Search

Inhibitory interneurons are among the most diverse cell types in the brain; the hippocampus alone contains more than 28 different inhibitory interneurons. Dysfunction of interneurons contributes to numerous neurological disorders and their subsequent study has yielded insights into brain function and clinical interventions. This dissertation will focus on the function of inhibitory interneurons in wild type and a mouse model of Fragile X syndrome. Using whole cell current-clamp, we found that spike frequency adaptation (SFA) was highly heterogeneous in low threshold spiking interneurons in the CA1 stratum oriens of wildtype mice. Analysis with k-means clustering parsed the data set into two distinct clusters based on a constellation of physiological parameters and reliably sorted strong and weak SFA cells into different groups. Interneurons with strong SFA fired fewer action potentials across a range of current inputs and had lower input resistance compared to cells with weak SFA. Strong SFA cells also had higher sag and rebound in response to hyperpolarizing current injections. Voltage-clamp recordings showed that the hyperpolarization activated current I [subscript h] was significantly larger in strong SFA cells compared to weak SFA cells. We suggest that the weak SFA cells are canonical OLM neurons and strong SFA cells represent a previously uncharacterized type of hippocampal interneuron, and we refer to them as Low Threshold High I[subscript h](LTH) cells. Using whole-cell current-clamp recordings from fast spiking (FS) and low-threshold spiking (LTS) in area CA1 stratum oriens interneurons from wild type and FX mice, we found that input resistance and action potential firing frequency was lower in FX LTS, but not FS, hippocampal interneurons. LTS neurons were separated into oriens lacunosum molecular (OLM) and LTH groups. Input resistance and action potential firing frequency of LTH, but not OLM neurons, was lower in FX mice compared to WT. The difference in LTH cell input resistance was absent in the presence of h-channel blocker ZD7288 suggesting a difference in I [subscript h] between WT and FX LTH cells. Voltage-clamp experiments revealed that I [subscript h] was significantly higher in FX LTH cells compared to WT. My results on inhibitory hippocampal interneurons, together with previous results from excitatory pyramidal neurons, suggest that changes to voltage-gated ion channels contribute to the altered excitatory/inhibitory balance in the hippocampus in FXS.

Recent advances in neurobiology have provided several molecular entrees for targeted treatments for Fragile X syndrome (FXS). However, the efficacy of these treatments has been demonstrated mainly in animal models and has not been consistently predictive of targeted drugs&rsquo, response in the preponderance of human clinical trials. Because of the heterogeneity of FXS at various levels, including the molecular level, phenotypic manifestation, and drug response, it is critically important to identify biomarkers that can help in patient stratification and prediction of therapeutic efficacy. The primary objective of this study was to assess the ability of molecular biomarkers to predict phenotypic subgroups, symptom severity, and treatment response to metformin in clinically treated patients with FXS. We specifically tested a triplex protein array comprising of hexokinase 1 (HK1), RAS (all isoforms), and Matrix Metalloproteinase 9 (MMP9) that we previously demonstrated were dysregulated in the FXS mouse model and in blood samples from patient with FXS. Seventeen participants with FXS, 12 males and 5 females, treated clinically with metformin were included in this study. The disruption in expression abundance of these proteins was normalized and associated with significant self-reported improvement in clinical phenotypes (CGI-I in addition to BMI) in a subset of participants with FXS. Our preliminary findings suggest that these proteins are of strong molecular relevance to the FXS pathology that could make them useful molecular biomarkers for this syndrome.

