Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and the leading form of the monogenic cause of autism. Fragile X mental retardation type 1 (FMR1) gene ...premutation is the first single‐gene cause of primary ovarian failure (Fragile X‐associated primary ovarian insufficiency FXPOI) and one of the most common causes of ataxia (fragile X‐associated tremor/ataxia syndrome FXTAS), multiple additional phenotypes such as fibromyalgia, hypothyroidism, migraine headaches, sleep disturbances, sleep apnea, restless legs syndrome, central pain syndrome, neuropathy and neuropsychiatric alterations has been described. Clinical involvement in men and women carrying the FMR1 premutation currently constitutes a real health problem in the society that should be taken into account. It is important to highlight that while in FXS there is a loss‐of‐function of the FMR1 gene, in premutation associated disorders there is a gain of FMR1 mRNA function. To date, the tremendous progress achieved in the understanding of the pathophysiology of FXS, has led to the development of several targeted therapies aimed at preventing or improving the neurological manifestations of the disease. This review is an update of the diseases associated with the FMR1 gene.
Scheme of the dynamic mutation of fragile X mental retardation type 1 (FMR1) gene: alleles range based in the CGG number, transcription, translation and associated phenotype.
Mitochondrial involvement plays an important role in neurodegenerative diseases. At least one-third of adult carriers of a
FMR1
premutation (55-200 CGG repeats) are at risk of presenting an ...adult-onset neurodegenerative disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). In an attempt to provide new insights into the mechanisms involved in the pathogenesis of FXTAS, we characterized mitochondrial function and dynamics by the assessment of oxidative respiratory chain function, mitochondrial content, oxidative stress levels, and mitochondrial network complexity. Regarding mitochondrial function, we found that mitochondrial respiratory capacity is compromised in skin fibroblasts whereas in blood, no differences were observed between the FXTAS and control groups. Furthermore, fibroblasts from FXTAS patients presented altered mitochondrial architecture, with more circular and less interconnected mitochondria being observed. Mitochondrial function and dynamics deregulation and characteristic of neurological disorders are present in FXTAS patients. These features might be limiting temporal and spatial bioenergetics cells supply and thus contributing to disease pathogenesis.
In magnetism, skyrmions correspond to classical three-dimensional spin textures characterized by a topological invariant that keeps track of the winding of the magnetization in real space, a property ...that cannot be easily generalized to the quantum case since the orientation of a quantum spin is, in general, ill defined. Moreover, as we show, the quantum skyrmion state cannot be directly observed in modern experiments that probe the local magnetization of the system. However, we show that this novel quantum state can still be identified and fully characterized by a special local three-spin correlation function defined on neighboring lattice sites-the scalar chirality-which reduces to the classical topological invariant for large systems and which is shown to be nearly constant in the quantum skyrmion phase.
Environment is assumed to play a negative role in quantum mechanics, destroying the coherence in a quantum system and, thus, randomly changing its state. However, for a quantum system that is ...initially in a degenerate ground state, the situation could be different. In this case, the infinite manifold of ground state eigenfunctions can contain a few states of zero entanglement, which can be demonstrated based on the minimization of the von Neumann entropy. Then, following quantum Darwinism, these “classical” combinations are selected and promoted by the quantum environment, which means that different independent observers find them in experiments. In this work, we find and explore such classical states in the eigenspectra of skyrmionic and antiferromagnetic quantum systems starting from a numerical realization of Anderson’s tower of states. The degeneracy of the quantum ground state is shown to be the key for explaining nontrivial properties of magnetic matter in the classical world including topological protection arising in the classical limit.
