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Editorial

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5 pages, 185 KiB

Open AccessEditorial

Towards Mechanism-Based Treatments for Fragile X Syndrome

by Daman Kumari and Inbal Gazy

Brain Sci. 2019, 9(8), 202; https://doi.org/10.3390/brainsci9080202 - 16 Aug 2019

Cited by 2 | Viewed by 3020

Abstract

Fragile X syndrome (FXS) is the most common heritable form of intellectual disability, as well as the most common known monogenic cause of autism spectrum disorder (ASD), affecting 1 in 4000–8000 people worldwide [...] Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

Research

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12 pages, 742 KiB

Open AccessArticle

A Pilot Quantitative Evaluation of Early Life Language Development in Fragile X Syndrome

by Debra L. Reisinger, Rebecca C. Shaffer, Ernest V. Pedapati, Kelli C. Dominick and Craig A. Erickson

Brain Sci. 2019, 9(2), 27; https://doi.org/10.3390/brainsci9020027 - 29 Jan 2019

Cited by 13 | Viewed by 4627

Abstract

Language delay and communication deficits are a core characteristic of the fragile X syndrome (FXS) phenotype. To date, the literature examining early language development in FXS is limited potentially due to barriers in language assessment in very young children. The present study is [...] Read more.

Language delay and communication deficits are a core characteristic of the fragile X syndrome (FXS) phenotype. To date, the literature examining early language development in FXS is limited potentially due to barriers in language assessment in very young children. The present study is one of the first to examine early language development through vocal production and the language learning environment in infants and toddlers with FXS utilizing an automated vocal analysis system. Child vocalizations, conversational turns, and adult word counts in the home environment were collected and analyzed in a group of nine infants and toddlers with FXS and compared to a typically developing (TD) normative sample. Results suggest infants and toddlers with FXS are exhibiting deficits in their early language skills when compared to their chronological expectations. Despite this, when accounting for overall developmental level, their early language skills appear to be on track. Additionally, FXS caregivers utilize less vocalizations around infants and toddlers with FXS; however, additional research is needed to understand the true gap between FXS caregivers and TD caregivers. These findings provide preliminary information about the early language learning environment and support for the feasibility of utilizing an automated vocal analysis system within the FXS population that could ease data collection and further our understanding of the emergence of language development. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

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13 pages, 1550 KiB

Open AccessArticle

Voice of People with Fragile X Syndrome and Their Families: Reports from a Survey on Treatment Priorities

by Jayne Dixon Weber, Elizabeth Smith, Elizabeth Berry-Kravis, Diego Cadavid, David Hessl and Craig Erickson

Brain Sci. 2019, 9(2), 18; https://doi.org/10.3390/brainsci9020018 - 23 Jan 2019

Cited by 31 | Viewed by 7506

Abstract

To date, there has been limited research on the primary concerns and treatment priorities for individuals with fragile X syndrome (FXS) and their families. The National Fragile X Foundation in collaboration with clinical investigators from industry and academia constructed a survey to investigate [...] Read more.

To date, there has been limited research on the primary concerns and treatment priorities for individuals with fragile X syndrome (FXS) and their families. The National Fragile X Foundation in collaboration with clinical investigators from industry and academia constructed a survey to investigate the main symptoms, daily living challenges, family impact, and treatment priorities for individuals with FXS and their families, which was then distributed to a large mailing list. The survey included both structured questions focused on ranking difficulties as well as qualitative analysis of open-ended questions. It was completed by 467 participants, including 439 family members or caretakers (family members/caretakers) of someone with FXS, 20 professionals who work with a person with FXS, and 8 individuals with FXS. Respondents indicated three main general areas of concern: Anxiety, behavioral problems, and learning difficulties. Important differences were noted, based on the sex and age of the individual with FXS. The results highlight the top priorities for treatment development for family members/caretakers, as well as a small group of professionals, and an even smaller group of individuals with FXS, while demonstrating challenges with “voice of the patient” research in FXS. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

