Fragile X syndrome, the search for a targeted treatment

Fragile X syndrome (FXS), the most common monogenetic cause of intellectual disability and autism spectrum disorders, is characterized by behavioral and physical problems. There is currently no adequate treatment available. While animal model studies seemed extremely promising, no success has been achieved in the larger clinical trials with human FXS patients. This short review describes the steps that have been taken in the development of a targeted treatment for FXS. Possible reasons for the lack of translation between animal models and human FXS patients are being explored and solutions are being proposed. The FXS story illustrates pitfalls and possibilities in translational research, that might especially be applicable for other neurodevelopmental disorders as well.

Paradoxical effect of baclofen on social behavior in the fragile X syndrome mouse model

Introduction: Fragile X syndrome (FXS) is a common monogenetic cause of intellectual disability, autism spectrum features, and a broad range of other psychiatric and medical problems. FXS is caused by the lack of the fragile X mental retardation protein (FMRP), a translational regulator of specific mRNAs at the postsynaptic compartment. The absence of FMRP leads to aberrant synaptic plasticity, which is believed to be caused by an imbalance in excitatory and inhibitory network functioning of the synapse. Evidence from studies in mice demonstrates that GABA, the major inhibitory neurotransmitter in the brain, and its receptors, is involved in the pathogenesis of FXS. Moreover, several FXS phenotypes, including social behavior deficits, could be corrected in Fmr1 KO mice after acute treatment with GABAB agonists. Methods: As FXS would probably require a lifelong treatment, we investigated the effect of chronic treatment with the GABAB agonist baclofen on social behavior in Fmr1 KO mice on two behavioral paradigms for social behavior: the automated tube test and the three-chamber sociability test. Results: Unexpectedly, chronic baclofen treatment resulted in worsening of the FXS phenotypes in these behavior tests. Strikingly, baclofen treatment also affected wild-type animals in both behavioral tests, inducing a phenotype similar to that of untreated Fmr1 KO mice. Conclusion: Altogether, the disappointing results of recent clinical trials with the R-baclofen enantiomer arbaclofen and our current results indicate that baclofen should be reconsidered and further evaluated before its application in targeted treatment for FXS

Epilepsy is an important feature of KBG syndrome associated with poorer developmental outcome

OBJECTIVE: To describe the epilepsy phenotype in a large international cohort of patients with KBG syndrome and to study a possible genotype-phenotype correlation. METHODS: We collected data of patients with ANKRD11 variants by contacting University Medical Centers in the Netherlands, an international network of collaborating clinicians, and study groups who previously published about KBG syndrome. All patients with a likely pathogenic or pathogenic ANKRD11 variant were included in our patient cohort and categorized into an 'epilepsy group' or 'non-epilepsy group'. Additionally, we included previously reported patients with (likely) pathogenic ANKRD11 variants and epilepsy from the literature. RESULTS: We included 75 patients with KBG syndrome of whom 26 had epilepsy. Those with epilepsy more often had moderate to severe intellectual disability (42.3% vs 9.1% , RR 4.6 (95% CI 1.7-13.1)). Seizure onset in patients with KBG syndrome occurred at a median age of four years (range 12 months - 20 years) and the majority had generalized onset seizures (57.7%)with tonic-clonic seizures being most common (23.1%). The epilepsy type was mostly classified as generalized (42.9%) or combined generalized and focal (42.9%), not fulfilling criteria of an electroclinical syndrome diagnosis. Half of the epilepsy patients (50.0%) were seizure free on anti-seizure medication (ASM) for at least one year at the time of last assessment, but 26.9% of patients had drug-resistant epilepsy (failure of ≥ 2 ASM). No genotype-phenotype correlation could be identified for the presence of epilepsy or epilepsy characteristics. SIGNIFICANCE: Epilepsy in KBG syndrome most often presents as a generalized or combined focal and generalized type. No distinctive epilepsy syndrome could be identified. Patients with KBG syndrome and epilepsy had a significant poorer neurodevelopmental outcome compared to those without epilepsy. Clinicians should consider KBG syndrome as a causal etiology of epilepsy and be aware of the poorer neurodevelopmental outcome in individuals with epilepsy

Epilepsy is an important feature of KBG syndrome associated with poorer developmental outcome

