Genetic Counselling Empowers Parents of Children with Intellectual Disabilities : A Fragile X Syndrome Perspective

The COVID-19 pandemic has led to a devastating loss of life, staggering economic losses, and untold psychological distress for people all over the world. People with intellectual and developmental disabilities (IDD) have been impacted as well and, in many ways, they are particularly vulnerable to the pernicious effects of the pandemic. Preliminary data reported in the popular press, for example, suggest that people with IDD who contracted COVID-19 have died at more than twice the rate of that of the general population. In addition, most of the services and supports required to optimize inclusion of people with IDD in their communities were severely disrupted during the pandemic. Diagnostic and developmental evaluations to determine eligibility for services, in-home behavioral services, special education and ancillary school-based therapies, and supported employment were limited or halted completely. Indeed, the vulnerability of our systems of services and supports for people with IDD to disruption by natural and human-made disasters was made abundantly clear during the past few months.The pandemic, however, has also provided glimpses into how we could redesign services and supports for people with IDD in ways that could make them more robust and less susceptible to disruption. At the heart of this redesign is technology. At the UC Davis MIND Institute and at other academic health systems around the country, clinic visits with psychologists, psychiatrists, developmental-behavioral pediatricians, genetic counselors, and other professionals were quickly shifted to video visits through video teleconferencing technology platforms, such as Skype© and Zoom©. K-12 schools shifted to online classrooms and curricula, including for students receiving special education services. Families even took educational and fun trips to museums and zoos through virtual reality technology.I believe that a lesson from the pandemic is that technology-delivered services should be more fully developed so as to allow us to continue to support people with IDD when the next disaster makes face-to-face contact difficult. Moreover, I would encourage the widespread use of technology-delivered services as a complement to face-to-face services even during non-disaster "normal" periods of life. Technology offers the promise of making professional expertise accessible to more people, removing barriers that create health disparities based on race, ethnicity, geography, and economic circumstances, and all while providing services in cost-effective ways.At the same time, not every service will lend itself to technology-based delivery, or at least not without considerable adaptation. Anecdotal reports from many parents suggest that online classrooms for students with special needs, without consideration of how to support engagement and reduce challenging behaviors, have not been effective. So, rather than just assuming that every service can be delivered through technology, we must do the hard work of adapting the services and the technologies in an iterative process designed to provide evidence of efficacy, to develop procedures for individualization, and to show that the technology-delivered services can be brought to scale and be cost effective. And finally, there must be evidence that the technology-delivered services reduce rather than reinforce or exacerbate disparities in access that are common according to race, ethnicity, income, etc. If technology just makes getting care more convenient for those citizens who already have access to the best care and does not reach those citizens who are typically marginalized, we have failed as researchers and professionals.In the remainder of this address, I will summarize some of the research conducted by my lab group to develop a distance-delivered, parent-implemented language intervention (PILI). I will also briefly touch on a few other examples of technology-delivered services by other researchers to provide a sense of the scope of work ongoing in the field.There is considerable evidence from longitudinal correlational studies that the ways in which caregivers interact with, and talk to, children shape language development in typically developing children (Hart & Risley, 1995). Importantly, there is also evidence that the same types of parent input and interaction that optimize typical development are facilitative of language in children with developmental challenges, including those with autism spectrum disorder (ASD) or an intellectual disability (ID) associated with conditions, such as Down syndrome and fragile X syndrome (e.g., Haebig et al., 2013; Warren et al., 2010). The unique learning and behavioral challenges associated with IDD, however, make it difficult for parents and other adult caregivers to engage in these language-facilitating behaviors – behaviors toward which the adults would be naturally inclined. In no way is this to suggest that parents are at fault for their children's language problems. Instead, it is the case that the unique characteristics of the child with IDD, which slow language learning in and of themselves, also "create" an environment that is less conducive to learning than it could be. The goal of PILI is to help parents learn ways to engage their children in adaptive interactions in which the use of language-facilitating strategies is again possible. In other words, we train parents to serve as "therapists" and deliver a naturalistic intervention to their children.The PILI training is largely delivered to parents individually in their homes through video teleconferencing and other digital technologies. Once trained, parents can then engage in supportive, "therapeutic" interactions with their children at home or in other settings