Fragile X cortex is characterized by decreased parvalbumin-expressing interneurons.

Fragile X syndrome is a genetic neurodevelopmental disorder caused by a mutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene in the X chromosome. Many fragile X syndrome cases present with autism spectrum disorder and fragile X syndrome cases account for up to 5% of all autism spectrum disorder cases. The cellular composition of the fragile X syndrome cortex is not well known. We evaluated alterations in the number of Calbindin, Calretinin, and Parvalbumin expressing interneurons across 5 different cortical areas, medial prefrontal cortex (BA46), primary somatosensory cortex (BA3), primary motor cortex (BA4), superior temporal cortex (BA22), and anterior cingulate cortex (BA24) of fragile X syndrome and neurotypical brains. Compared with neurotypical cases, fragile X syndrome brains displayed a significant reduction in the number of PV+ interneurons in all areas and of CR+ interneurons in BA22 and BA3. The number of CB+ interneurons did not differ. These findings are the first to demonstrate that fragile X syndrome brains are characterized by cortical wide PV+ interneuron deficits across multiple cortical areas. These add to the idea that deficits in PV+ interneurons could disrupt the cortical balance and promote clinical deficits in fragile X syndrome patients and help to develop novel therapies for neurodevelopmental disorders like fragile X syndrome and autism spectrum disorder.

Adaptive, behavioral, and cognitive outcomes in individuals with fragile X syndrome with varying autism severity.

This study aimed to determine the association between severity of autism spectrum disorder (ASD) and cognitive, behavioral, and molecular measures in individuals with fragile X syndrome (FXS). Study inclusion criteria included individuals with FXS and (1) age 6-40 years, (2) full-scale IQ < 84, and (3) language ≥3-word phrases. ASD symptom severity was determined by Autism Diagnostic Observation Schedule-2 (ADOS-2). Other measures identified non-verbal IQ, adaptive skills, and aberrant behaviors. Molecular measures included blood FMR1 and CYFIP1 mRNA levels, FMRP and MMP9 levels. Analysis of variance (ANOVA) and Spearman's correlations were used to compare ASD severity groups. Data from 54 individuals was included with no/mild (N = 7), moderate (N = 18), and severe (N = 29) ASD. Individuals with high ASD severity had lower adaptive behavior scores (47.48 ± 17.49) than the no/mild group (69.00 ± 20.45, p = 0.0366); they also had more challenging behaviors, lethargy, and stereotypic behaviors. CYFIP1 mRNA expression levels positively correlated with the ADOS-2 comparison score(r2  = 0.33, p = 0.0349), with no significant correlations with other molecular markers. In conclusion, autism symptom severity is associated with more adverse cognitive and adaptive skills and specific behaviors in FXS, whereas CYFIP1 mRNA expression levels may be a potential biomarker for severity of ASD in FXS.

Brain Metabolomics in Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).

The course of pathophysiological mechanisms involved in fragile X-associated tremor/ataxia syndrome (FXTAS) remains largely unknown. Previous proteomics and metabolomics studies conducted in blood samples collected from FMR1 premutation carriers with FXTAS reported abnormalities in energy metabolism, and precursors of gluconeogenesis showed significant changes in plasma expression levels in FMR1 premutation carriers who developed FXTAS. We conducted an analysis of postmortem human brain tissues from 44 donors, 25 brains with FXTAS, and 19 matched controls. We quantified the metabolite relative abundance in the inferior temporal gyrus and the cerebellum using untargeted mass spectrometry (MS)-based metabolomics. We investigated how the metabolite type and abundance relate to the number of cytosine-guanine-guanine (CGG) repeats, to markers of neurodegeneration, and to the symptoms of FXTAS. A metabolomic analysis identified 191 primary metabolites, the data were log-transformed and normalized prior to the analysis, and the relative abundance was compared between the groups. The changes in the relative abundance of a set of metabolites were region-specific with some overlapping results; 22 metabolites showed alterations in the inferior temporal gyrus, while 21 showed differences in the cerebellum. The relative abundance of cytidine was decreased in the inferior temporal gyrus, and a lower abundance was found in the cases with larger CGG expansions; oleamide was significantly decreased in the cerebellum. The abundance of 11 metabolites was influenced by changes in the CGG repeat number. A histological evaluation found an association between the presence of microhemorrhages in the inferior temporal gyrus and a lower abundance of 2,5-dihydroxypyrazine. Our study identified alterations in the metabolites involved in the oxidative-stress response and bioenergetics in the brains of individuals with FXTAS. Significant changes in the abundance of cytidine and oleamide suggest their potential as biomarkers and therapeutic targets for FXTAS.

