Paediatric Neurology
John W. Scadding, Nicholas A. Losseff in Clinical Neurology, 2011
Fragile X is the most common cause of X-linked learning disability. It affects approximately one in 4000 males and one in 6–8000 females. Dysmorphic features of this condition are hard to recognize in prepubertal children. Common features apart from the learning disability are: attention deficit hyperactivity disorder (ADHD), anxiety, gaze avoidance and other autistic traits, and seizures in approximately 25 per cent. Physical features include a long face with prominent jaw, large ears, flat feet and joint hypermobility with post-pubertal macroorchidism. A proportion of women (perhaps 30–50 per cent) have some intellectual difficulties. Fragile X is a trinucleotide repeat disorder, the endpoint of which is a blocking of production of the fragile X mental retardation protein (FMRP). A full mutation is defined as having at least 200 CGG repeats on Southern blot analysis. Pre-mutations are defined as having 60–200 repeats, typically without observable effects but some older adults have now been described with fragile X associated tremor/ataxia (FX-TAS). In Klinefelter’s (XXY), affected males are tall, with hypogonadism and low verbal IQ.
Fragile X and X-linked Mental Retardation
Merlin G. Butler, F. John Meaney in Genetics of Developmental Disabilities, 2019
The clinical syndrome delineated by Martin and Bell (3) led to the identification of the fragile site on the X chromosome (Xq27.3) for which the disorder was named. Geneticists subsequently used this syndrome in order to identify the fragile X mental retardation 1 gene (FMR1) and the CGG repeat expansion within the 5' untranslated region. Individuals with 55–200 repeats are carriers of the premutation and those with FXS have greater than 200 repeats (full mutation). The clinical and molecular research has revealed a broad spectrum of involvement in those with the full mutation. More recently, an effort to characterize patients with CGG repeats in the high premutation range has revealed that those patients present with a mild phenotype (4,5). Lower CGG expansions in the premutation range have also been associated with emotional symptoms and premature ovarian failure (POF) in women and recently to a new neurological syndrome in older males (6,7).
Genetic Counseling in Assisted Reproductive Technology
Carlos Simón, Carmen Rubio in Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Expansion of the CGG triplet repeat in the FMR1 gene is responsible for fragile X syndrome. Women who carry a premutation in this gene do not have fragile X syndrome but can have a unique set of symptoms associated with a premutation, including primary ovarian insufficiency (POI). Women who carry the full mutation in this gene can have a diagnosis of fragile X syndrome, although, because of skewed X-inactivation and the presence of a fully functioning copy of the FMR1 gene on their other X chromosome, may manifest a milder form of the disease than males who inherit a full mutation. Clinical trials report an incidence of the FMR1 premutation in as many as 14% to 20% of women with familial POI and 2% to 5% of women with sporadic POI (Torrealday et al., 2017).
GABAA receptor subtype modulators in medicinal chemistry: an updated patent review (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Letizia Crocetti, Gabriella Guerrini
The invention of the Children’s Hospital Medical Center [66], filed as a continuation of the granted United States Patents [67,68], discloses methods to alleviate or prevent one or more symptoms associated with Fragile X syndrome by the administration of a therapeutically effective dose of selective α2- and α3-GABAAR PAMs. The applicant has shown that using in FMRl knockout (KO) mouse model the cinnoline compound AZD7325 (Table 1) [46] several key behavioral deficits are normalized or attenuated. This model utilizes mice lacking Fragile X Mental Retardation Protein (FMRP), due to hypermethylation of the FMR1 gene, that is important for the regulation of protein expression. The pharmacological findings are also reported for other α2-/α3-GABAAR subtype PAMs, such as TPA-023, MK-0343, L-838,417, with triazolopyridazine core (Figure 2). Compounds were administered alone at a dose of 1 mg/kg and 3 mg/kg, and were able to significantly reduce the seizure activity in response to a loud stimulus (85 dB and 120 dB) in juvenile and in adult mice. The treatment with a lower dose of AZD7325 also attenuates deficits in objects memory when assessed in a novel object recognition paradigm.
Chinese women with 29–30 FMR1 CGG repeats have an earlier menopause
Published in Climacteric, 2020
R. Tang, R. Chen, M. Luo, S. Lin, Q. Yu
The fragile X mental retardation (FMR1) gene is located at the X chromosome (Xq27.3). Large numbers of triple CGG repeats of the FMR1 5′ untranslated region are related to premature ovarian insufficiency (POI) in women1. It has been estimated that around 11–14% of familial and 2–6% of sporadic POI cases are associated with premutations in FMR1 (55–199 CGG repeats)2. However, the distribution of FMR1 CGG repeats varies with ethnicity3. The pathogenic role of FMR1 premutation in Han Chinese women is controversial. Recent studies from China found that premutation carriers represented 0.82% (1/122)4, 0.5% (2/379)5, and 0.9% (1/117)6 of Chinese POI cases, much lower than studies from other countries2.
Gene therapy for neurological disorders: challenges and recent advancements
Published in Journal of Drug Targeting, 2020
Stefanie A. Pena, Rahul Iyengar, Rebecca S. Eshraghi, Nicole Bencie, Jeenu Mittal, Abdulrahman Aljohani, Rahul Mittal, Adrien A. Eshraghi
Another study explored gene therapy for Fragile X syndrome (FXS) which is caused by a mutation that silences the Fragile X Mental Retardation gene (FMR1) encoding the Fragile X Mental Retardation Protein (FMRP) [108]. The study investigated whether FMRP replacement could improve the fmr1 KO phenotype of enhanced long-term depression which is a form of synaptic plasticity that may be linked to cognitive impairment in FXS [108,109]. An AAV viral vector was used to induce expression of FMRP in the CNS. Analyses of hippocampal synaptic function in fmr1 KO mice showed that paired-pulse low frequency stimulation induced long-term depression in fmr1 KO mice that received the AAV injections of the vector [109]. This study suggests that gene therapy may have the potential to improve cognitive function in FXS. Further investigations are warranted to explore the potential of gene therapy as a treatment modality for ASD.
Related Knowledge Centers
- Gene
- Protein
- Cognitive Development
- Fragile X Syndrome
- Intellectual Disability
- Primary Ovarian Insufficiency
- Autism Spectrum
- Parkinson's Disease
- Phenotype
- Messenger Rna