that they experience together in daily life. There are many potential advantages of this distance-delivered approach.The goal of PILI is to teach parents to be more "verbally responsive" and thereby more supportive of their child's language learning. A verbally responsive style of interaction entails:Verbal responsivity provides the optimal interactive context for language learning throughout development, although the implementation will differ depending of the age and developmental capacity of the child. Verbally responsive interactions between a parent and preschooler with IDD will look different in many respects from a verbally responsive interaction between a parent and an adolescent with IDD.We have developed and tested different telehealth-delivered PILIs for people with fragile X syndrome (FXS), which is the leading inherited cause of ID and the leading single-gene cause of autism spectrum disorder (ASD). The different versions were adapted according to the ages and developmental levels of the target group. At the heart of all the interventions, however, was the goal of improving outcomes for people with FXS by teaching and supporting increased verbal responsivity of parents through technology.We have developed and tested the efficacy of a distance-delivered PILI for 2- to 5-year-olds with FXS (McDuffie, Oakes et al., 2016; Oakes et al., 2015). The intervention was delivered in the context of dyadic play with objects. The participants were six boys with FXS and their biological mothers. The boys ranged in age from 27 to 43 months at the start of their participation in the intervention. All had IQs in the range of ID, and the language levels ranged from no productive language to the production of an occasional multiword utterance.The primary focus of the intervention was on increasing child communication and secondarily on improving spoken language. Parents were taught three strategies. In follow-in commenting, the parent was to describe an object, activity, or event that was the focus of the child's attention. In interpreting/expanding, the parent was to respond to a child utterance with a fuller, more adult-like version and to a child nonverbal behavior with an utterance that ascribed an intention to that behavior. In indirect prompting, the parent was to create a need for the child to communicate by offering a choice or delaying a desired activity or object. The parent was also taught strategies to reduce child challenging behaviors.Parents were taught these strategies over a period of 17 weeks. The dyads visited the clinic once per month. In these clinic visits, the clinician presented the rationale for the strategies to be learned, along with video examples. This didactic session was followed by real-time coaching by the clinician as the parent played with the child. In addition to the clinic visits, there were weekly real-time dyadic play coaching sessions delivered into the home by the clinician through video teleconferencing. Parents were given a laptop computer equipped with a webcam for these in-home sessions. There were also weekly distance observation sessions for the purpose of taking data on the dyad's progress with no coaching or feedback provided. Finally, pre- and post-treatment assessments of play interactions without coaching were conducted in the clinic. Throughout the intervention, the clinician encouraged the parent to use the targeted strategies in naturally occurring interactions throughout the day.We used a multiple baseline design in which the length of the baselines varied and the initiation of the intervention was staggered across participants so that we could be more certain that changes in parent and child behavior were due to participation in the intervention. The primary data for evaluating the efficacy of the intervention came from the observation sessions. In terms of parental behavior, the frequency of use of the targeted strategies increased during the intervention relative to baseline. In fact, there was minimal overlap for most parents in terms of their frequency of use of the strategies between baseline and treatment, although there was variability across parents in the magnitude of change. In terms of child behavior, the frequency of communication acts was greater in treatment than in baseline. This was true in general both for prompted and spontaneous acts of child communication. Increased communicativeness is important because its leads to longer and more satisfying interactions for parent and child and creates opportunities for parents to provide the child with information about the language being learned, thereby creating a positive developmental cascade.Post-treatment surveys and interviews indicated that parents found the intervention to be helpful and felt that their interactions with their children were more positive and fulfilling as a result. These latter findings are important because positive parental attitudes are likely to be a prerequisite for the continued use of the targeted strategies after participation with the clinicians and the study has ended.We have developed and tested the efficacy of a parent-implemented language intervention for preadolescents and adolescents with FXS in three studies, one a series of three single-case analyses (McDuffie, Machalicek et al., 2016), the second a small-scale randomized controlled trial (RCT; McDuffie et al., 2018), and the third an RCT of a medication with all participants also receiving distance-delivered PILI (Thurman et al., 2020). Across the studies, the participants with FXS ranged from 10 to 17 years of age, most were male, and all had IQs in the range of ID. The language skills of the people with FXS ranged from largely single-word and only occasional multiword speech to frequent use of multiword utterances, with all participants well below age-level expectations as