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L'X fragile sera vaincu | Fragile X will be conquered

Archive for Randi Hagerman

Studies highlight promise of fragile X treatment

Jessica Wright, 30 April 2012 |

A promising approach to treating fragile X syndrome could benefit people even after the critical window of early brain development, and alleviate core symptoms of autism, according to two studies published this month.

Fragile X syndrome is caused by the loss of a single protein, FMRP, and is characterized by intellectual disability, unusual physical features and hyperactivity. As many as 30 percent of individuals with the syndrome also have autism; however, the underlying biology of fragile X syndrome may be distinct from that of autism.

The first study, published 12 April in Neuron, provides the first published evidence that many symptoms of fragile X syndrome may be reversible after they have developed1.

Although the results were shown only in mice, they suggest that a similar effect might be seen in people with the disorder, researchers say.

“Parents of adult patients have always thought that these kinds of new treatments might be too late for them, but this gives them a lot of hope,” saysRandi Hagerman, medical director of the MIND Institute at the University of California, Davis. Hagerman was not involved in the new study, but is conducting clinical trials for fragile X therapeutics.


Drug trials for fragile X syndrome lead the way for autism therapies

Randi Hagerman, Sfari.org |

A number of targeted trials on drugs that have the potential to reverse many of the behavioral and cognitive features of fragile X syndrome, are under way. Human and animal studies have shown that these medications can reverse many of the neurobiological and phenotypic features of fragile X syndrome. Along with these new trials, we will need accurate endpoints that can reliably measure the drugs’ effectiveness.

Fragile X syndrome is the most common inherited cause of intellectual disability and single-gene cause of autism. The full mutation has more than 200 repeats of a DNA sequence — CGG — at the front end of the FMR1 gene. This repeat number leads to a shutdown of the gene and a lack of the protein that it normally produces, fragile X mental retardation protein, or FMRP. The lack of FMRP causes fragile X syndrome and intellectual disability, in addition to autism, in 30 percent of individuals and pervasive developmental disorder-not otherwise specified in another 30 percent.

Between 55 and 200 repeats in the FMR1 gene causes what is called a premutation. The premutation leads to autism at a much lower rate — approximately ten percent of boys and less than two percent of girls.

The fragile X mutations cause autism through different molecular pathways. The absence or deficiency of FMRP affects the levels of many genes important for synaptic plasticity — how neurons strengthen important connections — and the outgrowth of neurites, the formation of new connections between neurons.

The fragile X premutation leads to higher levels of the RNA message for the FMR1 gene, which can bind to important proteins and dysregulate neuronal functions, leading to early cell death.

Promising trials:

Novartis and Roche both have an inhibitor of mGluR5, which activates a pathway that is overactive in those with fragile X syndrome.


FMRP function throughout life leading to targeted treatments for FXS

PubMed Central / ncbi.nlm.nih.gov |


FMRP is an mRNA-binding protein that is important for mRNA transport, mRNA stabilization and translation of mRNA into protein at the synapse [129-131]. FMRP is also a factor in the regulation of adult neurogenesis, so in the absence of FMRP there is dysregulation of glycogen synthase kinase (GSK)3β, reduced β-catenin and defective Wnt signaling. These alterations lead to downregulation of neurogenin 1, which is an early initiator of neuronal differentiation and an inhibitor of astrocyte differentiation [132]. Therefore, FMRP is important throughout life and there is a high incidence of motor problems, including Parkinson disease (PD), with aging in those with FXS [133]. In addition, in neuropathologic studies, there is evidence of migration problems in the hippocampus and in the cerebellum in those with FXS (Greco et al,. unpublished data), which are similar to those reported in individuals with autism [134]. These problems may be related to dysregulation of Wnt signaling in both FXS and autism.

Perhaps the most important change in protein expression in the absence of FMRP is the excess basal translation of proteins involved in the metabotropic glutamate receptor (mGluR) 5 receptor pathway [135]. Bear and colleagues have proposed the mGluR theory of FX, suggesting that the deficits associated with FXS are related to upregulation of the downstream effectors of the mGluR5 pathway, leading to enhanced long-term depression (LTD), and that treatment with an mGluR5 antagonist could be a targeted treatment for FXS [135,136]. Both FMRP and mGluRs play important roles in synaptogenesis and synaptic plasticity, and in the absence of FMRP there are long, thin and immature dendritic spines in both human and animal models of FXS [137-142]. There are also enhanced, abnormal epileptiform discharges consistent with an enhanced rate of clinical seizures in FXS [143,144].