FMR1 premutation carriers (55‐200 CGGs) are at risk of developing Fragile X‐associated primary ovarian insufficiency as well as Fragile X‐associated tremor/ataxia syndrome. FMR1 premutation alleles ...are also associated with a variety of disorders, including psychiatric, developmental, and neurological problems. However, there is a major concern regarding clinical implications of smaller CGG expansions known as intermediate alleles (IA) or gray zone alleles (45‐54 CGG). Although several studies have hypothesized that IA may be involved in the etiology of FMR1 premutation associated phenotypes, this association still remains unclear. The aim of this study was to provide new data on the clinical implications of IA. We reviewed a total of 17 011 individuals: 1142 with primary ovarian insufficiency, 478 with movement disorders, 14 006 with neurodevelopmental disorders and 1385 controls. Similar IA frequencies were detected in all the cases and controls (cases 1.20% vs controls 1.39%, P = .427). When comparing the allelic frequencies of IA ≥ 50CGGs, a greater, albeit not statistically significant, number of alleles were detected in all the cohorts of patients. Therefore, IA below 50 CGGs should not be considered as risk factors for FMR1 premutation‐associated phenotypes, at least in our population. However, the clinical implication of IA ≥ 50CGGs remains to be further elucidated.
FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). Insights from knock-in mouse model have recently demonstrated that FXPOI is due to an ...increased rate of follicle depletion or an impaired development of the growing follicles. Molecular mechanisms responsible for this reduced viability are still unknown. In an attempt to provide new data on the mechanisms that lead to FXPOI, we report the first investigation involving transcription profiling of total blood from FMR1 premutation female carriers with and without FXPOI. A total of 16 unrelated female individuals (6 FMR1 premutated females with FXPOI; 6 FMR1 premutated females without FXPOI; and 4 no-FXPOI females) were studied by whole human genome oligonucleotide microarray (Agilent Technologies). Fold change analysis did not show any genes with significant differential gene expression. However, functional profiling by gene set analysis showed large number of statistically significant deregulated GO annotations as well as numerous KEGG pathways in FXPOI females. These results suggest that the impairment of fertility in these females might be due to a generalized deregulation of key signaling pathways involved in oocyte maturation. In particular, the vasoendotelial growth factor signaling, the inositol phosphate metabolism, the cell cycle, and the MAPK signaling pathways were found to be down-regulated in FXPOI females. Furthermore, a high statistical enrichment of biological processes involved in cell death and survival were found deregulated among FXPOI females. Our results provide new strategic approaches to further investigate the molecular mechanisms and potential therapeutic targets for FXPOI not focused in a single gene but rather in the set of genes involved in these pathways.
•Transcription profiling from FMR1 premutation females has been performed.•Generalized deregulation of key pathways may lead to the impairment of fertility.•Biological processes involved in cell death and survival were deregulated in FXPOI.
Microcephaly is a rare condition in which the occipitofrontal circumference in a child is more than two standard deviations below the mean of children of the same age and gender. It is mainly caused ...by genetic abnormalities that interfere with the growth of the cerebral cortex during early months of fetal development. We present a case of a 12 years old patient with microcephaly. To identify a possible genetic origin of the phenotype, we performed array CGH and exome sequencing in the patient. Exome sequencing revealed the presence of a de novo missense mutation in the TUBB5 gene (E401K). Mutations in the TUBB5 are mainly responsible for microcephaly but the clinical spectrum is wide, from patients with severe developmental delay, and the presence of different brain malformations, to patients with only slightly cognitive impairment and normal motor development. Our patient shows a milder phenotype than other patients carrying the same mutation. These differences in the clinical features suggest that other factors, presumably genetic or epigenetic, could be modulating clinical expressivity of TUBB5. It is therefore evident that more functional studies are needed to understand the pathology that underlies the clinical spectrum of tubulin associated disease states.
•The patient described in this paper expands the clinical variability of TUBB5 mutations.•Additional genetic or environmental factors could be modulating the resulting phenotype in TUBB5 mutation patients.•More functional analyses are needed to understand adverse biological effects associated to mutations in the tubulin genes.