regards language.Parents were taught to use verbally responsive language strategies; however, because of the ages of the youth with FXS, the intervention was embedded in the context of shared story telling using wordless picture books rather than play with objects. The book functioned to provide a shared conversational topic for the dyad. In contrast to the study with young children, the focus was on building language skills. The intervention was delivered entirely into the family home through video teleconferencing, with no clinic-based instructional component. The intervention began with two parent education sessions that described the rationale for the targeted strategies and video examples. The intervention then continued for 12 weeks with four types of activities each week.A different book was used each week so that the youth with FXS was not simply learning how to tell a specific story but was instead gaining more generalized language skills. The books were digitized and presented on an iPad.Parents were taught three strategies. The first was to use open-ended wh-questions, such as, "What is the boy doing?" and "How is the boy feeling?" These questions tend to elicit a verbal response and thus, draw the youth with FXS into the conversation and allow him/her to practice new language skills. The second strategy was to use expansions, which entail the parent providing a fuller, more mature version of the youth's utterance and thereby an opportunity to learn new words and syntactic forms. The third strategy was the use of fill-in-the-blank statements in which the parent started a sentence but through a rising intonation and pause conveyed the expectation that the youth with FXS was to complete the sentence. Fill-in-the blank allowed the youth with FXS to participate in the conversation in way that increased the chances of communicative success.The results across the three studies were generally consistent in supporting the efficacy of the intervention. In assessing treatment-induced changes, we examined story-telling interaction with previously unseen books with the parent at home and in the clinic, as well with an examiner in the clinic. In terms of parent behavior, participation in the treatment led to increases in the use of all three targeted strategies. In terms of the behavior of the youths with FXS, participation in the treatment led to sizable increases in a measure of expressive vocabulary (i.e., the number of different words used). The intervention also led to an increase in the length of the dyadic story-telling sessions both in time and number of story-related utterances. It was also found that changes in youth vocabulary were correlated with changes in parental behavior; that is, the more progress the parents made learning the strategies, the more progress the youth with FXS made. Finally, the same pattern of findings was observed for measures derived from parent-youth interactions at home and in the clinic and some non-targeted language skills (e.g., inferential language) also improved (Nelson et al., 2018). These data suggest that the intervention promoted growth in both mother and child behavior that was not specific to a single story or setting but more general to the dyadic shared story-telling context.At the same time, however, there were limitations in the efficacy of the intervention. First, no consistent differences related to treatment were found in the expressive syntax of the youth with FXS. This suggests the possibility that more direct and explicit instruction may be needed to improve syntax in this population. Second, the gains observed for the youth with FXS in vocabulary in their interactions with their mothers did not generalize to their interactions with the examiner in the clinic context. We believe that this lack of generalizability to the examiner-led interaction reflects the fact that unlike the scaffolding that parents were providing through their use of verbally responsive strategies, the examiner by design minimized his/her participation and provided minimal scaffolding. Thus, it may be that the vocabulary skills of the youth with FXS were still forming and not sufficiently developed so as to be used without considerable supportIn summary, a training program for parents delivered into the home through telehealth technology can lead to improvements in communication and language for people with ID across a wide age range. At the same time, however, not all aspects of language seem to benefit from the intervention in its current form and generalization of gains may be limited to highly scaffolded contexts. We plan to address these limitations in future research. We also are exploring whether the coaching can be reduced and supplemented with self-guided online modules to make the intervention more cost effective.Telehealth technology is arguably the most widely used form of technology to deliver behavioral and mental health services to people with IDD. These uses extend beyond treatment delivery of the sort I have described above to in-home assessments and evaluations. No doubt there will be an explosion of examples of other technologies and uses post-pandemic. Here are just a few examples of technologies being tested now.As we move out of the pandemic and achieve some return to "normal" life, it is imperative that we not forget the lessons we have learned over the past several months. We desperately need a more robust and equitable system of services and supports for people with IDD. Evidence-based, technology-driven approaches to delivery of services will be an important part of the solution. However, additional resources and stronger government policies that lead to more and better coordinated systems are also needed. I know that AAIDD will help lead the way forward to improve choice and quality of life for people with IDD and their families.

