Intractable & Rare Diseases Research
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Volume 3 , Issue 4
Showing 1-9 articles out of 9 articles from the selected issue
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Editorial
  • Randi Hagerman, Reymundo Lozano, Andrea Schneider
    Volume 3 (2014) Issue 4 Pages 100
    Released: December 27, 2014
    JOURNALS FREE ACCESS
    This special issue on fragile X-associated disorders will open your eyes to the broad spectrum of clinical involvement that occurs with mutations in the FMR1 gene. This gene creates a protein, FMRP, which is a key protein for regulating the translation of hundreds of mRNAs, particularly those involved in synapse formation and plasticity. Fragile X syndrome (FXS) results from the loss or deficiency of FMRP and it is the most common cause of inherited intellectual disability and autism or autism spectrum disorder (ASD). The review of animal models for FXS by Kazdoba-Leach et al. (2014) in this issue, demonstrates how these models have led the way to targeted treatments for FXS and for ASD. One of the more promising new treatments for FXS is the use of low dose sertraline in young children 2 years and older with FXS. The paper by Hansen and Hagerman (in this edition) outlines the benefits of sertraline including the enhancement of serotonin neurotransmission, neurogenesis, and BDNF levels that has the potential to improve language and development for these children. GABA agonists and mGluR5 antagonists have also been studied in FXS but the mouse model is easily rescued with many different targeted treatments, whereas the patients with FXS have only responded well to a few new treatments. There is a great need to improve the participation of minorities in the new clinical trials of targeted treatments for FXS and this is reviewed in detail by Chechi et al. (2014) in this issue.
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Reviews
  • Zukhrofi Muzar, Reymundo Lozano
    Volume 3 (2014) Issue 4 Pages 101-109
    Released: December 27, 2014
    JOURNALS FREE ACCESS
    Fragile X-associated tremor/ataxia syndrome (FXTAS) is caused by a premutation CGG-repeat expansion in the 5'UTR of the fragile X mental retardation 1 (FMR1) gene. The classical clinical manifestations include tremor, cerebellar ataxia, cognitive decline and psychiatric disorders. Other less frequent features are peripheral neuropathy and autonomic dysfunction. Cognitive decline, a form of frontal subcortical dementia, memory loss and executive function deficits are also characteristics of this disorder. In this review, we present an expansion of recommendations for genetic testing for adults with suspected premutation disorders and provide an update of the clinical, radiological and molecular research of FXTAS, as well as the current research in the treatment for this intractable complex neurodegenerative genetic disorder.
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  • Alicia C Hanson, Randi J Hagerman
    Volume 3 (2014) Issue 4 Pages 110-117
    Released: December 27, 2014
    JOURNALS FREE ACCESS
    Fragile X Syndrome (FXS) is a trinucleotide repeat disorder that results in the silencing of the Fragile X Mental Retardation 1 gene (FMR1), leading to a lack of the FMR1 protein (FMRP). FMRP is an mRNA-binding protein that regulates the translation of hundreds of mRNAs important for synaptic plasticity. Several of these pathways have been identified and have guided the development of targeted treatments for FXS. Here we present evidence that serotonin is dysregulated in FXS and treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline may be beneficial for individuals with FXS, particularly in early childhood.
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  • Tatiana M. Kazdoba, Prescott T. Leach, Jill L. Silverman, Jacqueline ...
    Volume 3 (2014) Issue 4 Pages 118-133
    Released: December 27, 2014
    JOURNALS FREE ACCESS
    Fragile X Syndrome (FXS) is a commonly inherited form of intellectual disability and one of the leading genetic causes for autism spectrum disorder. Clinical symptoms of FXS can include impaired cognition, anxiety, hyperactivity, social phobia, and repetitive behaviors. FXS is caused by a CGG repeat mutation which expands a region on the X chromosome containing the FMR1 gene. In FXS, a full mutation (> 200 repeats) leads to hypermethylation of FMR1, an epigenetic mechanism that effectively silences FMR1 gene expression and reduces levels of the FMR1 gene product, fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that is important for the regulation of protein expression. In an effort to further understand how loss of FMR1 and FMRP contribute to FXS symptomology, several FXS animal models have been created. The most well characterized rodent model is the Fmr1 knockout (KO) mouse, which lacks FMRP protein due to a disruption in its Fmr1 gene. Here, we review the behavioral phenotyping of the Fmr1 KO mouse to date, and discuss the clinical relevance of this mouse model to the human FXS condition. While much remains to be learned about FXS, the Fmr1 KO mouse is a valuable tool for understanding the repercussions of functional loss of FMRP and assessing the efficacy of pharmacological compounds in ameliorating the molecular and behavioral phenotypes relevant to FXS.
