Fragile X Syndrome and Targeted Treatments

Tassanakijpanich, Nattaporn; Cabal-Herrera, Ana María; Salcedo-Arellano, María Jimena; Hagerman, Randi J.

doi:10.14710/jbtr.v6i1.7321

Cited by 6 publications

(5 citation statements)

References 92 publications

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“…Similarly, in clinical studies investigating gaze duration to facial stimuli, a behavior frequently altered in ASD and FXS patients, polymorphisms in the CNR1 gene were shown to modulate striatal responses and gaze duration to happy faces [46,47]. Together, these findings implicate the endocannabinoid-CB 1 receptor signaling system in psychological and behavioral conditions involving altered responsivity to emotional and social stimuli such as those observed in FXS (for reviews, see references [48][49][50]).…”

Section: Dysregulation Of the Ecs In Fxsmentioning

confidence: 86%

Role of the endocannabinoid system in fragile X syndrome: potential mechanisms for benefit from cannabidiol treatment

Palumbo

Thomas

Budimirović

et al. 2023

J Neurodevelop Disord

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Multiple lines of evidence suggest a central role for the endocannabinoid system (ECS) in the neuronal development and cognitive function and in the pathogenesis of fragile X syndrome (FXS). This review describes the ECS, its role in the central nervous system, how it is dysregulated in FXS, and the potential role of cannabidiol as a treatment for FXS. FXS is caused by deficiency or absence of the fragile X messenger ribonucleoprotein 1 (FMR1) protein, FMRP, typically due to the presence of >200 cytosine, guanine, guanine sequence repeats leading to methylation of the FMR1 gene promoter. The absence of FMRP, following FMR1 gene-silencing, disrupts ECS signaling, which has been implicated in FXS pathogenesis. The ECS facilitates synaptic homeostasis and plasticity through the cannabinoid receptor 1, CB1, on presynaptic terminals, resulting in feedback inhibition of neuronal signaling. ECS-mediated feedback inhibition and synaptic plasticity are thought to be disrupted in FXS, leading to overstimulation, desensitization, and internalization of presynaptic CB1 receptors. Cannabidiol may help restore synaptic homeostasis by acting as a negative allosteric modulator of CB1, thereby attenuating the receptor overstimulation, desensitization, and internalization. Moreover, cannabidiol affects DNA methylation, serotonin 5HT1A signal transduction, gamma-aminobutyric acid receptor signaling, and dopamine D2 and D3 receptor signaling, which may contribute to beneficial effects in patients with FXS. Consistent with these proposed mechanisms of action of cannabidiol in FXS, in the CONNECT-FX trial the transdermal cannabidiol gel, ZYN002, was associated with improvements in measures of social avoidance, irritability, and social interaction, particularly in patients who are most affected, showing ≥90% methylation of the FMR1 gene.

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Section: Dysregulation Of the Ecs In Fxsmentioning

confidence: 86%

Role of the endocannabinoid system in fragile X syndrome: potential mechanisms for benefit from cannabidiol treatment

Palumbo

Thomas

Budimirović

et al. 2023

J Neurodevelop Disord

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“…Although FXS has no cure, there are potential targeted treatments that have been studied and evidence suggests that some of these treatments may be more effective in younger children. (McCary & Roberts, 2013; Protic et al, 2019; Tassanakijpanich et al, 2020). For instance, there are data suggesting a beneficial effect on early administration of sertraline in children with FXS (Greiss Hess et al, 2016), and ongoing clinical trials are assessing targeted treatments in young children.…”

