Absent B Cells, agammaglobulinemia, and Hypertrophic Cardiomyopathy in Folliculin-interacting Protein 1 Deficiency

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity

Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. Objectives: This study sought to test the association between the rs9349379 genotype and SCAD. Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model

International audienceBACKGROUND:Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodopa-induced dyskinesias (LID) in Parkinson's disease (PD). We assessed the effect on LID of dipraglurant, a potent selective mGluR5 receptor negative allosteric modulator in the gold-standard LID macaque model.METHODS:Dipraglurant (3, 10, and 30 mg/kg, by mouth) was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model of LID in a four-way crossover, single-dose, controlled study (n = 8).RESULTS:Dipraglurant inhibited dyskinesias in the LID macaque model, with best effect reached at 30 mg/kg dose with no alteration of levodopa efficacy.CONCLUSION:Acute challenges of dipraglurant were efficacious on choreic and dystonic LID in the MPTP-macaque model. Dipraglurant pharmacokinetic variables were similar to those of levodopa, suggesting that both drugs can be co-administered simultaneously in further studies

Targeting type-2 metabotropic glutamate receptors to protect vulnerable hippocampal neurons against ischemic damage

To examine whether metabotropic glutamate (mGlu) receptors have any role in mechanisms that shape neuronal vulnerability to ischemic damage, we used the 4-vessel occlusion (4-VO) model of transient global ischemia in rats. 4-VO in rats causes a selective death of pyramidal neurons in the hippocampal CA1 region, leaving neurons of the CA3 region relatively spared. We wondered whether changes in the expression of individual mGlu receptor subtypes selectively occur in the vulnerable CA1 region during the development of ischemic damage, and whether post-ischemic treatment with drugs targeting the selected receptor(s) affords neuroprotection

Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression

International audienceThere is growing evidence suggesting that antagonists of group II metabotropic glutamate receptors (mGluR2/3) exhibit antidepressant-like properties in several preclinical models of depression. However, all those studies have been performed using competitive group II non-selective orthosteric antagonists. In this study we extensively characterized a group II selective negative allosteric modulator (4-[3-(2,6-Dimethylpyridin-4-yl)phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one, namely RO4491533, Woltering et al., 2010) in several in vitro biochemical assays and in vivo models of depression. In vitro, RO4491533 completely blocked the glutamate-induced Ca(2+) mobilization and the glutamate-induced accumulation in [(35)S]GTP(γS) binding in cells expressing recombinant human or rat mGluR2 and in native tissues. Results from Schild plot experiments and reversibility test at the target on both cellular and membrane-based assays confirmed the negative allosteric modulator properties of the compound. RO4491533 was equipotent on mGluR2 and mGluR3 receptors but not active on any other mGluRs. RO4491533 has acceptable PK properties in mice and rats, is bioavailable following oral gavage (F = 30%) and brain-penetrant (CSF conc/total plasma conc ratio = 0.8%). RO4491533 appeared to engage the central mGluR2 and mGluR3 receptors since the compound reversed the hypolocomotor effect of an mGluR2/3 orthosteric agonist LY379268 in a target-specific manner, as did the group II orthosteric mGluR2/3 antagonist LY341495. RO4491533 and LY341495 dose-dependently reduced immobility time of C57Bl6/J mice in the forced swim test. Also, RO4491533 and LY341495 were active in the tail suspension test in a line of Helpless (H) mice, a putative genetic model of depression. These data suggest that mGluR2/3 receptors are viable targets for development of novel pharmacotherapies for depression