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14 pages, 4761 KiB

Open AccessArticle

Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice

by Rachel Michelle Saré, Christopher Figueroa, Abigail Lemons, Inna Loutaev and Carolyn Beebe Smith

Brain Sci. 2019, 9(1), 13; https://doi.org/10.3390/brainsci9010013 - 16 Jan 2019

Cited by 11 | Viewed by 5117

Abstract

Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene leading to loss of the protein product fragile X mental retardation protein (FMRP). FXS is the most common monogenic cause of intellectual disability. There are two known mammalian paralogs of FMRP, [...] Read more.

Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene leading to loss of the protein product fragile X mental retardation protein (FMRP). FXS is the most common monogenic cause of intellectual disability. There are two known mammalian paralogs of FMRP, FXR1P, and FXR2P. The functions of FXR1P and FXR2P and their possible roles in producing or modulating the phenotype observed in FXS are yet to be identified. Previous studies have revealed that mice lacking Fxr2 display similar behavioral abnormalities as Fmr1 knockout (KO) mice. In this study, we expand upon the behavioral phenotypes of Fmr1 KO and Fxr2^+/− (Het) mice and compare them with Fmr1 KO/Fxr2 Het mice. We find that Fmr1 KO and Fmr1 KO/Fxr2 Het mice are similarly hyperactive compared to WT and Fxr2 Het mice. Fmr1 KO/Fxr2 Het mice have more severe learning and memory impairments than Fmr1 KO mice. Fmr1 KO mice display significantly impaired social behaviors compared to WT mice, which are paradoxically reversed in Fmr1 KO/Fxr2 Het mice. These results highlight the important functional consequences of loss or reduction of FMRP and FXR2P. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

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Review

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23 pages, 1116 KiB

Open AccessReview

Molecular Biomarkers in Fragile X Syndrome

by Marwa Zafarullah and Flora Tassone

Brain Sci. 2019, 9(5), 96; https://doi.org/10.3390/brainsci9050096 - 27 Apr 2019

Cited by 23 | Viewed by 10350

Abstract

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability (ID) and a known monogenic cause of autism spectrum disorder (ASD). It is a trinucleotide repeat disorder, in which more than 200 CGG repeats in the 5’ untranslated region (UTR) [...] Read more.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability (ID) and a known monogenic cause of autism spectrum disorder (ASD). It is a trinucleotide repeat disorder, in which more than 200 CGG repeats in the 5’ untranslated region (UTR) of the fragile X mental retardation 1 (FMR1) gene causes methylation of the promoter with consequent silencing of the gene, ultimately leading to the loss of the encoded fragile X mental retardation 1 protein, FMRP. FMRP is an RNA binding protein that plays a primary role as a repressor of translation of various mRNAs, many of which are involved in the maintenance and development of neuronal synaptic function and plasticity. In addition to intellectual disability, patients with FXS face several behavioral challenges, including anxiety, hyperactivity, seizures, repetitive behavior, and problems with executive and language performance. Currently, there is no cure or approved medication for the treatment of the underlying causes of FXS, but in the past few years, our knowledge about the proteins and pathways that are dysregulated by the loss of FMRP has increased, leading to clinical trials and to the path of developing molecular biomarkers for identifying potential targets for therapies. In this paper, we review candidate molecular biomarkers that have been identified in preclinical studies in the FXS mouse animal model and are now under validation for human applications or have already made their way to clinical trials. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

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12 pages, 825 KiB

Open AccessReview

Modelling Protein Synthesis as A Biomarker in Fragile X Syndrome Patient-Derived Cells

by Rakhi Pal and Aditi Bhattacharya

Brain Sci. 2019, 9(3), 59; https://doi.org/10.3390/brainsci9030059 - 11 Mar 2019

Cited by 8 | Viewed by 5616

Abstract

The most conserved molecular phenotype of Fragile X Syndrome (FXS) is aberrant protein synthesis. This has been validated in a variety of experimental model systems from zebrafish to rats, patient-derived lymphoblasts and fibroblasts. With the advent of personalized medicine paradigms, patient-derived cells and [...] Read more.

