Dejan B. Budimirovic

What Can We Learn about Autism from Studying Fragile X Syndrome

Despite early controversy, it is now accepted that a substantial proportion of children with fragile X syndrome (FXS) meets diagnostic criteria for autism spectrum disorder (ASD). This change has led to an increased interest in studying the association of FXS and ASD because of the clinical consequences of their co-occurrence and the implications for a better understanding of ASD in the general population. Here, we review the current knowledge on the behavioral, neurobiological (i.e., neuroimaging), and molecular features of ASD in FXS, as well as the insight into ASD gained from mouse models of FXS. This review covers critical issues such as the selectivity of ASD in disorders associated with intellectual disability, differences between autistic features and ASD diagnosis, and the relationship between ASD and anxiety in FXS patients and animal models. While solid evidence supporting ASD in FXS as a distinctive entity is emerging, neurobiological and molecular data are still scarce. Animal model studies have not been particularly revealing about ASD in FXS either. Nevertheless, recent studies provide intriguing new leads and suggest that a better understanding of the bases of ASD will require the integration of multidisciplinary data from FXS and other genetic disorders.

Autism Spectrum Disorder in Fragile X Syndrome: Differential Contribution of Adaptive Socialization and Social Withdrawal

The present study extends our previous work on characterizing the profile of social behavior abnormalities in boys with Fragile X (FraX) and autism spectrum disorder (ASD) using clinically oriented behavioral rating scales and standardized instruments. The goal was to further distinguish behavioral parameters contributing to the diagnostic classification of FraX + ASD. The study design included two cohorts of boys with FraX (3–8 years), a larger main cohort for cross‐sectional analyses (n = 56, 24 with ASD), and a longitudinal subset (n = 30, 11 with ASD) of the main cohort with up to 3 yearly observations. The focus was on the relative contribution of delayed adaptive socialization and social withdrawal, including item components of their corresponding rating instruments, to the diagnosis of ASD in boys with FraX. Using a combination of regression analyses, we demonstrated that: (1) as delayed socialization, social withdrawal is also a correlate of FraX + ASD; (2) items of social withdrawal scales representing avoidance were the main predictors of ASD status, particularly in older boys; (3) adaptive socialization skills reflecting rules of social behavior and recognition and labeling of emotions, linked to verbal reasoning abilities, were selectively associated with FraX + ASD; (4) adaptive socialization is the primary determinant over time of ASD status in boys with FraX; and (5) integrated adaptive socialization‐social withdrawal models allow the identification of distinctive FraX + ASD subgroups. Altogether, our findings suggest that two distinct but interrelated social behavior abnormalities, one linked to impaired cognitive processes (delayed socialization) and the second one to disturbance in limbic circuits (avoidance), play a role in the development of ASD in boys with FraX.

Mosaic FMR1 Deletion Causes Fragile X Syndrome and Can Lead to Molecular Misdiagnosis : A Case Report and Review of the Literature

The most common cause of fragile X syndrome is expansion of a CGG trinucleotide repeat in the 5′UTR of FMR1. This expansion leads to transcriptional silencing of the gene. However, other mutational mechanisms, such as deletions of FMR1, also cause fragile X syndrome. The result is the same for both the expansion mediated silencing and deletion, absence of the gene product, FMRP. We report here on an 11‐year‐old boy with a cognitive and behavioral profile with features compatible with, but not specific to, fragile X syndrome. A mosaic deletion of 1,013,395 bp was found using high‐density X chromosome microarray analysis followed by sequencing of the deletion breakpoints. We review the literature of FMR1 deletions and present this case in the context of other FMR1 deletions having mental retardation that may or may not have the classic fragile X phenotype.

Profiling Early Socio-Communicative Development in Five Young Girls with the Preserved Speech Variant of Rett Syndrome.

Highlights ► Various body movements, facial expressions, eye movements, and vocalizations were used to communicate. ► Non-verbal communicative forms dominated over verbal-communicative forms for most communicative functions. ► Early peculiarities in the speech-language domain during the first year of life became more prominent and evident during the second year of life. ► Socio-communicative deficits are present before regression and persist after this period. ► Assessing socio-communicative forms and functions at early age in children with RTT might essentially contribute to early detection.

Peculiarities in the gestural repertoire: An early marker for Rett syndrome?

Highlights ► The emergence of first gestures in girls with RTT is not necessarily delayed. ► The repertoire of communicative gestures, however, is restricted. ► Although girls with RTT have difficulties in their verbal communicative domain, gestures do not constitute a compensatory mechanism. ► A limited repertoire of gestures and qualitative peculiarities in other speech-language domains might be characteristic for a severe neurodevelopmental disorder like RTT.

Updated report on tools to measure outcomes of clinical trials in fragile X syndrome

