A hypomorphic allele of SLC35D1 results in Schneckenbecken-like dysplasia.

We report the case of a consanguineous couple who lost four pregnancies associated with skeletal dysplasia. Radiological examination of one fetus was inconclusive. Parental exome sequencing showed that both parents were heterozygous for a novel missense variant, p.(Pro133Leu), in the SLC35D1 gene encoding a nucleotide sugar transporter. The affected fetus was homozygous for the variant. The radiological features were reviewed, and being similar, but atypical, the phenotype was classified as a 'Schneckenbecken-like dysplasia.' The effect of the missense change was assessed using protein modelling techniques and indicated alterations in the mouth of the solute channel. A detailed biochemical investigation of SLC35D1 transport function and that of the missense variant p.(Pro133Leu) revealed that SLC35D1 acts as a general UDP-sugar transporter and that the p.(Pro133Leu) mutation resulted in a significant decrease in transport activity. The reduced transport activity observed for p.(Pro133Leu) was contrasted with in vitro activity for SLC35D1 p.(Thr65Pro), the loss-of-function mutation was associated with Schneckenbecken dysplasia. The functional classification of SLC35D1 as a general nucleotide sugar transporter of the endoplasmic reticulum suggests an expanded role for this transporter beyond chondroitin sulfate biosynthesis to a variety of important glycosylation reactions occurring in the endoplasmic reticulum.

Magnetic resonance imaging of the fetus.

Fetal magnetic resonance imaging (MRI) has become established as part of clinical practice in many centres worldwide especially when visualization of the central nervous system pathology is required. In this review we summarize the recent literature and provide an overview of fetal development and the commonly encountered fetal pathologies visualized with MRI and illustrated with numerous MR images. We aim to convey the role of fetal MRI in clinical practice and its value as an additional investigation alongside ultrasound yet emphasize the need for caution when interpreting fetal MR images especially where experience is limited.

Reproducibility and repeatability of measuring the electrical impedance of the pregnant human cervix-the effect of probe size and applied pressure.

BACKGROUND: The utility of cervical electrical impedance spectroscopy (EIS) as a diagnostic tool is being investigated in clinical trials. We sought to assess the reliability of two different sizes of tetrapolar probes used in measuring cervical impedance. METHODS: Cervical transfer impedance was measured at 14 frequencies between 76 and 625 000 Hz from 11 pregnant subjects at term. Repeated measurements were taken with two probes (3 mm and 12 mm diameter) applied softly (approximately 0.7 Newton of force), and firmly (approximately 2.2 Newton) to the surface of the cervix by two observers. The intra-class correlation coefficient (ICC), coefficient of variation (CV) and repeatability standard deviations (SD) were derived from these measurements and compared. RESULTS: Measurements taken by one observer were highly repeatable for both probes as demonstrated by high ICC and low CV values. Probe performance was improved further by firm application. Firm application of the 3 mm probe resulted in ICC values that ranged from 0.936 to 0.986 (p = 0.0001) and CV values between 1.0 and 3.4%. Firm pressure with the 12 mm probe resulted in ICC values that ranged between 0.914 and 0.988 (p = 0.0001) with CV values between 0.7 and 2.1%. In addition, the repeatability SD was low across all frequencies implying that there was low intra-observer variability. Measurements taken by 2 observers with firm application of the 12 mm probe demonstrated moderate reproducibility between 9.8 and 156 kHz, the frequency range in which previous clinical studies have shown predictive association between high cervical resistivity and vaginal delivery: ICC values ranged between 0.528 and 0.638 (p < 0.05), CV values were between 3.3 and 5.2% and reproducibility SD values were also low. In contrast the 3 mm probe demonstrated poor reproducibility at all study frequencies. CONCLUSION: Measuring cervical resistivity by a single observer with both the 3 and 12 mm probes is highly repeatable whilst inter-observer reproducibility is poor with the 3 mm probe but moderately good when the 12 mm probe is firmly applied to the cervix in the frequency range 9.8 to 156 kHz, consistent with our observations of probe performance in clinical trials.

The role of cervical Electrical Impedance Spectroscopy in the prediction of the course and outcome of induced labour.

BACKGROUND: Previous work by us and others had suggested that cervical electrical impedance spectroscopy (EIS) may be predictive of the outcome of induced labour. We sought to determine which probe configuration of the EIS device is predictive of the outcome of induced labour and compare this to digital assessment by the Bishop score. METHODS: In a prospective cohort of 205 women admitted for induction of labour, we used four probes of diameter 3, 6, 9 and 12 mm connected to an impedance meter to measure cervical resistivity (CR) in Ohm.meters at 14 electrical frequencies and compared their values to digital assessment of the cervix by the Bishop score for the prediction of the outcome of induced labour. We tested the association of labour characteristics and outcomes with CR and Bishop score by stepwise multilinear regression analyses, and the accuracy of prediction of categorical clinical outcomes by analysis of the area under the curves (AUC) of derived Receiver Operator Characteristic (ROC) curves. RESULTS: Of the four CR probe dimensions studied, only the 12 mm probe was predictive of any labour indices. In the frequency range 19 - 156 kHz, CR obtained with this probe was higher in women who delivered by caesarean section (CS) than those who delivered vaginally, and in labours lasting > 24 hrs. Cervical resistivity at 78.1 kHz best predicted vaginal delivery [optimal cut-off <2.25 Ohm.meter, AUC 0.66 (95% CI 0.59-0.72), sensitivity 71.0%, specificity 56.5%, LR+ 1.63, LR- 0.51, P < 0.01] and labour duration >24 hrs [optimal cut-off 2.27 Omega.m, AUC 0.65 (95% CI 0.58, 0.72), sensitivity 71%, specificity 59%, LR+ 1.72, LR- 0.50, P < 0.05]. In contrast digital assessment by the Bishop score neither predicted vaginal delivery nor the duration of labour. However, Bishop score predicted time to onset of labour > 12 hours and induction-delivery interval < 24 hrs [optimal cut-off

The impact of mitochondrial genetics on male infertility.

Summary Human mitochondrial DNA (mtDNA) encodes 13 of the polypeptides associated with the process of oxidative phosphorylation (OXPHOS), the cells most important ATP generating pathway. Until recently, the effects of mtDNA rearrangements on male fertility have been largely ignored. However, it is becoming increasingly evident that both point mutations and large-scale deletions may have an impact on sperm motility and morphology. We discuss the implications of these rearrangements in the context of the clinical setting. We further discuss the possible consequences resulting from the transmission of sperm mtDNA deletions to the offspring. The role of nucleo-cytoplasmic interaction is investigated in the context of nuclear transcription and replication factors that regulate mtDNA transcription and replication.