Objective: The aim of this study was to describe the epilepsy phenotype in a large international cohort of patients with KBG syndrome and to study a possible genotype–phenotype correlation. Methods: We collected data on patients with ANKRD11 variants by contacting University Medical Centers in the Netherlands, an international network of collaborating clinicians, and study groups who previously published about KBG syndrome. All patients with a likely pathogenic or pathogenic ANKRD11 variant were included in our patient cohort and categorized into an “epilepsy group” or “non-epilepsy group”. Additionally, we included previously reported patients with (likely) pathogenic ANKRD11 variants and epilepsy from the literature. Results: We included 75 patients with KBG syndrome of whom 26 had epilepsy. Those with epilepsy more often had moderate to severe intellectual disability (42.3% vs 9.1%, RR 4.6 [95% CI 1.7–13.1]). Seizure onset in patients with KBG syndrome occurred at a median age of 4 years (range 12 months – 20 years), and the majority had generalized onset seizures (57.7%) with tonic–clonic seizures being most common (23.1%). The epilepsy type was mostly classified as generalized (42.9%) or combined generalized and focal (42.9%), not fulfilling the criteria of an electroclinical syndrome diagnosis. Half of the epilepsy patients (50.0%) were seizure free on anti-seizure medication (ASM) for at least 1 year at the time of last assessment, but 26.9% of patients had drug-resistant epilepsy (failure of ≥2 ASM). No genotype–phenotype correlation could be identified for the presence of epilepsy or epilepsy characteristics. Significance: Epilepsy in KBG syndrome most often presents as a generalized or combined focal and generalized type. No distinctive epilepsy syndrome could be identified. Patients with KBG syndrome and epilepsy had a significantly poorer neurodevelopmental outcome compared with those without epilepsy. Clinicians should consider KBG syndrome as a causal etiology of epilepsy and be aware of the poorer neurodevelopmental outcome in individuals with epilepsy

Fragile X Syndrome : the quest for targeted treatment

markdownabstractFragile X syndrome is the most common hereditary cause of intellectual disability and autism. Currently, no targeted treatment is available. The identification of its causative gene, followed by the generation of animal models, has boosted research options. The past decades, preclinical research has focused on involved pathways as targets for therapeutic interventions. Targeting many of these pathways in animal models improved core features of the disease. These promising results were received with great enthusiasm, and led to clinical trials in patients with fragile X syndrome. The aim of this thesis was to develop and evaluate therapeutic intervention strategies for fragile X syndrome with the ultimate goal to advance care and treatment options for patients with the disorder. One aspect was to identify possible targets for therapeutic intervention using social behavior of _Fmr1_ knockout mice as outcome measure. In addition, new strategies were explored using combination therapy (chapter one - four). A second aspect was to investigate a potential target, the mGluR5, for its efficacy in clinical trials. The mGluR5 antagonist mavoglurant was studied in a multicenter randomized, double-blind, placebo-controlled trial (chapter five). A third aspect was to center patient care, in order to advance clinical expertise and enable clinical research. An expert center and clinical guidelines are indispensable in patient care and further development of treatment for fragile X syndrome (chapter seven). The findings were then placed in the light of current knowledge and future prospectives (chapter six and eight)

EARLY PRENATAL DISRUPTION; A FOETUS WITH FEATURES OF SEVERE LIMB BODY WALL SEQUENCE, BODY STALK ANOMALY AND AMNIOTIC BANDS

Early prenatal disruption; a foetus with features of severe limb body wall sequence, body stalk anomaly and amniotic bands: Disruption in early pregnancy can cause severe and multiple congenital anomalies in a foetus. Three sequences, Limb-body wall complex (LBWC), amniotic band sequence (ABS) and body-stalk anomaly (BSA) are thought to be caused by disruption. This case report describes a foetus with severe multiple congenital anomalies, that fit the diagnoses of all three sequences, which might advocate these syndromes are a spectrum of one sequence

Combination Therapy in Fragile X Syndrome; Possibilities and Pitfalls Illustrated by Targeting the mGluR5 and GABA Pathway Simultaneously

Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability and autism. The disorder is characterized by altered synaptic plasticity in the brain. Synaptic plasticity is tightly regulated by a complex balance of different synaptic pathways. In FXS, various synaptic pathways are disrupted, including the excitatory metabotropic glutamate receptor 5 (mGluR5) and the inhibitory γ-aminobutyric acid (GABA) pathways. Targeting each of these pathways individually, has demonstrated beneficial effects in animal models, but not in patients with FXS. This lack of translation might be due to oversimplification of the disease mechanisms when targeting only one affected pathway, in spite of the complexity of the many pathways implicated in FXS. In this report we outline the hypothesis that targeting more than one pathway simultaneously, a combination therapy, might improve treatment effects in FXS. In addition, we present a glance of the first results of chronic combination therapy on social behavior in Fmr1 KO mice. In contrast to what we expected, targeting both the mGluR5 and the GABAergic pathways simultaneously did not result in a synergistic effect, but in a slight worsening of the social behavior phenotype. This does implicate that both pathways are interconnected and important for social behavior. Our results underline the tremendous fine-tuning that is needed to reach the excitatory-inhibitory balance in the synapse in relation to social behavior. We believe that alternative strategies focused on combination therapy should be further explored, including targeting pathways in different cellular compartments or cell-types