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  • Reymundo Lozano, Carolina Alba Rosero, Randi J Hagerman
    Volume 3 (2014) Issue 4 Pages 134-146
    Released: December 27, 2014
    JOURNALS FREE ACCESS
    The fragile X mental retardation 1 gene (FMR1), which codes for the fragile X mental retardation 1 protein (FMRP), is located at Xp27.3. The normal allele of the FMR1 gene typically has 5 to 40 CGG repeats in the 5' untranslated region; abnormal alleles of dynamic mutations include the full mutation (> 200 CGG repeats), premutation (55-200 CGG repeats) and the gray zone mutation (45-54 CGG repeats). Premutation carriers are common in the general population with approximately 1 in 130-250 females and 1 in 250-810 males, whereas the full mutation and Fragile X syndrome (FXS) occur in approximately 1 in 4000 to 1 in 7000. FMR1 mutations account for a variety of phenotypes including the most common monogenetic cause of inherited intellectual disability (ID) and autism (FXS), the most common genetic form of ovarian failure, the fragile X-associated primary ovarian insufficiency (FXPOI, premutation); and fragile X-associated tremor/ataxia syndrome (FXTAS, premutation). The premutation can also cause developmental problems including ASD and ADHD especially in boys and psychopathology including anxiety and depression in children and adults. Some premutation carriers can have a deficit of FMRP and some unmethylated full mutation individuals can have elevated FMR1 mRNA that is considered a premutation problem. Therefore the term "Fragile X Spectrum Disorder" (FXSD) should be used to include the wide range of overlapping phenotypes observed in affected individuals with FMR1 mutations. In this review we focus on the phenotypes and genotypes of children with FXSD.
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Original Articles
  • Tasleem Chechi, Salpi Siyahian, Lucy Thairu, Randi Hagerman, Reymundo ...
    Volume 3 (2014) Issue 4 Pages 147-152
    Released: December 27, 2014
    JOURNALS FREE ACCESS
    The purpose of this study was to identify demographic data, motivational factors and barriers for participation in clinical trials (CTs) at the University of California Davis, MIND Institute. We conducted a cross-sectional survey in 100 participants (81 females and 19 males). The participants had high education levels (only 2% had not completed high school), a mean age of 44 years (SD ± 9.899) and had at least one child with a neurodevelopmental disorder. The diagnosis of Fragile X syndrome (FXS) had a significant association with past participation in CTs (p < 0.001). A statistical significance for age of diagnosis and participation in CTs was also found (z = ‒2.01, p = 0.045). The motivating factors were to help find cures/treatments for neurodevelopmental disorders and to relieve symptoms related to child's diagnosis. Factors explaining lack of participation, unwillingness to participate or unsure of participation were: lack of information/knowledge about the trials, time commitment to participation (screening, appointments, assessments, laboratory tests, etc.) and low annual household income. These results show that a portion of underrepresented minorities (URM) not participating in CTs are willing to participate and suggests that reducing barriers, particularly lack of knowledge/information and time commitment to trials are needed to improve recruitment.
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  • Carolyn M. Yrigollen, Stefan Sweha, Blythe Durbin-Johnson, Lili Zhou, ...
    Volume 3 (2014) Issue 4 Pages 153-161
    Released: December 27, 2014
    JOURNALS FREE ACCESS
    The CGG trinucleotide repeat within the FMR1 gene is associated with multiple clinical disorders, including fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X syndrome. Differences in the distribution and prevalence of CGG repeat length and of AGG interruption patterns have been reported among different populations and ethnicities. In this study we characterized the AGG interruption patterns within 3,065 normal CGG repeat alleles from nine world populations including Australia, Chile, United Arab Emirates, Guatemala, Indonesia, Italy, Mexico, Spain, and United States. Additionally, we compared these populations with those previously reported, and summarized the similarities and differences. We observed significant differences in AGG interruption patterns. Frequencies of longer alleles, longer uninterrupted CGG repeat segments and alleles with greater than 2 AGG interruptions varied between cohorts. The prevalence of fragile X syndrome and FMR1 associated disorders in various populations is thought to be affected by the total length of the CGG repeat and may also be influenced by the AGG distribution pattern. Thus, the results of this study may be important in considering the risk of fragile X-related conditions in various populations.
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Case Reports
  • Zukhrofi Muzar, Patrick E. Adams, Andrea Schneider, Randi J. Hagerman, ...
    Volume 3 (2014) Issue 4 Pages 162-165
    Released: December 27, 2014
    JOURNALS FREE ACCESS
    A debilitating late-onset disorder of the premutation in the FMR1 gene is the neurodegenerative disorder fragile X-associated tremor ataxia syndrome (FXTAS). We report two patients with FXTAS who have a history of substance abuse (opiates, alcohol, and cocaine) which may have exacerbated their rapid neurological deterioration with FXTAS. There has been no case report regarding the role of substance abuse in onset, progression, and severity of FXTAS symptoms. However, research has shown that substance abuse can have a negative impact on several neurodegenerative diseases, and we propose that in these cases, substance abuse contributed to a faster progression of FXTAS as well as exacerbated white matter disease.
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  • María Díez-Juan, Andrea Schneider, Tiffany Phillips, Reymundo Lozano, ...
    Volume 3 (2014) Issue 4 Pages 166-177
    Released: December 27, 2014
    JOURNALS FREE ACCESS
    The use of touchscreen applications for the iPad® allows children with disabilities to improve their personal autonomy and quality of life. In light of this emerging literature and our clinical experience with toddlers and children with Fragile X syndrome (FXS), a randomized clinical trial pilot study was conducted of whether an interactive iPad®based parent training program was efficacious for both individuals with FXS and autism spectrum disorder aged 2-to-12 compared to wait-listed controls. As a second goal, we assessed the difference between direct person-to-person therapy vs. online therapy sessions through telehealth. In this case series report it is presented preliminary results of four individuals with FXS enrolled in the study and described the innovative experience including qualitative and quantitative data analysis. Furthermore, we provide professionals with specific guidelines about the use of touchscreen devices as in-home learning tools and parent training strategies to actively involve families in educational treatments in conjunction with clinical guidance.
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