Fragile X Syndrome and Fetal Alcohol Syndrome: Occurrence of Dual Diagnosis in a Set of Triplets.

BACKGROUND: Fragile X syndrome (FXS) and fetal alcohol syndrome disorders are both common causes of intellectual disability in children. When both conditions are present in the same individual, the resultant phenotype may make identification of clinical issues and management challenging. CASE PRESENTATION: In this case report, we present a case of triplets who had significant in utero alcohol exposure; 2 of whom also have FXS and the other not having the fragile X mutation. The siblings with FXS have subtle differences in the physical phenotype compared with the other one, who has prominent features of partial fetal alcohol syndrome instead. However, all 3 siblings have intellectual impairment (although this is more severe in the 2 with FXS), meet diagnostic criteria for autism spectrum disorder, and present with severe behavioral challenges. The clinical presentation of the 2 siblings with FXS is much more severe as compared to a child with FXS alone, and this is likely due to the additive effect of in utero alcohol exposure and environmental factors. We discuss the combination of these 2 pathologies and how this can affect the overall clinical presentation. CONCLUSION: In the management of children with FXS, evaluation for other risk factors that can have neurobehavioral sequelae is important, and these can affect clinical presentation and prognosis.

A Postmortem MRI Study of Cerebrovascular Disease and Iron Content at End-Stage of Fragile X-Associated Tremor/Ataxia Syndrome.

Brain changes at the end-stage of fragile X-associated tremor/ataxia syndrome (FXTAS) are largely unknown due to mobility impairment. We conducted a postmortem MRI study of FXTAS to quantify cerebrovascular disease, brain atrophy and iron content, and examined their relationships using principal component analysis (PCA). Intracranial hemorrhage (ICH) was observed in 4/17 FXTAS cases, among which one was confirmed by histologic staining. Compared with seven control brains, FXTAS cases showed higher ratings of T2-hyperintensities (indicating cerebral small vessel disease) in the cerebellum, globus pallidus and frontoparietal white matter, and significant atrophy in the cerebellar white matter, red nucleus and dentate nucleus. PCA of FXTAS cases revealed negative associations of T2-hyperintensity ratings with anatomic volumes and iron content in the white matter, hippocampus and amygdala, that were independent from a highly correlated number of regions with ICH and iron content in subcortical nuclei. Post-hoc analysis confirmed PCA findings and further revealed increased iron content in the white matter, hippocampus and amygdala in FXTAS cases compared to controls, after adjusting for T2-hyperintensity ratings. These findings indicate that both ischemic and hemorrhagic brain damage may occur in FXTAS, with the former being marked by demyelination/iron depletion and atrophy, and the latter by ICH and iron accumulation in basal ganglia.

A postmortem MRI study of cerebrovascular disease and iron content at end-stage of fragile X-associated tremor/ataxia syndrome.

Brain changes at end-stage of fragile X-associated tremor/ataxia syndrome (FXTAS) are largely unknown due to mobility impairment. We conducted a postmortem MRI study of FXTAS to quantify cerebrovascular disease, brain atrophy, and iron content and examined their relationships using principal component analysis (PCA). Intracranial hemorrhage (ICH) was observed in 4/17 FXTAS cases among which one was confirmed by histologic staining. Compared with seven control brains, FXTAS cases showed higher ratings of T2-hyperintensities (indicating cerebral small vessel disease) in the cerebellum, globus pallidus, and frontoparietal white matter and significant atrophy in cerebellar white matter, red nucleus, and dentate nucleus. PCA of FXTAS cases revealed negative associations of T2-hyperintensity ratings with anatomic volumes and iron content in the white matter, hippocampus, and amygdala, that were independent from highly correlated number of regions with ICH and iron content in subcortical nuclei. Post hoc analysis confirmed PCA findings and further revealed increased iron content in the white matter, hippocampus, and amygdala in FXTAS cases than controls after adjusting for T2-hyperintensity ratings. These findings indicate that both ischemic and hemorrhagic brain damage may occur in FXTAS, with the former marked by demyelination/iron depletion and atrophy and the latter, ICH and iron accumulation in basal ganglia.

