Search

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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and autism. In most of cases, the molecular basis of this syndrome is a CGG repeat expansion in the 5' untranslated region of the FMR1 gene. It is inherited as an X linked dominant trait, with a reduced penetrance (80% for males and 30% for females). Full mutation (FM) expansion from premutated alleles (PM) is only acquired via maternal meiosis, while paternal transmission always remains in the PM range. We present a 16-year-old girl with a mild fragile X syndrome phenotype. FMR1 gene study showed that the patient inherited a mosaic premutation-full mutation with an unmethylated uninterrupted allele (175, >200 CGG) from her father. The father showed an 88 CGG uninterrupted unmethylated allele in blood and sperm cells. To our knowledge, this is the first case of a FMR1 mosaic premutation-full mutation allele inherited from a PM father. In our opinion, the most likely explanation could be a postzygotic somatic expansion. We can conclude that in rare cases of a child with a full mutation whose mother does not carry a premutation, the possibility of paternal transmission should be considered., (© 2017 Wiley Periodicals, Inc.)

Cytoplasmic FMRP interacting protein 1 ( CYFIP1 ) is a candidate gene for intellectual disability (ID), autism, schizophrenia and epilepsy. It is a member of a family of proteins that is highly conserved during evolution, sharing high homology with its Drosophila homolog, dCYFIP. CYFIP1 interacts with the Fragile X mental retardation protein (FMRP, encoded by the FMR1 gene), whose absence causes Fragile X syndrome, and with the translation initiation factor eIF4E. It is a member of the WAVE regulatory complex (WRC), thus representing a link between translational regulation and the actin cytoskeleton. Here, we present data showing a correlation between mRNA levels of CYFIP1 and other members of the WRC. This suggests a tight regulation of the levels of the WRC members, not only by post-translational mechanisms, as previously hypothesized. Moreover, we studied the impact of loss of function of both CYFIP1 and FMRP on neuronal growth and differentiation in two animal models - fly and mouse. We show that these two proteins antagonize each other's function not only during neuromuscular junction growth in the fly but also during new neuronal differentiation in the olfactory bulb of adult mice. Mechanistically, FMRP and CYFIP1 modulate mTor signaling in an antagonistic manner, likely via independent pathways, supporting the results obtained in mouse as well as in fly at the morphological level. Collectively, our results illustrate a new model to explain the cellular roles of FMRP and CYFIP1 and the molecular significance of their interaction., (© 2017. Published by The Company of Biologists Ltd.)

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., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that occurs in FMR1 premutation carriers. The prevalence of FMR1 premutation carriers in the general population is relatively high, and although rare, a premutation in both X chromosomes may occur in females inheriting a premutation allele from each of both parent carriers. Here, we report the first female with an autozygous (homozygous by descendent) FMR1 premutation allele, who fulfills neurological and radiological FXTAS findings/criteria. Molecular characterization included CGG repeat length, AGG interruption pattern, FMR1 messenger RNA (mRNA), fragile X mental retardation protein (FMRP) level quantification, and single-nucleotide polymorphism (SNP) microarray. Neuroradiological assessment of 3-T magnetic resonance imaging and neurological and cognitive/neuropsychological evaluations were performed. Neurological and neuroradiological examination of the female with the same FMR1 allele in the premutation range (77 CGGs) demonstrated FXTAS features. Further familial evaluation showed a similar neuropsychiatric profile, with impairments in cognitive flexibility and visuospatial function, mainly. A unique family with an autozygous FMR1 premutation female is presented. Neurological/cognitive and neuroradiological examinations revealed FXTAS-specific findings in the female with the autozygous FMR1 premutation allele. The consistent molecular and cognitive/psychiatric phenotype in family members suggests that carrying one or two FMR1 premutation alleles has no effect on illness severity.

