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Mutations in the N-terminal WD40 domain of coatomer protein complex subunit a (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis, and nephritis. We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI). In [COPA.sup.R1142X] and [COPA.sup.R1058C] fibroblasts, we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines, albeit through a distinct molecular mechanism in comparison with mutations in the WD40 domain of COPA. We showed that CTD COPA mutations induce an activation of ER stress and NF-[kappa]B signaling in patient-derived primary cell lines. These results demonstrate the importance of the integrity of the CTD of COPA for COPI function and homeostatic intracellular trafficking, essential to ER homeostasis. CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinflammatory signaling., Introduction The COPA gene encodes coatomer protein complex subunit [alpha] (COPA) (1). COPA was described in 1991 as a coat subunit of Golgi derived non-clathrin-coated vesicles, later termed 'coatomer' (2, [...]

Introduction: Fetal surgery for open spina bifida (OSB) requires comprehensive preoperative assessment using imaging for appropriate patient selection and to evaluate postoperative efficacy and complications. We explored patient access and conduct of fetal magnetic resonance imaging (MRI) for prenatal assessment of OSB patients eligible for fetal surgery. We compared imaging acquisition and reporting to the International Society of Ultrasound in Obstetrics and Gynecology MRI performance guidelines. Material and methods: We surveyed access to fetal MRI for OSB in referring fetal medicine units (FMUs) in the UK and Ireland, and two NHS England specialist commissioned fetal surgery centers (FSCs) at University College London Hospital, and University Hospitals KU Leuven Belgium. To study MRI acquisition protocols, we retrospectively analyzed fetal MRI images before and after fetal surgery for OSB. Results: MRI for fetal OSB was accessible with appropriate specialists available to supervise, perform, and report scans. The average time to arrange a fetal MRI appointment from request was 4 ± 3 days (range, 0–10), the average scan time available was 37 ± 16 min (range, 20–80 min), with 15 ± 11 min (range, 0–30 min) extra time to repeat sequences as required. Specific MRI acquisition protocols, and MRI reporting templates were available in only 32% and 18% of units, respectively. Satisfactory T2‐weighted (T2W) brain imaging acquired in three orthogonal planes was achieved preoperatively in all centers, and 6 weeks postoperatively in 96% of FSCs and 78% of referring FMUs. However, for T2W spine image acquisition referring FMUs were less able to provide three orthogonal planes presurgery (98% FSC vs. 50% FMU, p < 0.001), and 6 weeks post‐surgery (100% FSC vs. 48% FMU, p < 0.001). Other standard imaging recommendations such as T1‐weighted (T1W), gradient echo (GE) or echoplanar fetal brain and spine imaging in one or two orthogonal planes were more likely available in FSCs compared to FMUs pre‐ and post‐surgery (p < 0.001). Conclusions: There was timely access to supervised MRI for OSB fetal surgery assessment. However, the provision of images of the fetal brain and spine in sufficient orthogonal planes, which are required for determining eligibility and to determine the reversal of hindbrain herniation after fetal surgery, were less frequently acquired. Our evidence suggests the need for specific guidance in relation to fetal MRI for OSB. We propose an example guidance for MRI acquisition and reporting. [ABSTRACT FROM AUTHOR]

Objectives: Prenatal surgery is offered for selected fetuses with open spina bifida (OSB) to improve long‐term outcome. We studied the effect of fetal OSB surgery on brain development using advanced magnetic resonance imaging (MRI) techniques to quantify the volume, surface area and shape of cerebral structures and to analyze surface curvature by means of parameters that correspond to gyrification. Methods: We compared MRI data from 29 fetuses with OSB before fetal surgery (mean gestational age (GA), 23 + 3 weeks) and at 1 and 6 weeks after surgery, with that of 36 GA‐matched control fetuses (GA range, 21 + 2 to 36 + 2 weeks). Automated super‐resolution reconstruction provided three‐dimensional isotropic volumetric brain images. Unmyelinated white matter, cerebellum and ventricles were segmented automatically and refined manually, after which volume, surface area and shape parameter (volume/surface area) were quantified. Mathematical markers (shape index (SI) and curvedness) were used to measure gyrification. Parameters were assessed according to lesion type (myelomeningocele vs myeloschisis (MS)), postoperative persistence of hindbrain herniation (HH) and the presence of supratentorial anomalies, namely partial agenesis of the corpus callosum (pACC) and heterotopia (HT). Results: Growth in ventricular volume per week and change in shape parameter per week were higher at 6 weeks after surgery in fetuses with OSB compared with controls (median, 2500.94 (interquartile range (IQR), 1689.70–3580.80) mm3/week vs 708.21 (IQR, 474.50–925.00) mm3/week; P < 0.001 and 0.075 (IQR, 0.047–0.112) mm/week vs 0.022 (IQR, 0.009–0.042) mm/week; P = 0.046, respectively). Ventricular volume growth increased 6 weeks after surgery in cases with pACC (P < 0.001) and those with persistent HH (P = 0.002). During that time period, the change in unmyelinated white‐matter shape parameter per week was decreased in OSB fetuses compared with controls (0.056 (IQR, 0.044–0.092) mm/week vs 0.159 (IQR, 0.100–0.247) mm/week; P = 0.002), particularly in cases with persistent HH (P = 0.011), MS (P = 0.015), HT (P = 0.022), HT with corpus callosum anomaly (P = 0.017) and persistent HH with corpus callosum anomaly (P = 0.007). At 6 weeks postoperatively, despite OSB fetuses having a lower rate of change in curvedness compared with controls (0.061 (IQR, 0.040–0.093) mm–1/week vs 0.094 (IQR, 0.070–0.146) mm–1/week; P < 0.001), reversing the trend seen at 1 week after surgery (0.144 (IQR, 0.099–0.236) mm–1/week vs 0.072 (IQR, 0.059–0.081) mm–1/week; P < 0.001), gyrification, as determined using SI, appeared to be increased in OSB fetuses overall compared with controls. This observation was more prominent in fetuses with pACC and those with severe ventriculomegaly (P‐value range, < 0.001 to 0.006). Conclusions: Following fetal OSB repair, volume, shape and curvedness of ventricles and unmyelinated white matter differed significantly compared with those of normal fetuses. Morphological brain changes after fetal surgery were not limited to effects on the circulation of cerebrospinal fluid. These observations may have implications for postnatal neurocognitive outcome. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]