Fragile X Syndrome: From Molecular Aspect to Clinical Treatment.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the full mutation as well as highly localized methylation of the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome. Children with FXS are commonly co-diagnosed with Autism Spectrum Disorder, attention and learning problems, anxiety, aggressive behavior and sleep disorder, and early interventions have improved many behavior symptoms associated with FXS. In this review, we performed a literature search of original and review articles data of clinical trials and book chapters using MEDLINE (1990-2021) and ClinicalTrials.gov. While we have reviewed the biological importance of the fragile X mental retardation protein (FMRP), the FXS phenotype, and current diagnosis techniques, the emphasis of this review is on clinical interventions. Early non-pharmacological interventions in combination with pharmacotherapy and targeted treatments aiming to reverse dysregulated brain pathways are the mainstream of treatment in FXS. Overall, early diagnosis and interventions are fundamental to achieve optimal clinical outcomes in FXS.

Recent research in fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a cytosine-guanine-guanine repeat expansion neurological disease that occurs in a subset of aging carriers of the premutation (55-200 cytosine-guanine-guanine repeats) in the FMR1 gene located on the X chromosome. The clinical core involves intention tremor and gait ataxia. Current research seeks to clarify the pathophysiology and neuropathology of FXTAS, as well as the development of useful biomarkers to track the progression of FXTAS. Efforts to implement quantitative measures of clinical features, such as kinematics and cognitive measures, are of special interest, in addition to characterize the differences in progression in males compared with females and the efficacy of new treatments.

Raising Knowledge and Awareness of Fragile X Syndrome in Serbia, Georgia, and Colombia: A Model for Other Developing Countries?

Fragile X syndrome is the most common monogenetic cause of inherited intellectual disability and syndromic autism spectrum disorder. Fragile X syndrome is caused by an expansion (full mutation ≥200 CGGs repeats, normal 10-45 CGGs) of the fragile X mental retardation 1 (FMR1) gene, epigenetic silencing of the gene, which leads to reduction or lack of the gene's product: the fragile X mental retardation protein. In this cross-sectional study, we assessed general and pharmacotherapy knowledge (GK and PTK) of fragile X syndrome and satisfaction with education in neurodevelopmental disorders (NDDs) among senior medical students in Serbia (N=348), Georgia (N=112), and Colombia (N=58). A self-administered 18-item questionnaire included GK (8/18) and PTK (7/18) components and self-assessment of the participants education in NDDs (3/18). Roughly 1 in 5 respondents had correct answers on half or more facts about fragile X syndrome (GK>PTK), which ranged similarly 5-7 in Serbia, 6-8 in Georgia, and 5-8 in Colombia, respectively. No cohort had an average value greater than 9 (60%) that would represent passing score "cut-off." None of the participants answered all the questions correctly. More than two-thirds of the participants concluded that they gained inadequate knowledge of NDDs during their studies, and that their education in this field should be more intense. In conclusion, there is a major gap in knowledge regarding fragile X syndrome among senior medical students in these three developing countries. The finding could at least in part be generalized to other developing countries aimed toward increasing knowledge and awareness of NDDs and fostering an institutional collaboration between developed and developing countries.

Case Report: Coexistence of Alzheimer-Type Neuropathology in Fragile X-Associated Tremor Ataxia Syndrome.