The wide spectrum of clinical phenotypes associated with the FMR1 premutation affect more than two million people worldwide. The clinical implications have only been recognized recently despite this disorder constitutes a relevant health problem. The present issue of The Cerebellum is focused on the "2(nd) International Conference on the FMR1 Premutation: Basic Mechanisms and Clinical Involvement" held in Sitges, Barcelona (Spain), from September 30th to October 2nd, 2015. The conference was attended by professionals from different countries in Europe, the USA, Chile, Israel, Australia, and Indonesia and covered the latest clinical and molecular findings resulting from FMR1 premutation studies. Although the pathologies associated with the FMR1 premutation are considered as rare diseases, seventy abstracts were presented. This reflects the relevance of this topic in the medical community and the growing interest among professionals from other disciplines. The major topics discussed included why and how the mRNA toxicity due to a gain of function and non-canonical RAN are responsible for disorders associated with the premutation. Several presentations addressed the impact of these mechanisms in FXTAS and FXPOI, two clinical presentations caused by the FMR1 premutation. Interestingly, a deterioration of the DNA repair machinery was first proposed as the pathogenicity cause of premutation alleles. Communications related to FXTAS and FXPOI animal models were also presented. These models facilitate studies aimed to understand disease progression and early treatment interventions. Finally, there were presentations related to psychiatric, psychological, neurological, and radiological aspects. Interesting discussion on intermediate alleles and their involvement in clinical and reproductive aspects was generated. In this regards, genetic counselling is improved by taking into account the AGG interruptions and including information about the FMR1 premutation associated pathologies although there are still some uncertainties linked to the spectrum of these pathologies. Overall, the meeting covered all aspects of the different pathologies associated with the premutation of the FMR1 gene.

Background: Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a late-onset multisystem neurological disorder characterized by intention tremor and cerebellar ataxia., Objective: We hypothesized that in FMR1 premutation females with FXTAS, a normal X chromosome might more frequently be inactivated; therefore, the aim of this study was to determine the relationship between skewed X chromosome inactivation (XCI) and FXTAS., Methods: We studied the XCI patterns of cases of FMR1 premutation in 10 women with FXTAS and 21 without FXTAS., Results: The distribution of XCI patterns in the FXTAS and no-FXTAS groups showed differences regarding the allele presenting severe skewed XCI. In the FXTAS group, all cases preferentially inactivated the non-expanded X chromosome, whereas in the no-FXTAS group, all inactivated the expanded X chromosome. Nevertheless, no significant differences were found on comparing XCI frequencies among FMR1 premutation carriers with and without FXTAS. As expected, we found statistically significant differences in the skewed XCI on comparing FMR1 premutation women and controls., Conclusion: Although the reduced sample size and blood XCI patterns are two limitations of this study, our results suggest that the skewed XCI of the normal FMR1 allele may be a risk factor for the development of FXTAS. Furthermore, our findings also support the protective effect of the expression of a normal FMR1 allele., (© 2015 S. Karger AG, Basel.)

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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Male premutation carriers presenting between 55 and 200 CGG repeats in the Fragile-X-associated (FMR1) gene are at risk of developing Fragile X Tremor/Ataxia Syndrome (FXTAS), and females undergo Premature Ovarian Failure (POF1). Here, we have evaluated gene expression profiles from blood in male FMR1 premutation carriers and detected a strong deregulation of genes enriched in FXTAS relevant biological pathways, including inflammation, neuronal homeostasis and viability. Gene expression profiling distinguished between control individuals, carriers with FXTAS and carriers without FXTAS, with levels of expanded FMR1 mRNA being increased in FXTAS patients. In vitro studies in a neuronal cell model indicate that expression levels of expanded FMR1 5'-UTR are relevant in modulating the transcriptome. Thus, perturbations of the transcriptome may be an interplay between the CGG expansion size and FMR1 expression levels. Several deregulated genes (DFFA, BCL2L11, BCL2L1, APP, SOD1, RNF10, HDAC5, KCNC3, ATXN7, ATXN3 and EAP1) were validated in brain samples of a FXTAS mouse model. Downregulation of EAP1, a gene involved in the female reproductive system physiology, was confirmed in female carriers. Decreased levels were detected in female carriers with POF1 compared to those without POF1, suggesting that EAP1 levels contribute to ovarian insufficiency. In summary, gene expression profiling in blood has uncovered mechanisms that may underlie different pathological aspects of the premutation. A better understanding of the transcriptome dynamics in relation with expanded FMR1 mRNA expression levels and CGG expansion size may provide mechanistic insights into the disease process and a more accurate FXTAS diagnosis to the myriad of phenotypes associated with the premutation., (Copyright © 2014. Published by Elsevier Inc.)

