In this Issue/Abstract Thinking: Fragile X Syndrome and the Coming of Molecularly Targeted Treatments for Neurodevelopmental Disorders

2012 ◽  
Vol 51 (11) ◽  
pp. 1103-1104
Author(s):  
Jeremy Veenstra-VanderWeele
Keyword(s):  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Fragile X ◽  
Abstract Thinking ◽  
Targeted Treatments

Fragile X syndrome

2020 ◽  
Vol 13 (12) ◽  
pp. 712-716
Author(s):  
Rebecca Dunphy
Keyword(s):  
Primary Care ◽  
Learning Disability ◽  
Fragile X Syndrome ◽  
Clinical Features ◽  
Neurodevelopmental Disorders ◽  
Fragile X ◽  
Healthcare Services ◽  
Diagnosis And Management ◽  
Genetic Causes

Fragile X syndrome is one of the most common genetic causes of learning disability. Patients with this and other neurodevelopmental disorders will often present to primary care before a diagnosis is made, and this can be challenging and worrying for patients and other carers. These patients may face a number of barriers in accessing healthcare services including communication, behavioural and sensory difficulties. It may be difficult to understand whether symptoms are part of their condition or because of a comorbidity that needs to be addressed. Input from families and carers can be vital in helping with diagnosis. This article aims to outline the key clinical features, diagnosis and management of this syndrome.

scholarly journals Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X Syndrome

2020 ◽  
Vol 10 (6) ◽  
pp. 361
Author(s):  
Mittal Jasoliya ◽  
Heather Bowling ◽  
Ignacio Cortina Petrasic ◽  
Blythe Durbin-Johnson ◽  
Eric Klann ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Drug Response ◽  
Molecular Level ◽  
Fragile X ◽  
Primary Objective ◽  
Molecular Biomarkers ◽  
Target Engagement ◽  
Targeted Treatments ◽  
Expression Abundance ◽  
Metalloproteinase 9

Recent advances in neurobiology have provided several molecular entrees for targeted treatments for Fragile X syndrome (FXS). However, the efficacy of these treatments has been demonstrated mainly in animal models and has not been consistently predictive of targeted drugs’ response in the preponderance of human clinical trials. Because of the heterogeneity of FXS at various levels, including the molecular level, phenotypic manifestation, and drug response, it is critically important to identify biomarkers that can help in patient stratification and prediction of therapeutic efficacy. The primary objective of this study was to assess the ability of molecular biomarkers to predict phenotypic subgroups, symptom severity, and treatment response to metformin in clinically treated patients with FXS. We specifically tested a triplex protein array comprising of hexokinase 1 (HK1), RAS (all isoforms), and Matrix Metalloproteinase 9 (MMP9) that we previously demonstrated were dysregulated in the FXS mouse model and in blood samples from patient with FXS. Seventeen participants with FXS, 12 males and 5 females, treated clinically with metformin were included in this study. The disruption in expression abundance of these proteins was normalized and associated with significant self-reported improvement in clinical phenotypes (CGI-I in addition to BMI) in a subset of participants with FXS. Our preliminary findings suggest that these proteins are of strong molecular relevance to the FXS pathology that could make them useful molecular biomarkers for this syndrome.

scholarly journals The first awake simultaneous PET-MR study of an adult with fragile X syndrome: A case report

2021 ◽  
Author(s):  
Soujanya Gade ◽  
Trine Hjørnevik ◽  
Jun Hyung Park ◽  
Bin Shen ◽  
Meng Gu ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Serum Cortisol ◽  
Vineland Adaptive Behavior Scales ◽  
Cortisol Reactivity ◽  
Quantitative Pet ◽  
Observation Scale ◽  
Targeted Treatments ◽  
Dorsolateral Prefrontal

