Berry-Kravis E.,Rush University Medical Center |
Des Portes V.,University of Lyon |
Des Portes V.,French National Center for Scientific Research |
Hagerman R.,University of California at Davis |
And 12 more authors.
Science Translational Medicine | Year: 2016
Fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autistic spectrum disorder, is typically caused by transcriptional silencing of the X-linked FMR1 gene. Work in animal models has described altered synaptic plasticity, a result of the up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling, as a putative downstreameffect. Post hoc analysis of a randomized, placebo-controlled, crossover phase 2 trial suggested that the selective mGluR5 antagonist mavoglurant improved behavioral symptoms in FXS patients with completely methylated FMR1 genes. We present the results of two phase 2b, multicenter, randomized, double-blind, placebocontrolled, parallel-group studies of mavoglurant in FXS, designed to confirmthis result in adults (n = 175, aged 18 to 45 years) and adolescents (n = 139, aged 12 to 17 years). In both trials, participants were stratified by methylation status and randomized to receive mavoglurant (25, 50, or 100 mg twice daily) or placebo over 12 weeks. Neither of the studies achieved the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist-Community Edition using the FXS-specific algorithm (ABC-CFX) after 12 weeks of treatment with mavoglurant. The safety and tolerability profile of mavoglurant was as previously described, with fewadverse events. Therefore, under the conditions of our study, we could not confirmthemGluR theory of FXS nor the ability of the methylation state of the FMR1 promoter to predictmavoglurant efficacy. Preclinical results suggest that future clinical trials might profitably explore initiating treatment in a younger population with longer treatment duration and longer placebo run-ins and identifying new markers to better assess behavioral and cognitive benefits. Source
Muhlstein J.,University of Lyon |
Golfier F.,University of Lyon |
Rittore C.,Unite Medicale des Maladies Auto Inflammatoires |
Hajri T.,University of Lyon |
And 5 more authors.
European Journal of Obstetrics Gynecology and Reproductive Biology | Year: 2011
Objectives: The NLRP7 gene (19q13.42) is associated with recurrent and/or familial hydatidiform moles. Several mutations, histopathological types and reproductive outcomes have been described. We studied our recurrent hydatidiform mole cases recorded since 1999 in order to identify links between clinic, histology and genetics. Study: We present here the gestational history and the spectrum of NLRP7 mutations in our French series. Design: We performed a retrospective study from clinical forms received for genetic diagnosis. Cases declaration was based on a voluntary initiative coming from French practitioners, subjected to patients' agreement. Results: Among 12 recurrent hydatidiform moles investigated, we identified 3 cases of confirmed homozygous NLRP7 mutation and 3 cases of heterozygous NLRP7 mutation. One patient bore a novel mutation p.Leu880Ser in a homozygous state. Conclusions: We here identified a new homozygous NLRP7 mutation. Unfortunately, no modern therapeutic option has proven effective to obtain evolutive pregnancies. Then, fundamental and clinical researches seem to be necessary. Moreover, collecting RHM cases is essential. © 2011 Elsevier Ireland Ltd. Source
Al Ageeli E.,Unite Fonctionnelle de Genetique Medicale |
Mignot C.,Unite Fonctionnelle de Genetique Medicale |
Afenjar A.,Unite Fonctionnelle de Genetique Medicale |
Whalen S.,Unite Fonctionnelle de Genetique Medicale |
And 8 more authors.
European Journal of Medical Genetics | Year: 2012
Myhre syndrome is a very rare condition described thirty years ago and related to mutations in the SMAD4 gene. It has been reported in 19 patients, including 13 males and 6 females before the recent finding of heterozygous mutations in the SMAD4 gene in 19 patients. It is characterized by mental retardation, short stature, muscle hypertrophy, limitation of joints movements, deafness, skeletal anomalies, and facial dysmorphism. Ophthalmological involvement includes hypermetropia and congenital cataract. We report here the new finding of retinal involvement including retinitis pigmentosa and maculopathy in two unrelated patients with Myhre syndrome. The patient with retinitis pigmentosa carried the p.I500T mutation in SMAD4, but no mutation was found in the patient with the maculopathy. © 2012. Source