Genomic rearrangements of chromosome 15q11-q13 are responsible for diverse phenotypes including intellectual disabilities and autism. 15q11.2 deletion, implicating common PWS/AS breakpoints BP1-BP2, has been described in patients with delayed motor and speech development and behavioural problems. Here we report the clinical and molecular characterisation of a maternally inherited BP1-BP2 deletion in two siblings with intellectual, motor and speech delay, autistic syndrome disorder and several dysmorphic features. One of the patients was also a carrier of an FMR1 allele in the low premutation range. The four genes within the deletion were under-expressed in all deletion carriers but FMR1 mRNA levels remained normal. Our results suggest that BP1-BP2 deletion could be considered as a risk factor for neuropsychological phenotypes and that it presents with variable clinical expressivity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

During the last few years, several studies have reported an excess of intermediate FMR1 alleles in patients with cognitive and/or behavioural phenotypes. Here, we report the frequency of intermediate alleles (IAs) in three pathologies, intellectual disabilities (IDs), attention-deficit/hyperactivity disorder and autism, from different Spanish regions. We found 142 IAs among 9015 patients with ID (1.6%), 4 among the 415 ADHD patients (0.96%) and 4 among the 300 autistic patients (1.3%), similar to the frequency reported in our control population. No evidence was found of an excess of IA at the FRAXA locus in any of the study populations, although geographical variability was detected. Moreover, the analysis of 100 transmissions of IAs showed that 95% of these alleles were stable. Only 3% expanded within the same range and 2% expanded to a full mutation in two generations. No evidence of an association between IAs and behavioural or cognitive phenotypes was found, suggesting that IAs are not clearly implicated in these pathologies.

Objectives: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neuropsychiatric degenerative disorder that occurs predominantly in male FMR1 premutation carriers. Recently, a broader FXTAS spectrum that, besides the core features of tremor and gait ataxia, also includes neuropsychiatric symptoms and neuropathy as further clinically relevant symptoms has been described among females. Herein 2 fragile X syndrome families with a mother-daughter FXTAS transmission are described in detail in order to shed more light on the female FXTAS phenotype., Methods: Molecular characterization included CGG repeat length, X-chromosome inactivation pattern determination, as well as FMR1 mRNA and FMRP levels quantification. Neuroradiologic examination was performed by 3-T MRI. Neuropsychological assessment included global cognitive, attention, and executive prefrontal functions, verbal fluencies, verbal memory, and visuospatial perception., Results: Molecular, neurologic, neuropsychiatric, psychological, cognitive, and neuroradiologic features description of 2 fragile X syndrome families with a mother-daughter FXTAS transmission in which dementia is present in both mothers., Conclusions: Although it is not yet clear to what extent FXTAS shortens lifespan, our findings show that FXTAS progresses from mild tremor and/or ataxia to disabling motor and cognitive impairment, compromising the patients' quality of life. Furthermore, our results show that FXTAS in women can also develop as a multisystem neurodegenerative disorder with central and peripheral nervous system involvement, and both motor and mental disturbances.