Abstract Introduction: Fragile X syndrome (FXS) is a debilitating neurogenetic disorder that can result in a multitude of impairments in cognition, memory, and learning. Case Presentation: a 25-year-old male with FXS participated in this study. The participant obtained scores in the non-spectrum range on the Autism Diagnostic Observation Scale and obtained an full scale IQ score of 57 (Verbal IQ = 23 and Nonverbal IQ = 34) on the Stanford-Binet Intelligence Scales (SB-5). On the Vineland Adaptive Behavior Scales, 2nd Edition (VABS-2) he obtained a composite score of 66. Pre-scan serum cortisol reactivity was 16.45 mcg/dL. Following a [18F]flumazenil (5mCi) intravenous bolus injection, the participant was scanned without sedation on a hybrid PET-MR system (Signa, GE Healthcare, Waukesha, WI) for 60 mins. List mode PET data, structural and diffusion MRI (DWI), and MR spectroscopy (MRS) were acquired simultaneously. Quantitative PET and DWI measures were extracted from 83 pre-defined regions of interest. MRS data was collected from two 20 cc voxels (thalamus and dorsolateral prefrontal cortex). Conclusion: This is the first study to investigate neuromolecular behavior in FXS without the use of sedation using PET-MR. Mapping the neuromolecular differences in FXS can lead to targeted treatments that can significantly improve quality of life for families and individuals with intellectual disabilities.

scholarly journals Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome

2017 ◽  
Vol 17 (4) ◽  
pp. 280-299 ◽  
Author(s):  
Elizabeth M. Berry-Kravis ◽  
Lothar Lindemann ◽  
Aia E. Jønch ◽  
George Apostol ◽  
Mark F. Bear ◽  
...  
Keyword(s):  
Drug Development ◽  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Fragile X ◽  
Lessons Learned

Targeted treatments in fragile X syndrome

2014 ◽  
Vol 2 (6) ◽  
pp. 531-543 ◽  
Author(s):  
Emma B Hare ◽  
Randi J Hagerman ◽  
Reymundo Lozano
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Targeted Treatments

The behavioral neurogenetics of fragile X syndrome: Analyzing gene–brain–behavior relationships in child developmental psychopathologies

2003 ◽  
Vol 15 (4) ◽  
pp. 927-968 ◽  
Author(s):  
ALLAN L. REISS ◽  
CHRISTOPHER C. DANT
Keyword(s):  
Environmental Factors ◽  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Fragile X ◽  
Single Gene ◽  
Structure And Function ◽  
Research Approach ◽  
And Function ◽  
And Behavior ◽  
Brain Behavior

Analyzing gene–brain–behavior linkages in childhood neurodevelopmental disorders, a research approach called “behavioral neurogenetics,” has provided new insights into understanding how both genetic and environmental factors contribute to complex variations in typical and atypical human development. Research into etiologically more homogeneous disorders, such as fragile X syndrome, in particular, allows the use of more precise metrics of genetic risk so that we can more fully understand the complex pathophysiology of childhood onset neurodevelopmental disorders. In this paper, we review our laboratory's behavioral neurogenetics research by examining gene–brain–behavior relationships in fragile X syndrome, a single-gene disorder that has become a well-characterized model for studying neurodevelopmental dysfunction in childhood. Specifically, we examine genetic influences, trajectories of cognition and behavior, variation in brain structure and function, and biological and environmental factors that influence developmental and cognitive outcomes of children with fragile X. The converging approaches across these multilevel scientific domains indicate that fragile X, which arises from disruption of a single gene leading to the loss of a specific protein, is associated with a cascade of aberrations in neurodevelopment, resulting in a central nervous system that is suboptimal with respect to structure and function. In turn, structural and functional brain alterations lead to early disruption in emotion, cognition, and behavior in the child with fragile X. The combination of molecular genetics, neuroimaging, and behavioral research have advanced our understanding of the linkages between genetic variables, neurobiological measures, IQ, and behavior. Our research and that of others demonstrates that neurobehavior and neurocognition, genetics, and neuroanatomy are all different views of the same intriguing biological puzzle, a puzzle that today is rapidly emerging into a more complete picture of the intricate linkages among gene, brain, and behavior in developing children. Understanding the complex multilevel scientific perspective involved in fragile X will also contribute to our understanding of normal development by highlighting developmental events throughout the life span, thereby helping us to delineate the boundaries of pathology.

scholarly journals Fragile X syndrome, the search for a targeted treatment

2019 ◽  
Vol 5 (1) ◽  
pp. 12
Author(s):  
Shimriet Zeidler ◽  
Rob Willemsen
Keyword(s):  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Fragile X ◽  
Short Review ◽  
Autism Spectrum ◽  
Targeted Treatment ◽  
Adequate Treatment ◽  
Model Studies ◽  
Physical Problems ◽  
Spectrum Disorders

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. 

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