Fawaz Alkazaleh

Mutations in PYCR1 cause cutis laxa with progeroid features.

Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation. Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high-throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1. We found that the gene product, an enzyme involved in proline metabolism, localizes to mitochondria. Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis. Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues.

Vascular limb occlusion in twin-twin transfusion syndrome (TTTS): Case series and literature review

OBJECTIVE The purpose of this study was to evaluate the phenomenon of vascular ischemic limb necrosis in twin-twin transfusion syndrome (TTTS). STUDY DESIGN This was a multicenter retrospective review of ischemic limb necrosis in patients with TTTS. RESULTS Twenty cases of fetal ischemic limb necrosis in association with TTTS were identified from 10 fetal medicine centers. The recipient was affected in 19 cases, and the lower limb was affected in 17 cases. The extent of the damage correlated with TTTS severity. Eighty percent of limb defects (16/20) clearly were unrelated to laser treatment (3 cases untreated, 7 cases after amnioreduction, 6 cases present at time of laser). The recipient was relatively polycythemic in 5 of 7 cases in which neonatal or fetal hemoglobin/hematocrit levels were available. CONCLUSION Ischemic limb necrosis is a rare complication of TTTS. The lesion is unrelated to therapy and may be the result of polycythemia, hypertension, and vasoconstriction.

Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.

Perceptions and Expectations among Pregnant Women Receiving Second-Trimester Ultrasound Scans at Jordan University Hospital

Objectives: To evaluate women’s information about the purpose of the second-trimester ultrasound scan, their expectations before the scan, the extent to which these expectations are fulfilled after the scan, and their perceptions of the foetus. Methods: A sample of pregnant women (540) attending a second-trimester ultrasound scan at Jordan University Hospital were asked to complete two parts of a questionnaire during a 3-month period in 2011. The first part included patients’ characteristics, the purpose of the scan, and expectations before the scan. The second part included patients’ perceptions of the foetus and how the expectations of the scan were fulfilled. Results: Both parts of the questionnaires were completed by 503 (93%) of the women. Three fourths of the participants were accompanied by their husband or a family member. Sixty (12%) women were referred specifically to rule out congenital anomalies. Comparison between patients’ expectations before and after the scan using the chi-square test showed significant improvement in all expectations variables (P–value < 0.001). Conclusion: A routine second-trimester ultrasound scan is an important event for most participating women. Improvements are required in the provision of pre-ultrasound information.

OC120: Vascular limb occlusion in severe twin–twin transfusion syndrome (TTTS)

were reviewed. Peri-operative factors studied included maternal characteristics, severity of the fetal syndrome and characteristics of surgical procedures and were collected prospectively but analysed retrospectively. Primary outcome was survival > 28 days without severe impairment. Univariate and multivariate analyses using logistic regression were performed. Results: Ten of a total of 323 cases were lost to follow-up and excluded from further analysis. Overall survival rate of at least one twin (Outcome 1) and survival of both twins (Outcome 2) without severe impairment was 65% and 28% respectively. Univariate analysis found that estimated fetal weight at diagnosis (EFW), weight discordance and a high percentage of selective coagulations were significantly related to both outcomes. Quintero stages and amniotic fluid drained > 1.5 L were also significant factors for Outcome 1, whereas gestational age at diagnosis and previous history of miscarriage were additional significant factors for Outcome 2. Recipient’s EFW (OR 2.2; 95% CI, 1.3–3.6) and the number of selective coagulations (OR 1.9; 95% CI, 1.2–3.1) were independently predictive of Outcome 1 in multivariate analysis. Donor’s EFW (OR 1.95; 95% CI, 1.16–3.30), the number of selective coagulations (OR 1.85; 95% CI, 1.09–3.14) and a previous history of miscarriage (OR 0.30; 95% CI, 0.13–0.70) were independently predictive of Outcome 2. Conclusions: In severe TTTS treated by fetoscopic laser coagulation, perioperative prognosis is based upon EFW, previous history of miscarriage and the degree of selectivity of the procedure.