Support for the ‘mGluR theory’ has been shown by generating FMR1 mutant mice with a 50% reduction in mGluR5 expression [145]. The mGluR5 deficiency rescued most of the KO mouse abnormalities including altered ocular dominance plasticity, increased density of dendritic spines on cortical pyramidal neurons, increased basal protein synthesis in the hippocampus, exaggerated inhibitory avoidance extinction, audiogenic seizures and accelerated body growth. However, macroorchidism was not rescued. This work is supportive of the proposal by Bear et al. [146]that excessive mGluR5 signaling is responsible for the psychiatric and neurological symptoms of FXS, including cognitive deficits, seizures, anxiety, perseverative movements and social deficits.

Use of mGluR5 antagonists in animal models of FXS further supports the mGluR theory. MPEP (2-methyl-6-phenylethynyl pyridine hydrochloride) is a potent, highly selective antagonist of mGluR5 receptors [147]. In vitro, both MPEP and fenobam, another mGluR5 antagonist, were able to rescue hippocampal dendritic abnormalities in the KO mice [148,149]. MPEP has reversed audiogenic seizures, epileptiform discharges, open field hyperactivity and the defect in prepulse inhibition (PPI) of the startle response in KO mice [148-150]. When MPEP and lithium, a partial mGluR5 antagonist that also blocks GSK3β, were given to dfmr1 loss of function Drosophila mutants, the flies had restored normal courtship behavior, memory and brain structural abnormalities through the reduction of mGluR activity [151]. MPEP is toxic to humans, so other mGluR5 antagonists including fenobam have been studied in FXS [152,153]. Fenobam was found to be safe in a single dose trial in 12 adults with FXS. There were improvements in hyperactivity and anxiety, and 50% showed at least a 20% improvement in PPI [152]. Currently there are two additional mGluR5 antagonists undergoing trials in adults with FXS at multiple centers [153].

Other mechanisms to downregulate glutamate release and modulate mGluR overactivity have been investigated. γ Aminobutyric acid (GABA)B receptor agonists, such as baclofen, inhibit both presynaptic release of glutamate and postsynaptic transmission and/or intracellular signaling downstream from mGluR5 [154-156]. Baclofen has been shown to be efficacious in treating hyperactivity [157], marble burying (Seaside Therapeutics, unpublished data) and audiogenic seizure phenotypes in FX KO mice [158]. A double-blind, placebo-controlled, crossover trial of arbaclofen, the right sided isomer of baclofen that is significantly more potent than regular baclofen as a GABA agent, has just been completed at multiple centers,and involved over 60 individuals with FXS (aged 6 years and older). The preliminary safety and efficacy results are positive, with improvement in the Clinical Global Impression Improvement scale in those with the most severe baseline ratings [159]. There are also preliminary studies that are taking place involving individuals with autism without FXS, and these studies have also produced preliminary positive results. Therefore, further studies on both FXS and autism are set to take place.

The GABAergic system is also dysregulated in FXS, and GABA agents are important to consider for targeted treatment studies in FXS. GABA is a major inhibitory neurotransmitter receptor in the brain, which is important in anxiety, depression, epilepsy, insomnia, and learning and memory [160]. GABA-mediated inhibition is important for terminating ictal discharges and the spread of hyperexcitability, which can lead to seizures [161].

There are two main subtypes of GABA receptors: GABAA and GABAB. The main difference between them is that the first is a ligand gated Cl- channel that gives fast inhibition, whereas the latter is a G-protein coupled receptor which gives slower and more prolonged inhibitory signals [162,163]. The metabotropic GABAB receptor can either be presynaptic and inhibit the release of neurotransmitters through downregulation of high-voltage activated Ca2+-channels; or, when postsynaptic, decrease neuronal excitability through its influence on K+ channels. Thus, GABAB agonists such as arbaclofen mediate their downregulating effects on either side of the synapse. The ionotropic GABAA receptor is usually localized postsynaptically, and their activation leads to opening of Cl- channels and hyperpolarization of the membrane potential, thus making it difficult for excitatory neurotransmitters such as glutamate to generate an action potential. GABAA receptors are more abundant than GABAB receptors in mammalian brain, and disorders such as epilepsy, sleep disorders and anxiety are now being treated using drugs that act on the GABAA receptor[164].