This case documents the co-occurrence of the fragile X-associated tremor ataxia syndrome (FXTAS) and Alzheimer-type neuropathology in a 71-year-old premutation carrier with 85 CGG repeats in the fragile X mental retardation 1 (FMR1) gene, in addition to an apolipoprotein E (APOE) ε4 allele. FXTAS and Alzheimer's Disease (AD) are late-onset neurodegenerative diseases that share overlapping cognitive deficits including processing speed, working memory and executive function. The prevalence of coexistent FXTAS-AD pathology remains unknown. The clinical picture in this case was marked with rapid cognitive decline between age 67 and 71 years in addition to remarkable MRI changes. Over the 16 months between the two clinical evaluations, the brain atrophied 4.12% while the lateral ventricles increased 26.4% and white matter hyperintensities (WMH) volume increased 15.6%. Other regions atrophied substantially faster than the whole brain included the thalamus (-6.28%), globus pallidus (-10.95%), hippocampus (-6.95%), and amygdala (-7.58%). A detailed postmortem assessment included an MRI with confluent WMH and evidence of cerebral microbleeds (CMB). The histopathological study demonstrated FXTAS inclusions in neurons and astrocytes, a widespread presence of phosphorylated tau protein and, amyloid ß plaques in cortical areas and the hippocampus. CMBs were noticed in the precentral gyrus, middle temporal gyrus, visual cortex, and brainstem. There were high amounts of iron deposits in the globus pallidus and the putamen consistent with MRI findings. We hypothesize that coexistent FXTAS-AD neuropathology contributed to the steep decline in cognitive abilities.

Cerebral Microbleeds in Fragile X-Associated Tremor/Ataxia Syndrome.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome is a neurodegenerative disease of late onset developed by carriers of the premutation in the fragile x mental retardation 1 (FMR1) gene. Pathological features of neurodegeneration in fragile X-associated tremor/ataxia syndrome include toxic levels of FMR1 mRNA, ubiquitin-positive intranuclear inclusions, white matter disease, iron accumulation, and a proinflammatory state. OBJECTIVE: The objective of this study was to analyze the presence of cerebral microbleeds in the brains of patients with fragile X-associated tremor/ataxia syndrome and investigate plausible causes for cerebral microbleeds in fragile X-associated tremor/ataxia syndrome. METHODS: We collected cerebral and cerebellar tissue from 15 fragile X-associated tremor/ataxia syndrome cases and 15 control cases carrying FMR1 normal alleles. We performed hematoxylin and eosin, Perls and Congo red stains, ubiquitin, and amyloid ß protein immunostaining. We quantified the number of cerebral microbleeds, amount of iron, presence of amyloid ß within the capillaries, and number of endothelial cells containing intranuclear inclusions. We evaluated the relationships between pathological findings using correlation analysis. RESULTS: We found intranuclear inclusions in the endothelial cells of capillaries and an increased number of cerebral microbleeds in the brains of those with fragile X-associated tremor/ataxia syndrome, both of which are indicators of cerebrovascular dysfunction. We also found a suggestive association between the amount of capillaries that contain amyloid ß in the cerebral cortex and the rate of disease progression. CONCLUSION: We propose microangiopathy as a pathologic feature of fragile X-associated tremor/ataxia syndrome. © 2021 International Parkinson and Movement Disorder Society.

Overlapping Molecular Pathways Leading to Autism Spectrum Disorders, Fragile X Syndrome, and Targeted Treatments.

Autism spectrum disorders (ASD) are subdivided into idiopathic (unknown) etiology and secondary, based on known etiology. There are hundreds of causes of ASD and most of them are genetic in origin or related to the interplay of genetic etiology and environmental toxicology. Approximately 30 to 50% of the etiologies can be identified when using a combination of available genetic testing. Many of these gene mutations are either core components of the Wnt signaling pathway or their modulators. The full mutation of the fragile X mental retardation 1 (FMR1) gene leads to fragile X syndrome (FXS), the most common cause of monogenic origin of ASD, accounting for ~ 2% of the cases. There is an overlap of molecular mechanisms in those with idiopathic ASD and those with FXS, an interaction between various signaling pathways is suggested during the development of the autistic brain. This review summarizes the cross talk between neurobiological pathways found in ASD and FXS. These signaling pathways are currently under evaluation to target specific treatments in search of the reversal of the molecular abnormalities found in both idiopathic ASD and FXS.