Data de publicació electrònica: 25-03-2019 Background & aims: Despite the wide spectrum of experimental compounds tested in clinical trials, there is still no proven pharmacological treatment available for Fragile-X syndrome (FXS), since several targeted clinical trials with high expectations of success have failed to demonstrate significant improvements. Here we tested epigallocatechin-3-gallate (EGCG) as a treatment option for ameliorating core cognitive and behavioral features in FXS. Methods: We conducted preclinical studies in Fmr1 knockout mice (Fmr1−/y) using novel object-recognition memory paradigm upon acute EGCG (10 mg/kg) administration. Furthermore we conducted a double-blind placebo-controlled phase I clinical trial (TESXF; NCT01855971). Twenty-seven subjects with FXS (18–55 years) were administered of EGCG (5–7 mg/kg/day) combined with cognitive training (CT) during 3 months with 3 months of follow-up after treatment discontinuation. Results: Preclinical studies showed an improvement in memory using the Novel Object Recognition paradigm. We found that FXS patients receiving EGCG + CT significantly improved cognition (visual episodic memory) and functional competence (ABAS II-Home Living skills) in everyday life compared to subjects receiving Placebo + CT. Conclusions: Phase 2 clinical trials in larger groups of subjects are necessary to establish the therapeutic potential of EGCG for the improvement of cognition and daily life competences in FXS. This work was supported by the Spanish Ministry of Economy and Competitiveness; ‘Centro de Excelencia Severo Ochoa 2013-2017’; the ‘Centres de Recerca de Catalunya’ Programme / Generalitat de Catalunya’; the Centro de Investigación Biomédica en Red Enfermedades Raras (CIBER) of Rare Diseases; DIUE de la Generalitat de Catalunya [Grups consolidats SGR 2014/1125]; Ministerio de Economía, Industria y Competitividad de España MINECO [SAF2013-49129-C2-1-R and SAF2016-79956-R].

This study describes monozygotic (MZ) male twins with fragile X syndrome (FXS), mosaic for normal size (NS: &lt, 44 CGGs), premutation (PM: 55&ndash, 199 CGG) and full mutation (FM alleles &ge, 200) alleles, with autism. At 4 years of age chromosomal microarray confirmed monozygosity with both twins showing an XY sex complement. Normal size (30 CGG), PM (99 CGG) and FM (388&ndash, 1632 CGGs) alleles were detected in Twin 1 (T1) by standard polymerase chain reaction (PCR) and Southern blot testing, while only PM (99 CGG) and FM (672&ndash, 1025) alleles were identified in Twin 2 (T2). At ~5 years, T2 had greater intellectual impairments with a full scale IQ (FSIQ) of 55 and verbal IQ (VIQ) of 59, compared to FSIQ of 62 and VIQ of 78 for T1. This was consistent with the quantitative FMR1 methylation testing, revealing 10% higher methylation at 80% for T2, suggesting that less active unmethylated alleles were present in T2 as compared to T1. AmplideX methylation PCR also identified partial methylation, including an unmethylated NS allele in T2, undetected by standard testing. In conclusion, this report demonstrates significant differences in intellectual functioning between the MZ twins mosaic for NS, PM and FM alleles with partial FMR1 promoter methylation.

Fragile-X syndrome is one of the most common forms of inherited mental retardation and autistic behaviors. The reduction/absence of the functional FMRP protein, coded by the X-linked Fmr1 gene in humans, is responsible for the syndrome. Patients exhibit a variety of symptoms predominantly linked to the function of FMRP protein in the nervous system like autistic behavior and mild-to-severe intellectual disability. Fragile-X (FraX) individuals also display cellular and morphological traits including branched dendritic spines, large ears, and macroorchidism. The dFmr1 gene is the Drosophila ortholog of the human Fmr1 gene. dFmr1 mutant flies exhibit synaptic abnormalities, behavioral defects as well as an altered germline development, resembling the phenotypes observed in FraX patients. Therefore, Drosophila melanogaster is considered a good model to study the physiopathological mechanisms underlying the Fragile-X syndrome. In this review, we explore how the multifaceted roles of the FMRP protein have been addressed in the Drosophila model and how the gained knowledge may open novel perspectives for understanding the molecular defects causing the disease and for identifying novel therapeutical targets.