A large-scale cytogenetic study of the causes of intellectual disability (ID) in children from special schools and institutions was made in Taiwan between 1991 and 1996. The screening methods and the identification of subjects with ID consisted of both clinical evaluation (i.e. photographs, questionnaires on family, pre-, peri- and postnatal history, and hospital records, including IQ) and further laboratory studies for diagnosis (i.e. standard chromosome analysis, and if indicated, high-resolution banding, cytogenetic fragile-X study or molecular techniques). A total of 11,892 patients were enrolled in this study. After excluding the acquired causes of ID, such as infections and the sequelae of brain insults, or the well-known single-gene disorders and other multifactorial diseases, 4372 (36.8%) cumulative cases were recruited for karyotyping studies according to their phenotypes and medical records. Abnormal karyotypes were noted in 1889 children (43.2% of all selected children). Thus, the overall incidence of chromosomal aberrations in subjects with ID was estimated as 15.9%. Down's syndrome, the most common cause of ID, accounted for 82.4% of all patients with abnormal karyotypes. The causes of ID were considered to be prenatal in 55.2% (n = 6564) of cases, perinatal in 9.5% (n = 1130), postnatal in 3.3% (n = 392) and unknown in 32.0% (n = 3805) of cases. Two large groups were classified: (1) serious ID (37%), including profound, severe and moderate categories; and (2) mild ID (63%). The causes (pre-, peri- and postnatal, and unknown) in these two populations were: 70%, 10.5%, 5.4% and 14.1%, and 46.5%, 8.9%, 2.1% and 42.5%, respectively. Genetic causes accounted for 38.5% (n = 4578) of all cases in this study, including 1557 with Down's syndrome, 233 with fragile-X syndrome, 199 with other various chromosomal abnormalities (i.e. unbalanced translocation, supernumerary markers and structural rearrangements), 238 with a defined or presumed single-gene defect, and 98 with a recognized contiguous gene syndrome (Prader-Willi, 56; Angelman, 34; Williams, 5; and Kallmann, 3); 2120 cases had familial ID. Multiple anomalies of undefined pattern, but without chromosomal aberration, infantile autism, ID of normal phenotype or family history, were of the other categories. Patients with a single-gene disorder or chromosomal aberration, especially those with unbalanced translocated or rearranged chromosomes, had genetic counselling and family studies. Pre-screening with photographs and questionnaires may give a better costbenefit than blind mass cytogenetic studies for each individual with ID.

Self-determination refers to setting goals and making decisions regarding one's own life with support from others as needed. Research on people with intellectual and developmental disabilities has established the importance of self-determination for quality of life outcomes, such as increased independence and life satisfaction. However, self-determination has not been characterised specifically in fragile X syndrome (FXS), the leading inherited cause of intellectual disability. Relative to youth with other forms of intellectual and developmental disabilities, youth with FXS may face exceptional barriers to the development of self-determined behaviour. In addition to intellectual disability, the FXS behavioural profile is characterised by high rates of autism and anxiety that may further limit opportunities for youth with FXS. The heritable nature of the condition can also yield a distinctive family environment, with siblings and parents also living with fragile X or its associated conditions. Considering these unique challenges, the present study examined self-determination in young adult males and females with FXS and explored whether factors such as language skills, adaptive behaviour and autism traits were associated with self-determination capacity and opportunities. The present study included 9 females and 36 males with FXS between the ages of 17 and 25years. Caregivers (mothers or fathers) completed the American Institute for Research Self-Determination Assessment, which is a questionnaire that yields three scores: self-determination capacity, opportunities for self-determination at home and opportunities for self-determination at school. Caregivers endorsed a wide range of self-determination capacity and opportunities, with ratings for opportunities at home and school exceeding ratings of capacity. Better adaptive behaviour skills were associated with more self-determination capacity, and the presence of more autism traits was associated with fewer opportunities at school. Results from this study contribute to our understanding of avenues to best support young adults with FXS as they transition to adulthood. Our findings also have implications for practice, such that interventions targeting adaptive behaviours and self-determination may be an effective approach for promoting autonomy and independence for young adults with FXS. Additionally, caregivers and educators should continue to provide opportunities to practise self-determination, regardless of their perception of capacity.