Section: Discussionmentioning

confidence: 99%

Inequities in diagnosis of Fragile X syndrome in Colombia

Saldarriaga

Cabal-Herrera

Fandiño-Losada

et al. 2021

Research Intellect Disabil

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Fragile X syndrome (FXS) is a genetic disease inherited through the X chromosome and classified as a triplet repeat disorder with a special non-mendelian inheritance pattern, being the most common cause of inherited intellectual disability and autism. It is caused by an unstable expansion of the CGG repeat in the promoter region of the Fragile X Mental Retardation 1 gene (FMR1), located at Xq27.3 which leads to silencing of the gene (Hagerman et al., 2017). This gene encodes for the fragile X mental retardation 1 protein (FMRP), a ribonucleic acid (RNA)-binding protein that plays a major role in neurodevelopment by regulating synaptic plasticity, dendrite and axon development, learning and memory (Sidorov et al., 2013). There are four types of alleles in FMR1 with different clinical manifestations: normal alleles, with 6-44 CGG repeats, premutation (PM) alleles, with 55-200 CGG repeats, and full mutation alleles (FM) with more than 200 CGG repeats. Intermediate or grey zone alleles are those harbouring between 45 and 54 CGG repeats and are considered precursors of the PM allele (Monaghan et al., 2013). Patients with FM present with varying degrees of intellectual disability and characteristic features such as elongated face, long ears, flat feet, hyperextensible finger joints and macroorchidism (Hagerman, 1987;Saldarriaga et al., 2014). Carriers of the PM allele may have affected children since the number of CGG repeats is unstable and can undergo significant expansion upon generational transmission.Carriers are also at increased risk of presenting premutation disorders such as Fragile X-associated primary ovarian insufficiency (FXPOI) (Wheeler et al., 2014), fragile X-associated neuropsychiatric disorders (FXAND) (Hagerman et al., 2018) and fragile X-associated tremor/ataxia syndrome (Hagerman et al., 2001;Mila et al., 2018).The diagnosis of FXS was originally done through karyotype analysis by the identification of the distal region, known as fragile site, of the long arm of the X chromosome in the band under the light microscope. Nowadays, molecular methods that are

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“…We will mention three drugs that we consider having the potential to be approved for patients with Fragile X syndrome: metformin, cannabidiol and the phosphodiesterase inhibitor (PDE4D) that upregulates cAMP in the mouse and in patients with Fragile X syndrome 80 . For a more detailed review of targeted treatments that are under investigation, we recommend referring to reviews dedicated to this topic 61 , 81 .…”

Section: Treatmentmentioning

confidence: 99%

“…Haremos mención a tres medicamentos que consideramos tienen potencial para ser aprobados en pacientes con síndrome de X frágil, la metformin, el cannabidiol y el inhibidor de la fosfodiesterasa 4D (PDE4D) que aumenta los niveles de AMPc en el modelo murino y en pacientes con síndrome de X frágil 80 . Para una revisión detallada de los medicamentos dirigidos que están siendo estudiados recomendamos referirse a revisiones dedicadas a este tema 61 , 81 .…”

Section: Tratamientos Dirigidosunclassified

Fragile X syndrome in children

Acero-Garcés,

Saldarriaga,

Cabal-Herrera

et al. 2023

Colomb Med

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Fragile X syndrome is caused by the expansion of CGG triplets in the FMR1 gene, which generates epigenetic changes that silence its expression. The absence of the protein coded by this gene, FMRP, causes cellular dysfunction, leading to impaired brain development and functional abnormalities. The physical and neurologic manifestations of the disease appear early in life and may suggest the diagnosis. However, it must be confirmed by molecular tests. It affects multiple areas of daily living and greatly burdens the affected individuals and their families. Fragile X syndrome is the most common monogenic cause of intellectual disability and autism spectrum disorder; the diagnosis should be suspected in every patient with neurodevelopmental delay. Early interventions could improve the functional prognosis of patients with Fragile X syndrome, significantly impacting their quality of life and daily functioning. Therefore, healthcare for children with Fragile X syndrome should include a multidisciplinary approach.

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Fragile X Syndrome and Targeted Treatments

Cited by 6 publications

References 92 publications

Role of the endocannabinoid system in fragile X syndrome: potential mechanisms for benefit from cannabidiol treatment

Role of the endocannabinoid system in fragile X syndrome: potential mechanisms for benefit from cannabidiol treatment

Inequities in diagnosis of Fragile X syndrome in Colombia

Fragile X syndrome in children

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