Background: Trinucleotide repeat (TNR) expansion is a kind of mutation with instability in the number of microsatellite repeats. This nature of mutation leads to the different kinds of neurological and neuromuscular disorders; among them, fragile-X syndrome is the main cause of intellectual disability in which the increasing number of CGG TNR in 5' untranslated region is the main reason for epigenetic silencing of Fragile X mental retardation 1 gene. The aim of this study is to decrease the CG content of the candidate region to facilitate amplification by conventional polymerase chain reaction (PCR). Bisulfite treatment of the genomic DNA results in conversion of unmethylated cytosine to uridine and may overcome the diagnostic pitfalls. Materials and Methods: The whole blood DNA was extracted and bisulfite treated. Then any simplification in PCR process of desire sequence were assayed through following conventional PCR using specifically designed primers for converted sequence. Bisulfite-treated PCR product of a nearby sequence confirmed our results as a conversion control. Results: Both the control and the candidate sequences undergoing bisulfite treatment were successfully amplified by PCR. Conclusions: Decreasing the GC content of the sequence by bisulfite treating could be a new approach to overcome difficulties in amplifying GC-rich sequences.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability that can be traced to a single gene mutation. This disorder is caused by the hypermethylation of the Fmr1 gene, which impairs translation of Fragile X Mental Retardation Protein (FMRP). In Fmr1 knockout (KO) mice, the loss of FMRP has been shown to negatively impact adult hippocampal neurogenesis, and to contribute to learning, memory, and emotional deficits. Conversely, physical exercise has been shown to enhance cognitive performance, emotional state, and increase adult hippocampal neurogenesis. In the current experiments, we used two different voluntary running paradigms to examine how exercise impacts adult neurogenesis in the dorsal and ventral hippocampal dentate gyrus (DG) of Fmr1 KO mice. Immunohistochemical analyses showed that short-term (7 day) voluntary running enhanced cell proliferation in both wild-type (WT) and Fmr1 KO mice. In contrast, long-term (28 day) running only enhanced cell proliferation in the whole DG of WT mice, but not in Fmr1 KO mice. Interestingly, cell survival was enhanced in both WT and Fmr1 KO mice following exercise. Interestingly we found that running promoted cell proliferation and survival in the ventral DG of WTs, but promoted cell survival in the dorsal DG of Fmr1 KOs. Our data indicate that long-term exercise has differential effects on adult neurogenesis in ventral and dorsal hippocampi in Fmr1 KO mice. These results suggest that physical training can enhance hippocampal neurogenesis in the absence of FMRP, may be a potential intervention to enhance learning and memory and emotional regulation in FXS.

BACKGROUND: We describe a female infant with Fragile-X syndrome, with a fully expanded FMR1 allele and preferential inactivation of the homologous X-chromosome carrying a de novo deletion. This unusual and rare case demonstrates the importance of a detailed genomic approach, the absence of which could be misguiding, and calls for reflection on the current clinical and diagnostic workup for developmental disabilities. CASE PRESENTATION: We present a female infant, referred for genetic testing due to psychomotor developmental delay without specific dysmorphic features or relevant family history. FMR1 mutation screening revealed a methylated full mutation and a normal but inactive FMR1 allele, which led to further investigation. Complete skewing of X-chromosome inactivation towards the paternally-inherited normal-sized FMR1 allele was found. No pathogenic variants were identified in the XIST promoter. Microarray analysis revealed a 439 kb deletion at Xq28, in a region known to be associated with extreme skewing of X-chromosome inactivation. CONCLUSIONS: Overall results enable us to conclude that the developmental delay is the cumulative result of a methylated FMR1 full mutation on the active X-chromosome and the inactivation of the other homologue carrying the de novo 439 kb deletion. Our findings should be taken into consideration in future guidelines for the diagnostic workup on the diagnosis of intellectual disabilities, particularly in female infant cases. Dr. Paula Jorge received a research grant “Bolsa de Investigação DEFI 2015”, CHP, E.P.E. info:eu-repo/semantics/publishedVersion

Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability, with additional symptoms including attention deficit and hyperactivity, anxiety, impulsivity, and repetitive movements or actions. The majority of FXS cases are attributed to a CGG expansion that leads to transcriptional silencing and diminished expression of fragile X mental retardation protein (FMRP). FMRP, an RNA binding protein, regulates the synthesis of dendritically-translated mRNAs by stalling ribosomal translation. Loss of FMRP leads to increased translation of some of these mRNAs, including the CNS-specific tyrosine phosphatase STEP (STriatal-Enriched protein tyrosine Phosphatase). Genetic reduction of STEP in Fmr1 KO mice have diminished audiogenic seizures and a reversal of social and non-social anxiety-related abnormalities. This study investigates whether a newly discovered STEP inhibitor (TC-2153) could attenuate the behavioral and synaptic abnormalities in Fmr1 KO mice. TC-2153 reversed audiogenic seizure incidences, reduced hyperactivity, normalized anxiety states, and increased sociability in Fmr1 KO mice. Moreover, TC-2153 reduced dendritic spine density and improved synaptic aberrations in Fmr1 KO neuronal cultures as well as in vivo. TC-2153 also reversed the mGluR-mediated exaggerated LTD in brain slices derived from Fmr1 KO mice. These studies suggest that STEP inhibition may have therapeutic benefit in FXS.

In recent decades it has become clear that Autism Spectrum Disorder (ASD) possesses a diverse and heterogeneous genetic etiology. Aberrations in hundreds of genes have been associated with ASD so far, which include both rare and common variations. While one may expect that these genes converge on specific common molecular pathways, which drive the development of the core ASD characteristics, the task of elucidating these common molecular pathways has been proven to be challenging. Several studies have combined genetic analysis with bioinformatical techniques to uncover molecular mechanisms that are specifically targeted by autism-associated genetic aberrations. Recently, several analysis have suggested that particular signaling mechanisms, including the Wnt and Ca2+/Calmodulin-signaling pathways are often targeted by autism-associated mutations. In this review, we discuss several studies that determine specific molecular pathways affected by autism-associated mutations, and then discuss more in-depth into the biological roles of a few of these pathways, and how they may be involved in the development of ASD. Considering that these pathways may be targeted by specific pharmacological intervention, they may prove to be important therapeutic targets for the treatment of ASD.

A leading theory holds that neurodevelopmental brain disorders arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this one-dimensional model is rich enough to capture the multiple neural circuit alterations underlying brain disorders. Here, we combined computational simulations with analysis of in vivo two-photon Ca2+ imaging data from somatosensory cortex of Fmr1 knock-out (KO) mice, a model of Fragile-X Syndrome, to test the E/I imbalance theory. We found that: (1) The E/I imbalance model cannot account for joint alterations in the observed neural firing rates and correlations; (2) Neural circuit function is vastly more sensitive to changes in some cellular components over others; (3) The direction of circuit alterations in Fmr1 KO mice changes across development. These findings suggest that the basic E/I imbalance model should be updated to higher dimensional models that can better capture the multidimensional computational functions of neural circuits., eLife digest In many brain disorders, from autism to schizophrenia, the anatomy of the brain appears remarkably unchanged. This implies that the problem may reside in how neurons communicate with one another. Unfortunately, neuroscientists know little about how brain activity might differ from normal in these disorders, or how specific changes in activity give rise to symptoms. One leading theory, first proposed over a decade ago, is that these disorders reflect an imbalance in the activity of excitatory and inhibitory neurons. Excitatory neurons activate their targets, whereas inhibitory neurons suppress or silence them. While studies in mice have lent support to this theory, they have not yet culminated in new treatments for brain disorders. One limitation of the excitation-inhibition imbalance theory is that it is one-dimensional. It assumes that there is an optimal balance of excitation and inhibition, and that brain disorders can be arranged in an imaginary line on either side of this optimum. Disorders to the right of the optimum, such as epilepsy and some forms of autism, feature too much excitation. Disorders to the left, such as the developmental disorder Rett syndrome, feature too much inhibition. But can diverse brain disorders really be classified on the basis of a single property, or do scientists need to consider other factors? To find out, O’Donnell et al. analyzed recordings of brain activity from genetically modified mice with the mutation that causes fragile X syndrome, the most common form of inherited learning disability and autism. The mice showed changes in their overall brain activity compared to control animals. Their neurons also tended to fire in a more synchronized manner. A computer simulation revealed that an imbalance in excitation and inhibition alone could not explain these changes. Yet, a more complex simulation incorporating extra properties of neural circuits did a better job of explaining the altered neural activity seen in the mice. O’Donnell et al. propose that this more advanced multi-dimensional model of changes in neural circuits could be used to screen candidate drugs before testing them in patients. In principle, the model could even help with designing drugs or other interventions by making it easier for researchers to target more precisely the changes in neural circuits that occur in brain disorders.