The most conserved molecular phenotype of Fragile X Syndrome (FXS) is aberrant protein synthesis. This has been validated in a variety of experimental model systems from zebrafish to rats, patient-derived lymphoblasts and fibroblasts. With the advent of personalized medicine paradigms, patient-derived cells and their derivatives are gaining more translational importance, not only to model disease in a dish, but also for biomarker discovery. Here we review past and current practices of measuring protein synthesis in FXS, studies in patient derived cells and the inherent challenges in measuring protein synthesis in them to offer usable avenues of modeling this important metabolic metric for further biomarker development. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

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19 pages, 767 KiB

Open AccessReview

The Contribution of Pluripotent Stem Cell (PSC)-Based Models to the Study of Fragile X Syndrome (FXS)

by Manar Abu Diab and Rachel Eiges

Brain Sci. 2019, 9(2), 42; https://doi.org/10.3390/brainsci9020042 - 15 Feb 2019

Cited by 8 | Viewed by 5982

Abstract

Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from a deficiency in the fragile X mental retardation protein (FMRP) due to a CGG repeat expansion in the 5′-UTR of the X-linked FMR1 gene. When CGGs expand [...] Read more.

Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from a deficiency in the fragile X mental retardation protein (FMRP) due to a CGG repeat expansion in the 5′-UTR of the X-linked FMR1 gene. When CGGs expand beyond 200 copies, they lead to epigenetic gene silencing of the gene. In addition, the greater the allele size, the more likely it will become unstable and exhibit mosaicism for expansion size between and within tissues in affected individuals. The timing and mechanisms of FMR1 epigenetic gene silencing and repeat instability are far from being understood given the lack of appropriate cellular and animal models that can fully recapitulate the molecular features characteristic of the disease pathogenesis in humans. This review summarizes the data collected to date from mutant human embryonic stem cells, induced pluripotent stem cells, and hybrid fusions, and discusses their contribution to the investigation of FXS, their key limitations, and future prospects. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

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18 pages, 1010 KiB

Open AccessReview

Pharmacological Reactivation of the Silenced FMR1 Gene as a Targeted Therapeutic Approach for Fragile X Syndrome

by Daman Kumari, Inbal Gazy and Karen Usdin

Brain Sci. 2019, 9(2), 39; https://doi.org/10.3390/brainsci9020039 - 12 Feb 2019

Cited by 14 | Viewed by 6974

Abstract

More than ~200 CGG repeats in the 5′ untranslated region of the FMR1 gene results in transcriptional silencing and the absence of the FMR1 encoded protein, FMRP. FMRP is an RNA-binding protein that regulates the transport and translation of a variety of brain [...] Read more.

More than ~200 CGG repeats in the 5′ untranslated region of the FMR1 gene results in transcriptional silencing and the absence of the FMR1 encoded protein, FMRP. FMRP is an RNA-binding protein that regulates the transport and translation of a variety of brain mRNAs in an activity-dependent manner. The loss of FMRP causes dysregulation of many neuronal pathways and results in an intellectual disability disorder, fragile X syndrome (FXS). Currently, there is no effective treatment for FXS. In this review, we discuss reactivation of the FMR1 gene as a potential approach for FXS treatment with an emphasis on the use of small molecules to inhibit the pathways important for gene silencing. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

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15 pages, 636 KiB

Open AccessReview

The Application of Adeno-Associated Viral Vector Gene Therapy to the Treatment of Fragile X Syndrome

by David R. Hampson, Alexander W. M. Hooper and Yosuke Niibori

Brain Sci. 2019, 9(2), 32; https://doi.org/10.3390/brainsci9020032 - 2 Feb 2019

Cited by 25 | Viewed by 7379

Abstract

Viral vector-mediated gene therapy has grown by leaps and bounds over the past several years. Although the reasons for this progress are varied, a deeper understanding of the basic biology of the viruses, the identification of new and improved versions of viral vectors, [...] Read more.

