoids in the vitreous body decreased. The physiological role of the studied components of the vitreous body for prenatal development of human eye is discussed. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 11, pp. 522–525, November, 2007     

Haemolytic disease of the fetus and newborn: advancements in precision and prevention

In pregnant patients, the impact of blood type and the presence of red blood cell antibodies influence the course of the pregnancy and the health of the fetus and newborn infant. Throughout history, haemolytic disease of the fetus and newborn has played a fundamental role in the discovery of the blood group antibodies and their cognate antigens. The mid‐1900s were noted for the advent of Rh immunoglobulin. Now, the technological advancements in diagnosis and treatment of haemolytic disease of the fetus and newborn have provided the critical tools needed to support mothers with affected pregnancies. The knowledge of blood typing has been further refined with the explosion of understanding about blood group genes, particularly in the RH blood group. Genomic blood group typing, improvements in ultrasound technology and transfusion medicine progress have advanced the field. The care of women with potentially affected pregnancies has never been more robust. Despite this, the risk to the fetus is significant, and prevention strategies for maternal alloimmunization deserve continued attention.     

Dose‐response relationships between internally‐deposited uranium and select health outcomes in gaseous diffusion plant workers, 1948‐2011

Objective

To examine dose‐response relationships between internal uranium exposures and select outcomes among a cohort of uranium enrichment workers.

Methods

Cox regression was conducted to examine associations between selected health outcomes and cumulative internal uranium with consideration for external ionizing radiation, work‐related medical X‐rays and contaminant radionuclides technetium (⁹⁹Tc) and plutonium (²³⁹Pu) as potential confounders.

Results

Elevated and monotonically increasing mortality risks were observed for kidney cancer, chronic renal diseases, and multiple myeloma, and the association with internal uranium absorbed organ dose was statistically significant for multiple myeloma. Adjustment for potential confounders had minimal impact on the risk estimates.

Conclusion

Kidney cancer, chronic renal disease, and multiple myeloma mortality risks were elevated with increasing internal uranium absorbed organ dose. The findings add to evidence of an association between internal exposure to uranium and cancer. Future investigation includes a study of cancer incidence in this cohort.