Bi-allelic <em>ACBD6</em> variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders

Does the primary route of spread have a prognostic significance in stage III non-serous epithelial ovarian cancer?

Background: The purpose of this retrospective study was to determine the prognosis of non-serous epithelial ovarian cancer (EOC) patients with exclusively retroperitoneal lymph node (LN) metastases, and to compare the prognosis of these women to that of patients who had abdominal peritoneal involvement. Methods: A multicenter, retrospective department database review was performed to identify patients with stage III non-serous EOC at 7 gynecologic oncology centers in Turkey. Demographic, clinicopathological and survival data were collected. The patients were divided into three groups based on the initial sites of disease: 1) the retroperitoneal (RP) group included patients who had positive pelvic and / or para-aortic LNs only. 2) The intraperitoneal (IP) group included patients with > 2 cm IP dissemination outside of the pelvis. These patients all had a negative LN status, 3) The IP / RP group included patients with > 2 cm IP dissemination outside of the pelvis as well as positive LN status. Survival data were compared with regard to the groups. Results: We identified 179 women with stage III non-serous EOC who were treated at 7 participating centers during the study period. The median age of the patients was 53 years, and the median duration of follow-up was 39 months. There were 35 (19.6%) patients in the RP group, 72 (40.2%) in the IP group and 72 (40.2%) in the IP/RP group. The 5-year disease-free survival (DFS) rates for the RP, the IP, and IP/ RP groups were 66.4%, 37.6%, and 25.5%, respectively (p = 0.002). The 5-year overall survival (OS) rate for the RP group was significantly longer when compared to those of the IP, and the IP/RP groups (74.4% vs. 54%, and 36%, respectively; p = 0.011). However, we were not able to define "RP only disease" as an independent prognostic factor for increased DFS or OS. Conclusions: Primary non-serous EOC patients with node-positive-only disease seem to have better survival when compared to those with extra-pelvic peritoneal involvement

Comparison of stage III mucinous and serous ovarian cancer: a case-control study

Background: The purpose of this case-control study was to compare the prognoses of women with stage III mucinous ovarian carcinoma (MOC) who received maximal or optimal cytoreduction followed by paclitaxel plus carboplatin chemotherapy to those of women with stage III serous epithelial ovarian cancer (EOC) treated in the similar manner. Methods: We performed a multicenter, retrospective review to identify patients with stage III MOC at seven gynecologic oncology departments in Turkey. Eighty-one women with MOC were included. Each case was matched to two women with stage III serous EOC in terms of age, tumor grade, substage of disease, and extent of residual disease. Survival estimates were measured using Kaplan-Meier plots. Variables predictive of outcome were analyzed using Cox regression models. Results: With a median follow-up of 54months, the median progression-free survival (PFS) for women with stage III MOC was 18.0months (95% CI; 13.8-22.1, SE: 2.13) compared to 29.0 months (95% CI; 24.04-33.95, SE: 2.52) in the serous group (p = 0.19). The 5-year overall survival rate of the MOC group was significantly lower than that of the serous EOC group (44.9% vs. 66.3%, respectively; p < 0.001). For the entire cohort, presence of multiple peritoneal implants (Hazard ratio [HR] 2.39; 95% confidence interval [CI], 1.38-4.14, p = 0.002) and mucinous histology (HR 2.28; 95% CI, 1.53-3.40, p < 0.001) were identified as independent predictors of decreased OS. Conclusion: Patients with MOC seem to be 2.3 times more likely to die of their tumors when compared to women with serous EOC

Relationship between organizational commitment and organizational silence: A study in the insurance industry

In the study, it was aimed to determine the effect of organizational commitment on organizational silence. In this context, the related research was conducted on 416 employees working in an insurance sector company in Istanbul. In the study, after the concepts of organizational commitment and organizational silence are presented in a theoretical framework, to measure organizational commitment; the scale of organizational commitment by Meyer and Allen, which Wasti and Can translated into Turkish and adapted, and the organizational silence scale developed by Dyne et al. (Journal of Management Studies 40(6), 1359–1392) was used to measure organizational silence. As a result of the questionnaires, the data were evaluated and the relationship between organizational commitment and organizational silence was tried to be explained. The results of multiple regression analysis, which measures the effect of organizational commitment on organizational silence, were interpreted by correlation analysis, which measures the relationships of organizational commitment and organizational silence subdimensions. The results of the T-tests and ANOVA (F) tests, which measure the relationship between demographic variables and research variables, are also included. As a result of the analyzes, it was found that among the subdimensions of organizational commitment, continuing commitment, normative and emotional commitment, only continuing commitment and emotional commitment had a significant effect on accepting silence