Fragile X syndrome (FXS) is usually associated with a CGG repeat expansion >200 repeats within the FMR1 gene, known as a full mutation (FM). FM alleles produce abnormal methylation of the FMR1 promoter with reduction or silencing of FMR1 gene expression. Furthermore, premutation (PM: 55–199 CGGs) and full mutation alleles usually expand in size when maternally transmitted to progeny. This study describes a PM allele carried by the mother decreasing to a normal sized allele in a male from a dichorionic diamniotic (DCDA) twin pregnancy, with the female twin inheriting FM (200–790 CGGs), PM (130 CGGs) and normal-sized (39 CGGs) alleles. Further evidence of instability of the maternal PM allele was shown by a male proband (older brother) mosaic for PM (CGG 78 and 150 CGGs) and FM (200–813 CGGs), and a high level of FMR1 promoter methylation, between 50 and 70%, in multiple tissues. The fully-retracted, normal-sized allele was identified by PCR CGG sizing in the male twin, with no evidence of a FM allele identified using Southern blot analysis in multiple tissues collected postnatally and prenatally. Consistent with this, prenatal PCR sizing (35 CGGs) showed inconsistent inheritance of the maternal normal allele (30 CGGs), with single-nucleotide polymorphism (SNP) linkage analysis confirming that the abnormal FMR1 chromosome had been inherited from the mother’s PM chromosome. Importantly, the male twin showed no significant hypermethylation of the FMR1 promoter in all pre and postnatal tissues tested, as well as normal levels of FMR1 mRNA in blood. In summary, this report demonstrates the first postnatal follow up of a prenatal case in which FMR1 mRNA levels were approaching normal, with normal levels of FMR1 promoter methylation and normal CGG size in multiple pre and postnatally collected tissues.

Fragile-X syndrome is the most common form of inherited mental retardation accompanied by other phenotypes, including macroorchidism. The disorder originates with mutations in the Fmr1 gene coding for the FMRP protein, which, with its paralogs FXR1 and FXR2, constitute a well-conserved family of RNA-binding proteins. Drosophila melanogaster is a good model for the syndrome because it has a unique fragile X-related gene: dFmr1. Recently, in addition to its confirmed role in the miRNA pathway, a function for dFmr1 in the piRNA pathway, operating in Drosophila gonads, has been established. In this review we report a summary of the piRNA pathways occurring in gonads with a special emphasis on the relationship between the piRNA genes and the crystal-Stellate system; we also analyze the roles of dFmr1 in the Drosophila gonads, exploring their genetic and biochemical interactions to reveal some unexpected connections.

Fragile-X syndrome is a trinucleotide-repeat-expansion disorder in which the clinical phenotype is believed to result from transcriptional silencing of the fragile-X mental retardation 1 (FMR1) gene as the number of CGG repeats exceeds approximately 200. For premutation alleles ( approximately 55-200 repeats), no abnormalities in FMR1-gene expression have been described, despite growing evidence of clinical involvement in premutation carriers. To address this (apparent) paradox, we have determined, for 16 carrier males (55-192 repeats), the relative levels of leukocyte FMR1 mRNA, by use of automated fluorescence-detection reverse transcriptase-PCR, and the percent of lymphocytes that are immunoreactive for FMR1 protein (FMRP). For some alleles with100 repeats, there was a reduction in the number of FMRP-positive cells. Unexpectedly, FMR1 mRNA levels were elevated at least fivefold within this same range. No significant increase in FMR1 mRNA stability was observed in a lymphoblastoid cell line (160 repeats) derived from one of the carrier males, suggesting that the increased message levels are due to an increased rate of transcription. Current results support a mechanism of involvement in premutation carriers, in which reduced translational efficiency is at least partially compensated through increased transcriptional activity. Thus, diminished translational efficiency may be important throughout much of the premutation range, with a mechanistic switch occurring in the full-mutation range as the FMR1 gene is silenced.