Viral vector-mediated gene therapy has grown by leaps and bounds over the past several years. Although the reasons for this progress are varied, a deeper understanding of the basic biology of the viruses, the identification of new and improved versions of viral vectors, and simply the vast experience gained by extensive testing in both animal models of disease and in clinical trials, have been key factors. Several studies have investigated the efficacy of adeno-associated viral (AAV) vectors in the mouse model of fragile X syndrome where AAVs have been used to express fragile X mental retardation protein (FMRP), which is missing or highly reduced in the disorder. These studies have demonstrated a range of efficacies in different tests from full correction, to partial rescue, to no effect. Here we provide a backdrop of recent advances in AAV gene therapy as applied to central nervous system disorders, outline the salient features of the fragile X studies, and discuss several key issues for moving forward. Collectively, the findings to date from the mouse studies on fragile X syndrome, and data from clinical trials testing AAVs in other neurological conditions, indicate that AAV-mediated gene therapy could be a viable strategy for treating fragile X syndrome. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

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14 pages, 792 KiB

Open AccessReview

CRISPR to the Rescue: Advances in Gene Editing for the FMR1 Gene

by Carolyn M. Yrigollen and Beverly L. Davidson

Brain Sci. 2019, 9(1), 17; https://doi.org/10.3390/brainsci9010017 - 21 Jan 2019

Cited by 13 | Viewed by 7752

Abstract

Gene-editing using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is promising as a potential therapeutic strategy for many genetic disorders. CRISPR-based therapies are already being assessed in clinical trials, and evaluation of this technology in Fragile X syndrome has been performed by a [...] Read more.

Gene-editing using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is promising as a potential therapeutic strategy for many genetic disorders. CRISPR-based therapies are already being assessed in clinical trials, and evaluation of this technology in Fragile X syndrome has been performed by a number of groups. The findings from these studies and the advancement of CRISPR-based technologies are insightful as the field continues towards treatments and cures of Fragile X-Associated Disorders (FXADs). In this review, we summarize reports using CRISPR-editing strategies to target Fragile X syndrome (FXS) molecular dysregulation, and highlight how differences in FXS and Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) might alter treatment strategies for each syndrome. We discuss the various modifications and evolutions of the CRISPR toolkit that expand its therapeutic potential, and other considerations for moving these strategies from bench to bedside. The rapidly growing field of CRISPR therapeutics is providing a myriad of approaches to target a gene, pathway, or transcript for modification. As cures for FXADs have remained elusive, CRISPR opens new avenues to pursue. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

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29 pages, 335 KiB

Open AccessReview

Executive Function in Fragile X Syndrome: A Systematic Review

by Lauren M. Schmitt, Rebecca C. Shaffer, David Hessl and Craig Erickson

Brain Sci. 2019, 9(1), 15; https://doi.org/10.3390/brainsci9010015 - 16 Jan 2019

Cited by 34 | Viewed by 6393

Abstract

Executive function (EF) supports goal-directed behavior and includes key aspects such as working memory, inhibitory control, cognitive flexibility, attention, processing speed, and planning. Fragile X syndrome (FXS) is the leading inherited monogenic cause of intellectual disability and is phenotypically characterized by EF deficits [...] Read more.