ObjectiveFragile X syndrome (FXS) has been the neurodevelopmental disorder with the most active translation of preclinical breakthroughs into clinical trials. This process has led to a critical assessment of outcome measures, which resulted in a comprehensive review published in 2013. Nevertheless, the disappointing outcome of several recent phase III drug trials in FXS, and parallel efforts at evaluating behavioral endpoints for trials in autism spectrum disorder (ASD), has emphasized the need for re-assessing outcome measures and revising recommendations for FXS.MethodsAfter performing an extensive database search (PubMed, Food and Drug Administration (FDA)/National Institutes of Health (NIH)’s www.ClinicalTrials.gov, etc.) to determine progress since 2013, members of the Working Groups who published the 2013 Report evaluated the available outcome measures for FXS and related neurodevelopmental disorders using the COSMIN grading system of levels of evidence. The latter has also been applied to a British survey of endpoints for ASD. In addition, we also generated an informal classification of outcome measures for use in FXS intervention studies as instruments appropriate to detect shorter- or longer-term changes.ResultsTo date, a total of 22 double-blind controlled clinical trials in FXS have been identified through www.ClinicalTrials.gov and an extensive literature search. The vast majority of these FDA/NIH-registered clinical trials has been completed between 2008 and 2015 and has targeted the core excitatory/inhibitory imbalance present in FXS and other neurodevelopmental disorders. Limited data exist on reliability and validity for most tools used to measure cognitive, behavioral, and other problems in FXS in these trials and other studies. Overall, evidence for most tools supports a moderate tool quality grading. Data on sensitivity to treatment, currently under evaluation, could improve ratings for some cognitive and behavioral tools. Some progress has also been made at identifying promising biomarkers, mainly on blood-based and neurophysiological measures.ConclusionDespite the tangible progress in implementing clinical trials in FXS, the increasing data on measurement properties of endpoints, and the ongoing process of new tool development, the vast majority of outcome measures are at the moderate quality level with limited information on reliability, validity, and sensitivity to treatment. This situation is not unique to FXS, since reviews of endpoints for ASD have arrived at similar conclusions. These findings, in conjunction with the predominance of parent-based measures particularly in the behavioral domain, indicate that endpoint development in FXS needs to continue with an emphasis on more objective measures (observational, direct testing, biomarkers) that reflect meaningful improvements in quality of life. A major continuous challenge is the development of measurement tools concurrently with testing drug safety and efficacy in clinical trials.

Genomic studies in fragile X premutation carriers

BackgroundThe FMR1 premutation is defined as having 55 to 200 CGG repeats in the 5′ untranslated region of the fragile X mental retardation 1 gene (FMR1). The clinical involvement has been well characterized for fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). The behavior/psychiatric and other neurological manifestations remain to be specified as well as the molecular mechanisms that will explain the phenotypic variability observed in individuals with the FMR1 premutation.MethodsHere we describe a small pilot study of copy number variants (CNVs) in 56 participants with a premutation ranging from 55 to 192 repeats. The participants were divided into four different clinical groups for the analysis: those with behavioral problems but no autism spectrum disorder (ASD); those with ASD but without neurological problems; those with ASD and neurological problems including seizures; and those with neurological problems without ASD.ResultsWe found 12 rare CNVs (eight duplications and four deletions) in 11 cases (19.6%) that were not found in approximately 8,000 controls. Three of them were at 10q26 and two at Xp22.3, with small areas of overlap. The CNVs were more commonly identified in individuals with neurological involvement and ASD.ConclusionsThe frequencies were not statistically significant across the groups. There were no significant differences in the psychometric and behavior scores among all groups. Further studies are necessary to determine the frequency of second genetic hits in individuals with the FMR1 premutation; however, these preliminary results suggest that genomic studies can be useful in understanding the molecular etiology of clinical involvement in premutation carriers with ASD and neurological involvement.

Fragile X targeted pharmacotherapy: lessons learned and future directions

Our understanding of fragile X syndrome (FXS) pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS-specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts.

Parental reports on early language and motor milestones in fragile X syndrome with and without autism spectrum disorders

Objective: This study examined features of early language and motor milestones in children with fragile X syndrome (FXS) and contrasted these features with a diagnosis of Autism Spectrum Disorder (ASD) later in life in these children. Methods: We retrospectively examined parental report of age of onset for walking and first words for primarily boys with FXS, both with ASD (FXS + ASD) and FXS-only. The diagnosis of ASD was established by DSM-IV criteria, which were complemented by the ADOS. The age of onset was analyzed as a continuous and categorical variable, which were compared to the upper limit of typically developing children. Results: Individuals with FXS-only are more delayed in the onset of first words than first walks. The finding represents a pattern suggesting a continuum as robustly demonstrated in individuals with FXS + ASD vs. FXS-only. Conclusion: Our results support validity of FXS + ASD co-morbidity as a distinct phenotype in individuals with FXS.

Autism spectrum disorder in fragile X syndrome: Cooccurring conditions and current treatment

BACKGROUND AND OBJECTIVE: Individuals with fragile X syndrome (FXS) are frequently codiagnosed with autism spectrum disorder (ASD). Most of our current knowledge about ASD in FXS comes from family surveys and small studies. The objective of this study was to examine the impact of the ASD diagnosis in a large clinic-based FXS population to better inform the care of people with FXS. METHODS: The study employed a data set populated by data from individuals with FXS seen at specialty clinics across the country. The data were collected by clinicians at the patient visit and by parent report for nonclinical and behavioral outcomes from September 7, 2012 through August 31, 2014. Data analyses were performed by using χ2 tests for association, t tests, and multiple logistic regression to examine the association between clinical and other factors with ASD status. RESULTS: Half of the males and nearly 20% of females met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for current ASD. Relative to the FXS-only group, the FXS with ASD (FXS+ASD) group had a higher prevalence of seizures (20.7% vs 7.6%, P < .001), persistence of sleep problems later in childhood, increased behavior problems, especially aggressive/disruptive behavior, and higher use of α-agonists and antipsychotics. Behavioral services, including applied behavior analysis, appeared to be underused in children with FXS+ASD (only 26% and 16% in prekindergarten and school-age periods, respectively) relative to other populations with idiopathic ASD. CONCLUSIONS: These findings confirm among individuals with FXS an association of an ASD diagnosis with important cooccurring conditions and identify gaps between expected and observed treatments among individuals with FXS+ASD.