Abstrat publicado em: European Journal of Human Genetics jun 2012;20(Suppl1):308 (P12.097). Disponível em: https://www.eshg.org/fileadmin/www.eshg.org/conferences/2012/ESHG2012Abstracts.pdf Among the genetic causes involved in X-linked intellectual disability (XLID), pathogenic variations in FMR1 (Fragile Mental Retardation 1), AFF2 (AF4/ FMR2 family member 2) and ARX (Aristaless Related Homeobox) genes emerge as main causes. FMR1 and AFF2 genes contain (polymorphic repetitive regions) a repeat polymorphism which is susceptible to suffer dynamic mutation, a process that may induce pathogenic expansions. FRAXEassociated mental retardation (FRAXE-MR) is mainly a non-syndromic form of XLID and is due to AFF2 gene silencing as a consequence of 5’UTR-CCG expansion or gene mutations. A CCG triplet number up to 30 repeats is consider normal, while full expansion (>200 repeats) and hypermethylation of CCG cluster results in FRAXE-MR. AFF2 variants are not frequently sought. An implementation of a cost-effective strategy (co-amplification with other ID genes) represents an improvement in molecular diagnosis with consequent gains in clinical genetic diagnosis and counseling. Herein we present results of AFF2 molecular analysis in a subpopulation of 5000 intellectually-disabled individuals with primary referral for FRAXA screening, by a novel multiplex-PCR strategy. This approach accurately detected normal to pre-mutated alleles. A pre-mutated allele with 68 CCG was identified and further characterized by Southern blot analysis in order to exclude methylation and/or repeat number mosaics, as well as PCR failure. Possible phenotype-genotype correlations based on the clinical data of one previously diagnosed family with AFF2 full expansion, the newly characterized pre-mutation carrier and one case with a new variant of the AFF2 gene will be investigated and presented. Genelink

X-linked intellectual disability (XLID) represents a common cause of monogenic mental retardation, where X-linked conditions are easily identified in affected males, who inevitably manifest a phenotype when harboring a mutant allele, due to their hemizygozity (Chiurazzi et al., 2008). Among the genetic causes involved in XLID, mutations in the Fragile Mental Retardation 1 (FMR1), AF4/FMR2 family member 2 (FMR2) and Aristaless Related Homeobox (ARX) genes emerge as important causes. FMR1 (FRAXA, locus A) and FMR2 (AFF2, FRAXE, locus E) contain polymorphic repetitive regions susceptible to suffer dynamic mutations, a process that may give rise to pathogenic expansions. The expansion to over 200 [CGG] triplets in the FMR1 gene, known as full mutation, is associated with the Fragile X Syndrome [FXS; MIM#300624], the most common form of familial severe intellectual disability (ID). In the case of the ARX gene, different mutational phenomena occur that include insertions, deletions, duplications, missense, nonsense and splice mutations. This makes it difficult to establish genotype/phenotype correlations and concomitantly clinical and molecular guidelines for the molecular analysis of ARX gene (Shoubridge et al., 2010). With the aim to perform pre-screening in ID populations, a multiplex molecular test was developed based on basic PCR methods. The method was applied in intellectually-disabled individuals after exclusion of FMR1 full mutation, focusing on mutational hotspots within the FMR1, FMR2 and ARX genes.