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55-200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms.

Fragile X associated neuropsychiatric disorders in a male without FXTAS.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder. In most cases, it is due to an expansion of the CGG triplet to more than 200 repeats within the promoter region of the FMR1 gene. In the premutation (PM) the trinucleotide is expanded to 55-200 repeats. PM carriers can present with disorders associated with the PM including fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated ovarian insufficiency (FXPOI). Recently fragile X-associated neuropsychiatric disorders (FXAND) was proposed as an umbrella term to include the neuropsychiatric disorders that are more prevalent in PM carriers compared to the general population such as anxiety, depression, chronic fatigue, alcohol abuse, and psychosis, among others. The patient in our study was evaluated by a team of clinicians from the University del Valle in Cali who traveled to Ricaurte, a Colombian town known for being a genetic geographic cluster of FXS. A detailed medical history was collected and complete physical, neurological and psychiatric evaluations were performed in addition to molecular and neuroradiological studies. We report the case of a 78-year-old man, PM carrier, without FXTAS whose main clinical presentation consists of behavioral changes and psychosis. Brain imaging revealed white matter lesions in the periventricular region and mild cerebral atrophy. Although anxiety and depression are the most common neuropsychiatric manifestations in PM carriers, it is important to perform a complete psychiatric evaluation since some patients may present with behavioral changes and psychosis.

Ataxia as the Major Manifestation of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Case Series.

Fragile X-associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disease developed by carriers of a premutation in the fragile X mental retardation 1 (FMR1) gene. The core clinical symptoms usually manifest in the early 60s, typically beginning with intention tremor followed by cerebellar ataxia. Ataxia can be the only symptom in approximately 20% of the patients. FXTAS has a slow progression, and patients usually experience advanced deterioration 15 to 25 years after the initial diagnosis. Common findings in brain imaging include substantial brain atrophy and white matter disease (WMD). We report three cases with an atypical clinical presentation, all presenting with gait problems as their initial manifestation and with ataxia as the dominant symptom without significant tremor, as well as a faster than usual clinical progression. Magnetic resonance imaging (MRI) was remarkable for severe brain atrophy, ventriculomegaly, thinning of the corpus callosum, and periventricular WMD. Two cases were diagnosed with definite FXTAS on the basis of clinical and radiological findings, with one individual also developing moderate dementia. Factors such as environmental exposure and general anesthesia could have contributed to their clinical deterioration. FXTAS should be considered in the differential diagnosis of patients presenting with ataxia, even in the absence of tremor, and FMR1 DNA testing should be sought in those with a family history of fragile X syndrome or premutation disorders.

Parkinsonism Versus Concomitant Parkinson's Disease in Fragile X-Associated Tremor/Ataxia Syndrome.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. FXTAS is characterized by the presence of ubiquitin-positive inclusions in neurons and astrocytes and by cerebellar tremor and ataxia. Parkinsonism has been reported in FXTAS, but most patients lack the characteristic rest tremor and severe rigidity seen in idiopathic Parkinson's disease (PD). OBJECTIVE: To describe the frequency of concomitant PD in FXTAS. METHODS: We reviewed the medical record of 40 deceased patients diagnosed with FXTAS and performed a pathology analysis to confirm both FXTAS and PD. RESULTS: Clinical histories indicated that 5 FXTAS patients were diagnosed with idiopathic PD and 2 with atypical parkinsonian syndrome. After pathological examination, we found that 7 patients in the PD clinical diagnosis group had dopaminergic neuronal loss; however, only 2 of 7 presented Lewy bodies (LBs) in the substantia nigra. Therefore, a total of 5% of the 40 cohort patients met the pathologic criteria for the concomitant diagnosis of FXTAS and PD. In addition, 2 patients not clinically diagnosed with PD also had nigral neuronal loss with LBs in substantia nigra. In total 10% of these 40 patients had LBs. CONCLUSION: This report expands our understanding of clinical symptoms and unusual presentations in patients with FXTAS and the concept that the parkinsonism found in FXTAS is sometimes indistinguishable from PD. We propose that FMR1 should be recognized as one of the exceptional genetic causes of parkinsonism with presynaptic dopaminergic loss and LBs.