Executive function (EF) supports goal-directed behavior and includes key aspects such as working memory, inhibitory control, cognitive flexibility, attention, processing speed, and planning. Fragile X syndrome (FXS) is the leading inherited monogenic cause of intellectual disability and is phenotypically characterized by EF deficits beyond what is expected given general cognitive impairments. Yet, a systematic review of behavioral studies using performance-based measures is needed to provide a summary of EF deficits across domains in males and females with FXS, discuss clinical and biological correlates of these EF deficits, identify critical limitations in available research, and offer suggestions for future studies in this area. Ultimately, this review aims to advance our understanding of the underlying pathophysiological mechanisms contributing to EF in FXS and to inform the development of outcome measures of EF and identification of new treatment targets in FXS. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

14 pages, 1880 KiB

Open AccessReview

Closing the Gender Gap in Fragile X Syndrome: Review of Females with Fragile X Syndrome and Preliminary Research Findings

by Kristi L. Bartholomay, Cindy H. Lee, Jennifer L. Bruno, Amy A. Lightbody and Allan L. Reiss

Brain Sci. 2019, 9(1), 11; https://doi.org/10.3390/brainsci9010011 - 12 Jan 2019

Cited by 70 | Viewed by 11495

Abstract

Fragile X syndrome (FXS) is a genetic condition known to increase the risk of cognitive impairment and socio-emotional challenges in affected males and females. To date, the vast majority of research on FXS has predominantly targeted males, who usually exhibit greater cognitive impairment [...] Read more.

Fragile X syndrome (FXS) is a genetic condition known to increase the risk of cognitive impairment and socio-emotional challenges in affected males and females. To date, the vast majority of research on FXS has predominantly targeted males, who usually exhibit greater cognitive impairment compared to females. Due to their typically milder phenotype, females may have more potential to attain a higher level of independence and quality of life than their male counterparts. However, the constellation of cognitive, behavioral, and, particularly, socio-emotional challenges present in many females with FXS often preclude them from achieving their full potential. It is, therefore, critical that more research specifically focuses on females with FXS to elucidate the role of genetic, environmental, and socio-emotional factors on outcome in this often-overlooked population. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

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12 pages, 219 KiB

Open AccessReview

Early Identification of Fragile X Syndrome through Expanded Newborn Screening

by Katherine C. Okoniewski, Anne C. Wheeler, Stacey Lee, Beth Boyea, Melissa Raspa, Jennifer L. Taylor and Donald B. Bailey, Jr.

Brain Sci. 2019, 9(1), 4; https://doi.org/10.3390/brainsci9010004 - 3 Jan 2019

Cited by 22 | Viewed by 6161

Abstract

Over the past 20 years, research on fragile X syndrome (FXS) has provided foundational understanding of the complex experiences of affected individuals and their families. Despite this intensive focus, there has been little progress on earlier identification, with the average age of diagnosis [...] Read more.

Over the past 20 years, research on fragile X syndrome (FXS) has provided foundational understanding of the complex experiences of affected individuals and their families. Despite this intensive focus, there has been little progress on earlier identification, with the average age of diagnosis being 3 years. For intervention and treatment approaches to have the greatest impact, they need to begin shortly after birth. To access this critical timespan, differential methods of earlier identification need to be considered, with an emerging focus on newborn screening practices. Currently, barriers exist that prevent the inclusion of FXS on standard newborn screening panels. To address these barriers, an innovative program is being implemented in North Carolina to offer voluntary screening for FXS under a research protocol, called Early Check. This program addresses the difficulties observed in prior pilot studies, such as recruitment, enrollment, lab testing, and follow-up. Early Check provides an opportunity for stakeholders and the research community to continue to gain valuable information about the feasibility and greater impact of newborn screening on the FXS population. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

15 pages, 256 KiB

Open AccessReview

Clinical Development of Targeted Fragile X Syndrome Treatments: An Industry Perspective

by Anna W. Lee, Pamela Ventola, Dejan Budimirovic, Elizabeth Berry-Kravis and Jeannie Visootsak

Brain Sci. 2018, 8(12), 214; https://doi.org/10.3390/brainsci8120214 - 5 Dec 2018

Cited by 30 | Viewed by 6154

Abstract

Fragile X syndrome (FXS) is the leading known cause of inherited intellectual disability and autism spectrum disorder. It is caused by a mutation of the fragile X mental retardation 1 (FMR1) gene, resulting in a deficit of fragile X mental retardation [...] Read more.