The presence of chromosomal fragility in locus FRAXA, located at Xq27.3, is directly related with Fragile X Syndrome (FXS), where the main symptoms include intellectual and emotional disabilities. The main cause of this monogenic disorder is the transcriptional silencing of the FMR1 gene, due to an expansion of more than 200 CGG repeats, found in the 5’-untranslated region, and its consequent hypermethylation which extends to the promoter region. The diagnostic complexity of FXS is proportional to the heterogeneity underlying this disease. In situations that strongly suggest a clinical diagnosis of FXS, but in which the repetitive region is not expanded, studying the presence of the encoded protein has proved to be very helpful as a complement to the molecular diagnosis. The Fragile X Mental Retardation Protein (FMRP), a selective RNA-binding protein that negatively regulates local protein synthesis in neuronal dendrites, may be detected applying specific antibodies either by immunocytochemistry or Western Blot analysis. The aim of the present work was to optimize such techniques, so as to complement the routine molecular procedures employed in prenatal and postnatal FXS diagnosis. In order to test the efficacy of the procedure, different types of biological samples were used, namely leukocytes from peripheral blood, human brain tissue, cultured amniocytes and chorionic villi. Additionally, slide preparation and detection method for immunocytochemistry, as well as protein isolation for Western Blot, were optimized resorting to several approaches. Both immunocytochemistry and Western Blot techniques allowed the detection of FMRP and were equally suitable. The advantages and disadvantages of the implementation of these techniques in terms of laboratory workflow and specimen type as well as in diagnostic and research context are discussed herein.

The fragile-X syndrome is the most common cause of inherited mental retardation and it is associated with the FMR1 gene on X chromosome. The origin of anatomic anomalies of maxillo-facial complex is still discussed in literature. The authors describe the syndrome and report a clinical case.Genetical and clinical aspects and the incidence of caries, periodontal disease and occlusal abrasion are reviewed. Occlusal conditions, particularly openbite and crossbite, are considered.The incidence of fragile-X syndrome is 1: 2000 in males and 1:4000 in females, despite this the syndrome is diagnosed with a lot of difficulties yet, because of extreme variability of the phenomenological aspects. Patients often show severe mental retardation, linked to a peculiar profile of cognitive, behavioural, and emotional dysfunction and to distinctive anatomic features, which become more evident after puberty. Concerning oral characteristics, it doesn't seem to be a significant association between the syndrome and the incidence of caries or periodontal diseases, while an ogival shaped palate is peculiar.Literature review suggests that when male patients with severe mental retardation without well-known cause are visited, the ipothesis of X-fragile syndrome should be considered. Even though the diagnostic hypothesis may arise from the observation of typical somatic features, the diagnosis can be confirmed only by genetical tests.

A prospective study of the fragile X syndrome [fra(X)] was initiated one year ago to refine the estimates of recurrence risks based on the phenotype of the mother and the family history of the syndrome. The basic unit of data consists of the description of the conceptus of women known to carry the fra(X) gene or of mothers of an isolated case. To date, information on 261 women and their conceptuses was ascertained primarily through prenatal diagnosis; these data are summarized here. Although tests of significance were limited due to small sample sizes in subgroups, the following trends were observed: 1) the penetrance of fra(X) site expression was 80% in both male and female conceptuses suggesting that fra(X) site expression is equally penetrant early in development; 2) the sex ratio at the time of prenatal diagnosis did not differ from one, indicating that selection against fra(X) fetuses, if any, does not differ among sexes; 3) the recurrence risk among offspring of borderline/mildly retarded mothers was higher than that among offspring of intellectually normal mothers; 4) the recurrence risk in offspring did not differ based on the mother's fra(X) site expression; and 5) the recurrence risk in offspring of mothers with isolated cases was slightly less (34%) than that of obligate carrier mothers (41%) although this was not significant. The potential use of these prospective data on the fra(X) syndrome is emphasized.