Direct binding between FMRP and the mRNA of the delta subunit of the GABAA receptor has been shown [165]. Reduced expression and dysfunction of several subunits of the GABAA receptor (α1, α3, α4; β1, β2; γ1, γ2 and δ) have been shown in FX animal models [166-168]. FMR1 Drosophila mutants destined to die from glutamate toxicity were rescued after administering molecules involved in the GABAergic pathway [166]. In addition, abnormal male courtship behavior and mushroom body abnormalities were rescued by GABA agents [166].

There is a profound reorganization of neocortical inhibitory circuits of GABAergic intraneurons in the KO mouse [164,167-173]. Recent evidence indicates that deficits in GABA-mediated inhibition may underlie many of the key symptoms in FXS, including the seizures, anxiety and autistic-like behaviors [167,169,173]. The neocortex in KO mice exhibits a marked reduction in the density of GABAergic interneurons that stain with parvalbumin. Moreover, electrophysiological studies in brain slices from these animals exhibit impaired GABAA receptor-mediated inhibitory function [174]. In addition to a gross reduction in GABA-mediated inhibition caused by the maldevelopment of inhibitory circuits and the loss of GABAergic interneurons, there is also evidence of altered GABAA receptor subunit expression in the FX KO mouse [167]. In particular, there appears to be a selective reduction in the expression of δ subunits [167,168]. Global expression analysis by means of the differential display in the FX mouse model revealed consistent underexpression of only three genes, one of which was the GABAA receptor subunit δ. As GABAA receptors are the major inhibitory receptors in the brain, and are specifically involved in processes that are disturbed in FX, including neuronal excitability (leading to enhanced seizure susceptibility), anxiety, sleep and learning, enhancement of the function of GABAA receptors may have major therapeutic benefits for FXS. Kooy and colleagues [175] have demonstrated that use of the GABAA agonist ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one) improved seizures in the KO mouse model of FXS. Ganaxolone is a 3β-methylated synthetic analog of the progesterone metabolite allopregnanolone, which is itself a neuroactive steroid. Unlike progesterone, neither allopregnanolone nor ganaxolone have direct hormonal activity via progesterone receptor activation, and cannot cause hormonal side-effects. However, allopregnanolone and ganaxolone are powerful positive allosteric modulators of GABAA receptors [161]. Human trials indicate that ganaxolone is well tolerated and that it may be efficacious in the treatment of diverse forms of epilepsy in children and adults [176-180]. Plans for studies on ganaxolone are currently underway in children and adults with FXS.

Minocycline, a widely used antibiotic used to treat acne and skin infections, is another promising drug that may target core symptoms of FXS and autism. Minocycline inhibits matrix metalloproteinase (MMP)-9 and reduces inflammation in the central nervous system. MMPs are enzymes involved in synaptic plasticity, and are associated with immature dendritic spine morphology [140,181]; MMP-9 is elevated in FXS. When minocycline was administered to FMR1 KO mice, their hippocampal neurons exhibited mature dendritic spines, and behaviorally, they showed decreased anxiety and improved exploration skills [140]. Off-label use of minocycline to treat 50 individuals with FXS resulted in two-thirds of families noticing positive improvements in their child’s language, attention and/or behavioral improvements while on the medication [182]. An open-label trial is ongoing to investigate the effects of minocycline on children with regressive autism at the National Institute of Mental Health (NIMH). Paribello reported beneficial effects on the CGI and the Aberrant Behavior checklist in an open trial of minocycline involving patients with FXS who were aged 13 and older [183]. Currently, a double-blind, placebo-controlled clinical trial is in progress at the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute for individuals with FXS who are aged 3.5 to 16 years

FXS has led the way for targeted treatments in neurodevelopmental disorders, and many of the treatments guided by molecular abnormalities in FXS may also be helpful for non-FX autism. The treatment trials will now combine targeted treatments, which strengthen synaptic connections, with enhanced educational and behavioral interventions to further develop appropriate synaptic connections in FXS. These targeted treatments combined with educational interventions look promising for reversing the intellectual and behavioral problems of FXS. Because of the shared neurobiological and molecular pathways, these interventions will hopefully also prove helpful in a subset of patients with idiopathic autism



FX syndrome and autism are intertwined, because FMRP regulates the translation of many messages that affect synaptic plasticity and connectivity in the central nervous system. The absence of FMRP also leads to upregulation of mGluR5 pathways and downregulation of GABAA pathways. Targeted treatments to reverse these problems are currently being studied in patients with FXS. Many of these targeted treatments may also be helpful for ASD without FXS.