Within the past few years, there has been a significant change in identifying and characterizing the FMR1 premutation associated phenotypes. The premutation has been associated with elevated FMR1 mRNA levels and slight to moderate reductions in FMRP levels. Furthermore, it has been established that approximately 20% of female premutation carriers present primary ovarian insufficiency (POI) and that fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in one-third of all male premutation carriers older than 50 years. Besides POI and FXTAS, new disorders have recently been described among individuals (especially females) with the FMR1 premutation. Those pathologies include thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. However there are few reports related to FXTAS penetrance among female premutation carriers or regarding these disorders recently associated to the FMR1 premutation. Therefore, we have evaluated 398 fragile X syndrome (FXS) families in an attempt to provide an estimation of the premutation associated phenotypes penetrance. Our results show that signs of FXTAS are detected in 16.5% of female premutation carriers and in 45.5% of premutated males older than 50 years. Furthermore, among females with the FMR1 premutation, penetrance of POI, thyroid disease and chronic muscle pain is 18.6, 15.9 and 24.4%, respectively. The knowledge of this data might be useful for accurate genetic counselling as well as for a better characterization of the clinical phenotypes of FMR1 premutation carriers.

Objective: The association between FMR1 premutation and ovarian dysfunction has been widely studied, and many factors such as the repeat tract size, the sequence organization of the CGG repeat tract, the parental origin of the premutation, and the FMR1 mRNA levels have been examined. X-chromosome inactivation has also been studied as a risk factor, but the reported results are inconclusive. Although some authors did not find an association with the premature ovarian failure manifestation, others suggest that the severity of FMR1 premutation-associated phenotypes may be related to this X-inactivation ratio., Methods: To evaluate the significance of skewed X-inactivation patterns among female premutated carriers, we examined and compared the X-inactivation ratios of 220 female samples from the general population and 260 female premutation carriers phenotypically unaffected or affected by premature ovarian failure., Results: The results failed to show a direct effect of X-inactivation in the manifestation of premature ovarian failure among FMR1 premutation carriers. However, a negative correlation has been found between X-chromosome inactivation and low-medium CGG repeat size alleles., Conclusions: The manifestation of premature ovarian failure cannot be merely explained by the X-chromosome inactivation patterns; however, we speculate that together with other genetic factors, it might contribute.

Fragile X syndrome is the most common form of hereditary mental retardation. The molecular basis of this syndrome is mainly a CGG expansion in the 5' untranslated region of the FMR1 gene. Expansions with more than 200 CGG repeats abolish gene expression causing the classical fragile X phenotype. Premutation carriers (55-200 CGG) have normal cognitive function with increased risk of developing premature ovarian failure and fragile X-associated tremor-ataxia syndrome (FXTAS). Some clinical features associated with FXTAS, such as tremor, gait ataxia, cognitive decline, and generalized brain atrophy, are also seen in other movement disorders. Ninety-five patients referred for HD, who tested negative for the expansion in the IT15 gene, were screened for FMR1 CGG-repeat expansion. One FMR1 premutation male carrier was detected, giving an FXTAS frequency of 1.6%. Our results highlight that FXTAS is still not well diagnosed; therefore, we recommend FMR1 premutation screenings in all patients with late-onset tremor, ataxia, and cognitive dysfunction.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a newly described disorder characterized by progressive action tremor and ataxia that occurs in premutation carriers of the FMR1 gene. The incidence of FMR1 premutated carriers in the general population is relatively high, and therefore FXTAS might explain a considerable number of sporadic, late-onset ataxias. To better establish the prevalence of FXTAS among undiagnosed Spanish patients with ataxia, we have performed a FMR1 premutation screening. Our results evidenced three individuals carrying premutated alleles, giving an estimated FXTAS prevalence of 1.95% among patients with late-onset ataxia (1.15% for males and 3% for females). Molecular characterization of premutation carriers evidences lower fragile X mental retardation 1 protein levels and increased FMR1 mRNA levels. Clinical and neuroimaging findings support FXTAS diagnosis in these patients. Because of the high prevalence of FMR1 premutation in the general population, the description and characterization of the FXTAS syndrome is of great interest as it may represent one of the more common monogenic causes of ataxia, tremor, and dementia. The results obtained in this study demonstrate that FXTAS should be incorporated to spinocerebellar ataxia genetic screening protocols. Early diagnosis of these patients benefits not only them but also the rest of the family that should be advised for the fragile X syndrome.