An experimental study of executive function and social impairment in Cornelia de Lange syndrome

Background Extreme shyness and social anxiety is reported to be characteristic of adolescents and adults with Cornelia de Lange syndrome (CdLS); however, the nature of these characteristics is not well documented. In this study, we develop and apply an experimental assessment of social anxiety in a group of adolescents and adults with CdLS to determine the nature of the social difficulties and whether they are related to impairments in executive functioning. Methods A familiar and unfamiliar examiner separately engaged in socially demanding tasks comprising three experimental conditions with a group of individuals with CdLS (n = 25; % male = 44; mean age = 22.16; SD = 8.81) and a comparable group of individuals with Down syndrome (DS; n = 20; % male = 35; mean age = 24.35; SD = 5.97). Behaviours indicative of social anxiety were coded. The Behavior Rating Inventory of Executive Function-Preschool version, an informant measure of executive function, was completed by participants’ caregivers. Results Significantly less verbalisation was observed in the CdLS group than the DS group in conditions requiring the initiation of speech. In the CdLS group, impairments in verbalisation were not associated with a greater degree of intellectual disability but were significantly correlated with impairments in both planning and working memory. This association was not evident in the DS group. Conclusions Adolescents and adults with CdLS have a specific difficulty with the initiation of speech when social demands are placed upon them. This impairment in verbalisation may be underpinned by specific cognitive deficits, although further research is needed to investigate this fully

Cohesin Proteins Promote Ribosomal RNA Production and Protein Translation in Yeast and Human Cells

Cohesin is a protein complex known for its essential role in chromosome segregation. However, cohesin and associated factors have additional functions in transcription, DNA damage repair, and chromosome condensation. The human cohesinopathy diseases are thought to stem not from defects in chromosome segregation but from gene expression. The role of cohesin in gene expression is not well understood. We used budding yeast strains bearing mutations analogous to the human cohesinopathy disease alleles under control of their native promoter to study gene expression. These mutations do not significantly affect chromosome segregation. Transcriptional profiling reveals that many targets of the transcriptional activator Gcn4 are induced in the eco1-W216G mutant background. The upregulation of Gcn4 was observed in many cohesin mutants, and this observation suggested protein translation was reduced. We demonstrate that the cohesinopathy mutations eco1-W216G and smc1-Q843Δ are associated with defects in ribosome biogenesis and a reduction in the actively translating fraction of ribosomes, eiF2α-phosphorylation, and 35S-methionine incorporation, all of which indicate a deficit in protein translation. Metabolic labeling shows that the eco1-W216G and smc1-Q843Δ mutants produce less ribosomal RNA, which is expected to constrain ribosome biogenesis. Further analysis shows that the production of rRNA from an individual repeat is reduced while copy number remains unchanged. Similar defects in rRNA production and protein translation are observed in a human Roberts syndrome cell line. In addition, cohesion is defective specifically at the rDNA locus in the eco1-W216G mutant, as has been previously reported for Roberts syndrome. Collectively, our data suggest that cohesin proteins normally facilitate production of ribosomal RNA and protein translation, and this is one way they can influence gene expression. Reduced translational capacity could contribute to the human cohesinopathies

Potential immunological consequences of pharmacological suppression of gastric acid production in patients with multiple sclerosis

Corticosteroids are standard treatment for patients with multiple sclerosis experiencing acute relapse. Because dyspeptic pain is a common side effect of this intervention, patients can be given a histamine receptor-2 antagonist, proton pump inhibitor or antacid to prevent or ameliorate this disturbance. Additionally, patients with multiple sclerosis may be taking these medications independent of corticosteroid treatment. Interventions for gastric disturbances can influence the activation state of the immune system, a principal mediator of pathology in multiple sclerosis. Although histamine release promotes inflammation, activation of the histamine receptor-2 can suppress a proinflammatory immune response, and blocking histamine receptor-2 with an antagonist could shift the balance more towards immune stimulation. Studies utilizing an animal model of multiple sclerosis indicate that histamine receptor-2 antagonists potentially augment disease activity in patients with multiple sclerosis. In contrast, proton pump inhibitors appear to favor immune suppression, but have not been studied in models of multiple sclerosis. Antacids, histamine receptor-2 antagonists and proton pump inhibitors also could alter the intestinal microflora, which may indirectly lead to immune stimulation. Additionally, elevated gastric pH can promote the vitamin B12 deficiency that patients with multiple sclerosis are at risk of developing. Here, we review possible roles of gastric acid inhibitors on immunopathogenic mechanisms associated with multiple sclerosis

Diagnosis and management of Cornelia de Lange syndrome:first international consensus statement

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome

We found that the clinical phenotype associated with BRD4 haploinsufficiency overlapped with that of Cornelia de Lange syndrome (CdLS), which is most often caused by mutation of NIPBL. More typical CdLS was observed with a de novo BRD4 missense variant, which retained the ability to coimmunoprecipitate with NIPBL, but bound poorly to acetylated histones. BRD4 and NIPBL displayed correlated binding at super-enhancers and appeared to co-regulate developmental gene expression