Fragile X mental retardation protein (FMRP) loss causes Fragile X syndrome (FXS), a major disorder characterized by autism, intellectual disability, hyperactivity, and seizures. FMRP is both an RNA- and channel-binding regulator, with critical roles in neural circuit formation and function. However, it remains unclear how these FMRP activities relate to each other and how dysfunction in their absence underlies FXS neurological symptoms. In testing circuit level defects in the Drosophila FXS model, we discovered a completely unexpected and highly robust neuronal dye iontophoresis phenotype in the well mapped giant fiber (GF) circuit. Controlled dye injection into the GF interneuron results in a dramatic increase in dye uptake in neurons lacking FMRP. Transgenic wild-type FMRP reintroduction rescues the mutant defect, demonstrating a specific FMRP requirement. This phenotype affects only small dyes, but is independent of dye charge polarity. Surprisingly, the elevated dye iontophoresis persists in shaking B mutants that eliminate gap junctions and dye coupling among GF circuit neurons. We therefore used a wide range of manipulations to investigate the dye uptake defect, including timed injection series, pharmacology and ion replacement, and optogenetic activity studies. The results show that FMRP strongly limits the rate of dye entry via a cytosolic mechanism. This study reveals an unexpected new phenotype in a physical property of central neurons lacking FMRP that could underlie aspects of FXS disruption of neural function.SIGNIFICANCE STATEMENT FXS is a leading heritable cause of intellectual disability and autism spectrum disorders. Although researchers established the causal link with FMRP loss >;25 years ago, studies continue to reveal diverse FMRP functions. The Drosophila FXS model is key to discovering new FMRP roles, because of its genetic malleability and individually identified neuron maps. Taking advantage of a well characterized Drosophila neural circuit, we discovered that neurons lacking FMRP take up dramatically more current-injected small dye. After examining many neuronal properties, we determined that this dye defect is cytoplasmic and occurs due to a highly elevated dye iontophoresis rate. We also report several new factors affecting neuron dye uptake. Understanding how FMRP regulates iontophoresis should reveal new molecular factors underpinning FXS dysfunction.

28 - Fragile X Syndrome and FMR1 Variants

Fragile X Mental Retardation Protein positively regulates PKA anchor Rugose and PKA activity to control actin assembly in learning/memory circuitry

Fragile X Syndrome (FXS) is the most common x-linked monogenic cause of Intellectual Disability (ID) and Autism Spectrum Disorder (ASD). Taking care of children with ID is challenging and overwhelming due to the multiple facets of caregiving. This scoping review aimed at summarizing the qualitative literature on the experiences of families living with FXS, identify key themes and determine the gaps in the extant literature. We conducted a literature search in May 2019 using four databases; PubMed, Web of Science, African-Wide-Information, and Scopus. The keywords used in our search strategy were associated with caregivers, lived experiences, FXS, and qualitative research. All English language articles with full-text reporting were included. Studies associated with other neurodevelopmental conditions and quantitative studies were excluded. We identified 12 out of 203 articles that described the lived experiences of families with FXS. Most articles originated from the United States of America and mothers were the main caregivers. We summarized our findings into four major themes which are; grief experiences, challenges of living with FXS, coping mechanisms and the need to plan for future outcomes. This scoping review highlights the scarcity of qualitative FXS literature in the African population and frustrations endured by families with FXS due to the low knowledge of FXS by healthcare workers. More research is needed to evaluate the impact of living with FXS in males and fathers.