Congrès scientifique international sur l’X fragile à l’Institut Pasteur, Paris :24 26 mars prochain

Sous la présidence d’honneur de Randi Hagerman, du MIND Institute, CA, USA |

Chers Collègues,Chers Amis,

Je suis très heureuse de vous inviter aux deuxièmes Journées Internationales Jérôme Lejeune (JIJL), qui auront lieu à Paris, à l’Institut Pasteur. Cette conférence, organisée par la Fondation Jérôme Lejeune, réunira médecins, chercheurs et professionnels de santé autour d’un thème important et en pleine expansion : Déficience intellectuelle d’origine génétique : progrès vers des traitements ciblés

En effet, au cours des dernières années, voire même des derniers mois, la recherche sur le déficit intellectuel a fait un bond en avant spectaculaire, de la souris à l’homme, particulièrement dans le domaine thérapeutique. Des experts de haut niveau nous donneront leurs informations sur les enjeux généraux et spécifiques de la thérapeutique appliquée à la déficience intellectuelle. Notre programme scientifique met l’accent sur les nouveautés dans la recherche en biologie moléculaire, génétique, neurobiologie et neuropsychologie conduisant à de nouveaux essais thérapeutiques dans de nombreux désordres du neuro-développement. Les traits communs à ces désordres du neuro-développement seront mis en évidence et il est probable que nombre de traitements exposés seront utiles à plus d’une pathologie.

Ces trois journées de conférence permettront aux chercheurs et cliniciens d’échanger sur leurs connaissances et leurs idées et de stimuler des collaborations dans le domaine des thérapeutiques du futur.

Une exposition de posters présentera les travaux récents sur ce thème riche et intéressant. A la fin de la conférence, des prix seront remis aux deux meilleurs posters, ceci afin de souligner les étapes clefs réalisées dans le traitement des patients atteints de déficit intellectuel.

Nous souhaitons que cet évènement vous apporte l’information scientifique la plus récente possible, ainsi que les suggestions et contacts les plus utiles à votre activité professionnelle.

Dans cette perspective, je me fais une joie de vous accueillir à Paris pour ces trois journées.

Professeur Randi HAGERMAN
Présidente du Comité Scientifique

Researchers win congressional grant to study fragile X

$3M grant will fund efficacy tests of new approach to treating children with fragile X, the most common single-gene cause of autism.

Three internationally respected UC Davis researchers — two expert in fragile X syndrome and one in epilepsy — have joined forces to test the efficacy of an innovative new approach to treating children with fragile X, through a $3 million grant from the U.S. Congress.

The researchers will explore the safety and effectiveness of a synthetic neuroactive steroid drug, ganaxolone, for treating the anxiety that is common in children with fragile X, a condition that is the leading cause worldwide of inherited intellectual disability and the most common single-gene cause of autism. The collaboration includes Randi Hagerman, an international authority on fragile X-related disorders, Michael Rogawski, known worldwide for his epilepsy research, and David Hessl, an expert in psychophysiologic studies.

“We believe that this drug will be highly effective for treating the anxiety, inattention and impulsivity in children with the full fragile X syndrome mutation,” said Hagerman, who is medical director of the UC Davis MIND Institute and treats people with fragile X syndrome. “This compound opens up a whole new avenue of treatment for people with fragile X.”

Fragile X syndrome is the result of a defect on the X chromosome. It is estimated to affect 1 in 3,600 males and 1 in 4,000 females. One-third of all children with fragile X syndrome develop autism and approximately 5 percent of children with an autism-spectrum disorder have fragile X.

“In fragile X syndrome, in addition to the intellectual disability, there is a range of learning disabilities and other neurological problems such as seizures,” said Rogawski, who is chair of the UC Davis neurology department. “Ganaxolone originally was developed to treat epilepsy and has anti-seizure and anti-anxiety properties.”

For the study, the researchers will enroll 60 children between the ages of 6 and 17 years over a four-year period. Participants initially will receive either ganaxolone or a placebo and then after six weeks will receive the opposite medication, ganaxolone or a placebo. The effects will be studied through a variety of tests and outcome measures, including eye-tracking to determine children’s ability to make eye contact and levels of hyperactivity. The drug will be provided by Marinus Pharmaceuticals.

Funding for the study is provided by the Department of Defense Peer-Reviewed Medical Research Program of the Congressionally Directed Medical Research Program.