Fragile X syndrome (FXS) is the leading known cause of inherited intellectual disability and autism spectrum disorder. It is caused by a mutation of the fragile X mental retardation 1 (FMR1) gene, resulting in a deficit of fragile X mental retardation protein (FMRP). The clinical presentation of FXS is variable, and is typically associated with developmental delays, intellectual disability, a wide range of behavioral issues, and certain identifying physical features. Over the past 25 years, researchers have worked to understand the complex relationship between FMRP deficiency and the symptoms of FXS and, in the process, have identified several potential targeted therapeutics, some of which have been tested in clinical trials. Whereas most of the basic research to date has been led by experts at academic institutions, the pharmaceutical industry is becoming increasingly involved with not only the scientific community, but also with patient advocacy organizations, as more promising pharmacological agents are moving into the clinical stages of development. The objective of this review is to provide an industry perspective on the ongoing development of mechanism-based treatments for FXS, including identification of challenges and recommendations for future clinical trials. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

Other

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15 pages, 2084 KiB

Open AccessPerspective

Repeat Instability in the Fragile X-Related Disorders: Lessons from a Mouse Model

by Xiaonan Zhao, Inbal Gazy, Bruce Hayward, Elizabeth Pintado, Ye Hyun Hwang, Flora Tassone and Karen Usdin

Brain Sci. 2019, 9(3), 52; https://doi.org/10.3390/brainsci9030052 - 1 Mar 2019

Cited by 17 | Viewed by 4653

Abstract

The fragile X-related disorders (FXDs) are a group of clinical conditions that result primarily from an unusual mutation, the expansion of a CGG-repeat tract in exon 1 of the FMR1 gene. Mouse models are proving useful for understanding many aspects of disease pathology [...] Read more.

The fragile X-related disorders (FXDs) are a group of clinical conditions that result primarily from an unusual mutation, the expansion of a CGG-repeat tract in exon 1 of the FMR1 gene. Mouse models are proving useful for understanding many aspects of disease pathology in these disorders. There is also reason to think that such models may be useful for understanding the molecular basis of the unusual mutation responsible for these disorders. This review will discuss what has been learnt to date about mechanisms of repeat instability from a knock-in FXD mouse model and what the implications of these findings may be for humans carrying expansion-prone FMR1 alleles. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

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9 pages, 197 KiB

Open AccessCommentary

Best Practices in Fragile X Syndrome Treatment Development

by Craig A. Erickson, Walter E. Kaufmann, Dejan B. Budimirovic, Ave Lachiewicz, Barbara Haas-Givler, Robert M. Miller, Jayne Dixon Weber, Leonard Abbeduto, David Hessl, Randi J. Hagerman and Elizabeth Berry-Kravis

Brain Sci. 2018, 8(12), 224; https://doi.org/10.3390/brainsci8120224 - 15 Dec 2018

Cited by 33 | Viewed by 6551

Abstract

Preclinical studies using animal models of fragile X syndrome have yielded several agents that rescue a wide variety of phenotypes. However, translation of these treatments to humans with the disorder has not yet been successful, shedding light on a variety of limitations with [...] Read more.

Preclinical studies using animal models of fragile X syndrome have yielded several agents that rescue a wide variety of phenotypes. However, translation of these treatments to humans with the disorder has not yet been successful, shedding light on a variety of limitations with both animal models and human trial design. As members of the Clinical Trials Committee of the National Fragile X Foundation, we have discussed a variety of recommendations at the level of preclinical development, transition from preclinical to human projects, family involvement, and multi-site trial planning. Our recommendations are made with the vision that effective new treatment will lie at the intersection of innovation, rigorous and reproducible research, and stakeholder involvement. Full article

(This article belongs to the Special Issue Towards Mechanism-based Treatments for Fragile X Syndrome)

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