Affichage des articles dont le libellé est FMR1. Afficher tous les articles
Affichage des articles dont le libellé est FMR1. Afficher tous les articles

11 juin 2017

Détection automatisée des porteurs de prémutation X fragile basée sur des phénotypes de calcul linguistique et cognitive

Aperçu: G.M.
Des millions de personnes à l'échelle mondiale sont à risque élevé de troubles neurodégénératifs, d'infertilité ou d'avoir des enfants handicapés à la suite de la prémutation X Fragile(FX), une anomalie génétique dans FMR1 qui est sous-diagnostiquée, la plupart des porteurs ne connaissent pas leur état.
Dans une approche novatrice du phénotypage, l'équipe a utilisé des enregistrements audio et des profils cognitifs évalués via des questionnaires auto-administrés sur 200 femmes. Des méthodes d'apprentissage par machine ont été développées pour discriminer les porteurs de prématuration FX des mères d'enfants avec un diagnostic de "troubles du spectre de l'autisme", le groupe témoin. 
En utilisant des forêts d'arbres décisionnels, les porteurs de prématuration FX pourraient être identifiés de manière automatisée avec une haute précision et un rappel (score 0,81 F1). Les phénotypes linguistiques et cognitifs hautement associés aux porteurs de prématuration FX étaient une dysfluidité élevée du langage, une faible capacité à organiser du matériel et une faible auto-surveillance. Le cadre de la recherche définit les bases de stratégies de phénotypage computationnel pour présélectionner de grandes populations pour cette variante génétique avec des coûts nominaux. 


Sci Rep. 2017 Jun 1;7(1):2674. doi: 10.1038/s41598-017-02682-4.

Automated screening for Fragile X premutation carriers based on linguistic and cognitive computational phenotypes

Author information

1
Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
2
Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA.
3
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA.
4
Waisman Center, University of Wisconsin-Madison, Madison, WI, USA. marsha.mailick@wisc.edu.
5
Waisman Center, University of Wisconsin-Madison, Madison, WI, USA. audra.sterling@wisc.edu.
6
Department of Communication Sciences and Disorders, University of Wisconsin-Madison, Madison, WI, USA. audra.sterling@wisc.edu.
7
Department of Social Work, University of Wisconsin-Madison, Madison, WI, USA.
8
Waisman Center, University of Wisconsin-Madison, Madison, WI, USA. ksaha@wisc.edu.
9
Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA. ksaha@wisc.edu.
10
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA. ksaha@wisc.edu.

Abstract

Millions of people globally are at high risk for neurodegenerative disorders, infertility or having children with a disability as a result of the Fragile X (FX) premutation, a genetic abnormality in FMR1 that is underdiagnosed. Despite the high prevalence of the FX premutation and its effect on public health and family planning, most FX premutation carriers are unaware of their condition. Since genetic testing for the premutation is resource intensive, it is not practical to screen individuals for FX premutation status using genetic testing. In a novel approach to phenotyping, we have utilized audio recordings and cognitive profiling assessed via self-administered questionnaires on 200 females. Machine-learning methods were developed to discriminate FX premutation carriers from mothers of children with autism spectrum disorders, the comparison group. By using a random forest classifier, FX premutation carriers could be identified in an automated fashion with high precision and recall (0.81 F1 score). Linguistic and cognitive phenotypes that were highly associated with FX premutation carriers were high language dysfluency, poor ability to organize material, and low self-monitoring. Our framework sets the foundation for computational phenotyping strategies to pre-screen large populations for this genetic variant with nominal costs.
PMID:28572606
PMCID:PMC5454004
DOI:10.1038/s41598-017-02682-4

20 décembre 2007

Inherited Retardation And Autism Corrected In Mice

ScienceDaily — Researchers at MIT's Picower Institute for Learning and Memory have corrected key symptoms of mental retardation and autism in mice. They have significantly alleviated a wide range of abnormalities due to fragile X syndrome by altering only a single gene, countering the effects of the fragile X mutation.

The work also indicates that a certain class of drugs could have the same effect. These drugs are not yet approved by the FDA, but will soon be entering into human clinical trials. There is currently no treatment or therapy for fragile X syndrome, whose symptoms include mental retardation, epilepsy, and abnormal body growth.

Fragile X syndrome (FXS), affecting 100,000 Americans, is the most common inherited cause of mental retardation and autism. The MIT researchers corrected FXS in mice modeling the disease. "These findings have major therapeutic implications for fragile X syndrome and autism," said study lead author Mark F. Bear, director of the Picower Institute and Picower Professor of Neuroscience at MIT.

The findings support the theory that many of FXS's psychiatric and neurological symptoms-learning disabilities, autistic behavior, childhood epilepsy- stem from too much activation of one of the brain's chief network managers-the metabotropic glutamate receptor mGluR5.

"Fragile X is a disorder of excess-excess synaptic connectivity, protein synthesis, memory extinction, body growth, excitability-and remarkably, all these excesses can be reduced by reducing mGluR5," said Bear, a Howard Hughes Medical Institute investigator.

Individuals with FXS have mutations in the X chromosome's FMR1 gene, which encodes the fragile X mental retardation protein, FMRP. The MIT study found that FMRP and mGluR5 are at opposite ends of a kind of molecular seesaw. They keep each other in check, and without FMRP, mGluR5 signals run rampant.

Bear and colleagues study how genes and environment interact to refine connections in the brain. Synapses are the brain's connectors and their modifications are the basis for all learning and memory. There's a growing consensus among researchers that developmental brain disorders such as FXS, autism and schizophrenia should be considered "synapsopathies"- diseases of synaptic development and plasticity (the ability to change in response to experience).

Dendritic spines--little nubs on neurons' branchlike projections-receive many of the synaptic inputs from other neurons. Abnormal spines have long been associated with various forms of human mental retardation. In FXS, spines are more numerous, longer and more spindly than they should be. Thin spines tend to form weak connections.

The research team found that a 50 percent reduction in mGluR5 fixed multiple defects in the fragile X mice. In addition to correcting dendritic spines, reduced mGluR5 improved altered brain development and memory, restored normal body growth, and reduced seizures-many of the symptoms experienced by humans with FXS.

The researchers used genetic engineering to reduce mGluR5, but the same thing could be accomplished by a drug. Although not yet approved by the FDA, mGluR5 blockers are entering into human clinical trials. "Insights gained by this study suggest novel therapeutic approaches, not only for fragile X but also for autism and mental retardation of unknown origin," Bear said.

Earlier this year, MIT Picower Institute researcher Susumu Tonegawa and colleagues reported positive results using a different approach to reversing FXS symptoms. Tonegawa and colleagues identified a key enzyme called p21-activated kinase, or PAK, that affects the number, size and shape of connections between neurons.

This research is scheduled to be published in the Dec. 20 issue of Neuron. In addition to Bear, authors include Brown University graduate student Gul Dolen; Picower Institute postdoctoral fellow Emily Osterweil, B.S. Shankaranarayana Rao of the National Institute of Mental Health and Neuroscience in India; MIT graduate students Gordon B. Smith and Benjamin D. Auerbach; and Sumantra Chattarji of the National Center for Biological Sciences and Tata Institute of Fundamental Research in India.

This work is supported by the National Institute of Mental Health; the National Institute of Child Health and Human Development; the National Fragile X Foundation; FRAXA, a Fragile X research foundation; and the Simons Foundation.

Adapted from materials provided by Massachusetts Institute of Technology.