Fragile X syndrome: clinical presentation, pathology and treatment.

Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their methylation entail the silencing of the FMR1 gene. The FMRP protein (product of the FMR1 gene) interacts with ribosomes by controlling the translation of specific messengers, and its loss causes alterations in synaptic connectivity. Screening for fragile X syndrome is performed by polymerase chain reaction. Current recommendation of the American Academy of Pediatrics is to test individuals with intellectual disability, global developmental retardation or with a family history of presence of the mutation or premutation. Hispanic countries such as Colombia, Chile and Spain report high prevalence of fragile X syndrome and have created fragile X national associations or corporations that seek to bring patients closer to available diagnostic and treatment networks.

El síndrome X frágil es la condición monogenética que produce más casos de autismo y de discapacidad intelectual. La repetición de tripletes CGG (> 200) y su metilación conllevan el silenciamiento del gen FMR1. La proteína FMRP (producto del gen FMR1) interacciona con los ribosomas, controlando la traducción de mensajeros específicos y su pérdida produce alteraciones de la conectividad sináptica. El tamizaje de síndrome X frágil se realiza por reacción en cadena de la polimerasa. La recomendación actual de la Academia Americana de Pediatría es realizar pruebas a quienes presenten discapacidad intelectual, retraso global del desarrollo o antecedentes familiares de afección por la mutación o premutación. Países hispanos como Colombia, Chile y España reportan altas prevalencias de síndrome X frágil y han creado asociaciones o corporaciones nacionales de X frágil que buscan acercar a los pacientes a redes disponibles de diagnóstico y tratamiento.

Síndrome X frágil: presentación clínica, patología y tratamiento / Fragile X syndrome: clinical presentation, pathology and treatment

Resumen El síndrome X frágil es la condición monogenética que produce más casos de autismo y de discapacidad intelectual. La repetición de tripletes CGG (> 200) y su metilación conllevan el silenciamiento del gen FMR1. La proteína FMRP (producto del gen FMR1) interacciona con los ribosomas, controlando la traducción de mensajeros específicos y su pérdida produce alteraciones de la conectividad sináptica. El tamizaje de síndrome X frágil se realiza por reacción en cadena de la polimerasa. La recomendación actual de la Academia Americana de Pediatría es realizar pruebas a quienes presenten discapacidad intelectual, retraso global del desarrollo o antecedentes familiares de afección por la mutación o premutación. Países hispanos como Colombia, Chile y España reportan altas prevalencias de síndrome X frágil y han creado asociaciones o corporaciones nacionales de X frágil que buscan acercar a los pacientes a redes disponibles de diagnóstico y tratamiento.

Abstract Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their methylation entail the silencing of the FMR1 gene. The FMRP protein (product of the FMR1 gene) interacts with ribosomes by controlling the translation of specific messengers, and its loss causes alterations in synaptic connectivity. Screening for fragile X syndrome is performed by polymerase chain reaction. Current recommendation of the American Academy of Pediatrics is to test individuals with intellectual disability, global developmental retardation or with a family history of presence of the mutation or premutation. Hispanic countries such as Colombia, Chile and Spain report high prevalence of fragile X syndrome and have created fragile X national associations or corporations that seek to bring patients closer to available diagnostic and treatment networks.

Fragile X syndrome and associated disorders: Clinical aspects and pathology.

This review aims to assemble many years of research and clinical experience in the fields of neurodevelopment and neuroscience to present an up-to-date understanding of the clinical presentation, molecular and brain pathology associated with Fragile X syndrome, a neurodevelopmental condition that develops with the full mutation of the FMR1 gene, located in the q27.3 loci of the X chromosome, and Fragile X-associated tremor/ataxia syndrome a neurodegenerative disease experienced by aging premutation carriers of the FMR1 gene. It is important to understand that these two syndromes have a very distinct clinical and pathological presentation while sharing the same origin: the mutation of the FMR1 gene; revealing the complexity of expansion genetics.