Objective To analyze sleep architecture and NREM sleep alterations by means of the Cyclic Alternating Pattern (CAP) in children with Down syndrome (DS) and Fragile-X syndrome (fraX), the two most common causes of inherited mental retardation, in order to find out eventual alterations of their sleep microstructure related to their mental retardation phenotypes. Methods Fourteen patients affected by fraX (mean age 13.1 years) and 9 affected by Down syndrome (mean age 13.8 years) and 26 age-matched normal controls were included. All subjects underwent overnight polysomnography in the sleep laboratory, after one adaptation night and their sleep architecture and CAP were visually scored. Results FraX subjects showed a reduced time in bed compared to DS subjects, whereas DS subjects showed a lower sleep efficiency, a higher percentage of wakefulness after sleep onset, and a reduced percentage of stage 2 NREM compared to the other groups. Furthermore, DS and fraX subjects, compared to normal controls, showed a higher percentage of stage 1 NREM and a lower percentage of REM sleep. FraX subjects showed the most disrupted sleep microstructure with low total CAP rate and CAP rate in S2 NREM. Both patient groups showed a lower percentage of A1 and higher percentage of A2 and A3 compared to normal controls. Conclusions The analysis of CAP might be able to disclose new important findings in the sleep architecture of children with mental retardation and might characterize sleep microstructural patterns of the different phenotypes of intellectual disability. Significance The NREM sleep microstructure alterations found in our subjects, associated with the reduction in REM sleep percentage, seem to be distinctive features of intellectual disability.

We previously described a significant association between the HOXA1 G218 allele and increased head circumference in autism [Conciatori et al. (2004); Biol Psychiatry 55:413–419]. The present study reveals identical effects also in normal children. HOXA1 A218G alleles and sex explain as much as 10.9 and 6.8% of the variance in head circumference in 142 pediatric controls and in 191 autistic children, aged 3–16 years (F = 6.777, 3 and 141 df, P

Autism Spectrum Disorders (ASD) are group of developmental disabilities with a complex neurobiological basis including putative changes in the immune system. They are characterized by pervasive qualitative abnormalities in social interactions, communication, and stereotyped behaviour. Matrix metalloproteinases (MMPs) represent a group of proteases which play an important role in neuroinflammation and neurodevelopment. Therefore, they possibly have a crucial function in the etiopathology of ASD. In this review, we summarize the plausibility of the hypothesis that MMPs are involved in the neuropathology of ASD. Possible pathways through which MMPs can contribute to the pathogenesis of ASD are discussed including neuroinflammatory mechanisms inclusive of mediating neuropathological effects of infections, the associations between MMPs and other biomarkers such as cytokines, chemokines and neurotrophic factors. Despite sufficient evidence for such an involvement of MMPs in the neuropathology of ASD, they have not yet been extensively studied in this context. Thus, further research in this field is not only urgently needed but also very promising and may also lead to new therapeutic approaches.

A prospective study of the fragile X syndrome [fra(X)] was initiated one year ago to refine the estimates of recurrence risks based on the phenotype of the mother and the family history of the syndrome. The basic unit of data consists of the description of the conceptus of women known to carry the fra(X) gene or of mothers of an isolated case. To date, information on 261 women and their conceptuses was ascertained primarily through prenatal diagnosis; these data are summarized here. Although tests of significance were limited due to small sample sizes in subgroups, the following trends were observed: 1) the penetrance of fra(X) site expression was 80% in both male and female conceptuses suggesting that fra(X) site expression is equally penetrant early in development; 2) the sex ratio at the time of prenatal diagnosis did not differ from one, indicating that selection against fra(X) fetuses, if any, does not differ among sexes; 3) the recurrence risk among offspring of borderline/mildly retarded mothers was higher than that among offspring of intellectually normal mothers; 4) the recurrence risk in offspring did not differ based on the mother's fra(X) site expression; and 5) the recurrence risk in offspring of mothers with isolated cases was slightly less (34%) than that of obligate carrier mothers (41%) although this was not significant. The potential use of these prospective data on the fra(X) syndrome is emphasized.

A characteristic epileptogenic EEG pattern is described in five of 12 male subjects with fragile-X syndrome evaluated at the Instituto Oasi, via C. Ruggero, Troina, Italy, and Clinica Neurologica, II Universita Roma and Bologna, Italy.