Expanding the phenotype of the truncating eIF2 pathogenic variant p.(Ile465Serfs*4) identified in two brothers with MEHMO syndrom

We describe two brothers with a truncating variant in EIF2S3 and expand the phenotypic description of MEHMO. Our cases had the previously described facial dysmorphic features, severe microcephaly, hypoglycaemia, hypothyreosis, epilepsy, hypertonus, obesity, micropenis and death due to multiorgan failure. Additionally, we describe hypothermia and reduced umbilical blood flow.

CSH RNA Interference Reduces Global Nutrient Uptake and Umbilical Blood Flow Resulting in Intrauterine Growth Restriction

Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development of intrauterine growth restriction (IUGR). To gain insight into the physiological consequences of CSH RNA interference (RNAi), the trophectoderm of hatched blastocysts (nine days of gestational age; dGA) was infected with a lentivirus expressing either a scrambled control or CSH-specific shRNA, prior to transfer into synchronized recipient sheep. At 90 dGA, umbilical hemodynamics and fetal measurements were assessed by Doppler ultrasonography. At 120 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies with the 3H2O transplacental diffusion technique at 130 dGA. Nutrient uptake rates were determined and tissues were subsequently harvested at necropsy. CSH RNAi reduced (p ≤ 0.05) both fetal and uterine weights as well as umbilical blood flow (mL/min). This ultimately resulted in reduced (p ≤ 0.01) umbilical IGF1 concentrations, as well as reduced umbilical nutrient uptakes (p ≤ 0.05) in CSH RNAi pregnancies. CSH RNAi also reduced (p ≤ 0.05) uterine nutrient uptakes as well as uteroplacental glucose utilization. These data suggest that CSH is necessary to facilitate adequate blood flow for the uptake of oxygen, oxidative substrates, and hormones essential to support fetal and uterine growth.

Pengaruh Diabetes Mellitus Gestasional Terhadap Sirkulasi Uteroplasenta

Diabetes mellitus pada kehamilan (Gestational diabetes mellitus/GDM) adalah intoleransi glukosa yang ditemukan pertama kali pada masa kehamilan dan sering menimbulkan komplikasi pada ibu yang mengandung maupun janin yang dikandung. Beberapa organ pada GDM mengalami perubahan struktur dan perubahan fungsi termasuk disfungsi endothel mikrosirkulasi dan makrosirkulasi fetoplasenta. Endothelium-derived Relaxing Factors (EDRF) khususnya prostasiklin dan nitrik oksid berperan penting dalam mengontrol sirkulasi fetoplasental. Endothel vaskuler pasien GDM mengalami disfungsi, sehingga sintesa dan pelepasan prostasiklin dan nitrik oksid (NO) mengalami gangguan sehingga tonus arteria meningkat. Peningkatan tonus arteri yang menuju uterus akan menurunkan aliran darah uteroplasenta dan akhirnya menurunkan umbilical blood flow (UmBF). Endothel pembuluh darah merupakan target utama dari stress oksidatif. Sintesa NO merupakan mekanisme penting yang mendasari perubahan pembuluh darah sistemik dan pembuluh darah uterine selama kehamilan. Beberapa evidensi penelitian membuktikan peranan NO dan ADMA pada kehamilan normal dan insufiensi plasenta. Dengan berkembangnya pengetahuan akan mekanisme gangguan jalur ADMA-NO, pilihan tambahan untuk intervensi terapetik akan dapat ditemukan. Tatalaksana GDM secara umum adalah dengan pengaturan diet, latihan fisik selama tidak ada kontraindikasi, pengawasan dan kontrol gula darah, dan terapi farmakologi Berbagai penelitian lain terus berusaha menemukan terapi-terapi baru untuk memperbaiki endothel dan sirkulasi uteroplasenta pada pasien GDM.