Fragile X‐associated tremor/ataxia syndrome (FXTAS) is a late‐onset neurodegenerative disorder associated with FMR1 gene premutation alleles (55–200 CGG repeats). Fragile X‐associated tremor/ataxia ...syndrome clinical core features include action tremor, gait ataxia, cognitive deficits progressing to dementia, and frequently parkinsonism. Although the pathogenic molecular mechanism of FXTAS is not completely understood, the restriction of the phenotype to the FMR1 premutation range has given rise to a model based on a RNA toxic gain‐of‐function. Since the identification of the first microRNAs (miRNAs) and their role in normal development, several studies have associated them with neurodegenerative diseases such as Parkinson, Alzheimer and Huntington diseases, suggesting that they play a key role in brain development, as well as in its morphogenesis. Herein, we present the characterization of miRNA expression profiles in FXTAS male patients using deep sequencing‐based technologies and microarray technology. Deep sequencing analysis evidenced 83 miRNAs that were significantly deregulated whereas microarray analysis showed 31. When comparing these results, 14 miRNAs were found deregulated in FXTAS patients. MiR‐424 and miR‐574‐3p showed significant fold change adjusted P‐values in both platforms in FXTAS patients. MiR‐424 has been founded substantially and specifically enriched in human cerebral cortical white matter of Alzheimer disease patients, which, together with cerebral atrophy, is a prominent imaging finding in individuals with FXTAS. The study provides the first systematic evidence of differential miRNA expression changes in FXTAS blood samples. Although further studies are necessary to better characterize the miRNA function in FXTAS disorder, our results suggest that they might contribute to its pathogenesis.
High‐throughput technologies have revealed 14 miRNAs deregulated in blood FXTAS samples relative to controls.
Behavioral symptoms and traits have been proposed as early markers in neurodegenerative diseases. The aim of this study was to evaluate social anxiety and autism in FMR1 premutation carriers using ...the Social Phobia Inventory (SPIN) and the Autism‐Spectrum Quotient (AQ) questionnaires. Fifty‐nine premutation carriers were compared with 50 controls. The SPIN test showed statistically significant differences between female but not male carriers. The AQ questionnaire found statistically significant differences between premutation carriers and controls in the total AQ as well as in the social skills and attention switching subdomains. A gender effect was only observed for the social skills subdomain. Spearman's correlation analysis revealed a moderately positive correlation with the total AQ scores as well as the social skills and communication subdomains. Our results show that fragile X‐associated tremor/ataxia syndrome (FXTAS) patients have higher AQ scores. Moreover, this is the first study to find statistically significant differences between FXTAS and no‐FXTAS premutation carriers in the communication and the imagination subdomains, suggesting that FXTAS patients present a broader autistic phenotype than premutation carriers without FXTAS. Based on our results, a wide range of behavioral/psychiatric traits should be included within the broader phenotypic presentation of individuals with the FMR1 premutation.
BackgroundCompounded sterile drugs have to be prepared in appropriate conditions that ensure their safety in order to prevent medication error and avoid patient harm.PurposeTo analyse risks ...associated with preparation of intravitreal injections (aflibercept and ranibizumab) in our Pharmacy Department to classify them according to their risk level.Material and methodsA risk assessment was conducted to determinate the risk level that had to be applied in the preparation of aflibercept and ranibizumab intravitreal injections.We used two documents as a base: ‘Guide to good manufacturing practice for medicinal products in hospital pharmacy services’, promoted by our national Ministry of Health, and a form elaborated by Group of Pharmaceutical Compounding of our national association of hospital pharmacists to calculate in an easy and quick way the final risk level.Six items were analysed:Preparation procedure.Route of administration.Drug safety profile.Number (quantity) of prepared units.Sensitivity to microbiological contamination.Distribution of the sterile preparation.The assessment of each one resulted in a letter which ranged from the lowest (A) to the highest (D) risk. A combination of all letters allowed us to classify every drug preparation procedure at an appropriate level. If we obtained at least a ‘D’, it was considered a high-risk preparation; if there were a ‘C’ or at least three ‘B’ (and no ‘D’), it had a medium risk; and if less than three ‘B’ (and no ‘C’ and ‘D’) were present, it was classified as a low-risk preparation.ResultsIn the case of aflibercept and ranibizumab intravitreal injections we obtained more than one ‘C’ (and no ‘D’) when matrix risk was applied, and their preparation process was considered to have a medium risk level. It implies they had to be prepared in a laminar flow cabinet in a clean room and be stored in a refrigerator for 9 days.ConclusionMatrix risk application to the compounding process of aflibercept and ranibizumab intravitreal injections in our Pharmacy Department has allowed us to classify them according to their appropriate risk level, and to check their preparation and conservation conditions.No conflict of interest
PDF