Critical periods are developmental windows during which neural circuits effectively adapt to the new sensory environment. Animal models of fragile X syndrome (FXS), a common monogenic autism spectrum disorder (ASD), exhibit profound impairments of sensory experience-driven critical periods. However, it is not known whether the causative fragile X mental retardation protein (FMRP) acts uniformly across neurons, or instead manifests neuron-specific functions. Here, we use the genetically-tractable Drosophila brain antennal lobe (AL) olfactory circuit of both sexes to investigate neuron-specific FMRP roles in the odorant experience-dependent remodeling of the olfactory sensory neuron (OSN) innervation during an early-life critical period. We find targeted OSN class-specific FMRP RNAi impairs innervation remodeling within AL synaptic glomeruli, whereas global dfmr1 null mutants display relatively normal odorant-driven refinement. We find both OSN cell autonomous and cell non-autonomous FMRP functions mediate odorant experience-dependent remodeling, with AL circuit FMRP imbalance causing defects in overall glomerulus innervation refinement. We find OSN class-specific FMRP levels bidirectionally regulate critical period remodeling, with odorant experience selectively controlling OSN synaptic terminals in AL glomeruli. We find OSN class-specific FMRP loss impairs critical period remodeling by disrupting responses to lateral modulation from other odorant-responsive OSNs mediating overall AL gain control. We find that silencing glutamatergic AL interneurons reduces OSN remodeling, while conversely, interfering with the OSN class-specific GABAA signaling enhances remodeling. These findings reveal control of OSN synaptic remodeling by FMRP with neuron-specific circuit functions, and indicate how neural circuitry can compensate for global FMRP loss to reinstate normal critical period brain circuit remodeling.SIGNIFICANCE STATEMENT Fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism spectrum disorder (ASD), manifests severe neurodevelopmental delays. Likewise, FXS disease models display disrupted neurodevelopmental critical periods. In the well-mapped Drosophila olfactory circuit model, perturbing the causative fragile X mental retardation protein (FMRP) within a single olfactory sensory neuron (OSN) class impairs odorant-dependent remodeling during an early-life critical period. Importantly, this impairment requires activation of other OSNs, and the olfactory circuit can compensate when FMRP is removed from all OSNs. Understanding the neuron-specific FMRP requirements within a developing neural circuit, as well as the FMRP loss compensation mechanisms, should help us engineer FXS treatments. This work suggests FXS treatments could use homeostatic mechanisms to alleviate circuit-level deficits.

Fragile X Syndrome (FXS) is the most common cause of hereditary intellectual disability and the second most common cause of intellectual disability of genetic etiology. This complex neurodevelopmental disorder is caused by an alteration in the CGG trinucleotide expansion in fragile X mental retardation gene 1 (FMR1) leading to gene silencing and the subsequent loss of its product: fragile X mental retardation protein 1 (FMRP). Molecular diagnosis is based on Polymerase Chain Reaction (PCR) screening followed by Southern blotting (SB) or Triplet primer-PCR (TP-PCR) to determine the number of CGG repeats in the FMR1 gene. We performed, for the first time, screening in 247 Ecuadorian male individuals with clinical criteria to discard FXS. Analysis was carried out by the Genetics Service of the Hospital de Especialidades No. 1 de las Fuerzas Armadas (HE-1), Ecuador. The analysis was performed using endpoint PCR for CGG fragment expansion analysis of the FMR1 gene. Twenty-two affected males were identified as potentially carrying the full mutation in FMR1 and thus diagnosed with FXS that is 8.1% of the sample studied. The average age at diagnosis of the positive cases was 13 years of age, with most cases from the geographical area of Pichincha (63.63%). We confirmed the familial nature of the disease in four cases. The range of CGG variation in the population was 12 - 43 and followed a modal distribution of 27 repeats. Our results were similar to those reported in the literature, however, since it was not possible to differentiate between premutation and mutation cases, we can only establish a molecular screening approach to identify an expanded CGG repeat, which makes it necessary to generate national strategies to optimize molecular tests, establish proper protocols for the diagnosis, management, and follow-up of patients, families, and communities at risk of presenting FXS.

Fragile X syndrome (FXS) is the most common cause of hereditary intellectual disability and the second most common cause of intellectual disability of genetic etiology. This complex neurodevelopmental disorder is caused by an alteration in the CGG trinucleotide expansion in fragile X mental retardation gene 1 (FMR1) leading to gene silencing and the subsequent loss of its product: fragile X mental retardation protein 1 (FMRP). Molecular diagnosis is based on polymerase chain reaction (PCR) screening followed by Southern blotting (SB) or Triplet primer-PCR (TP-PCR) to determine the number of CGG repeats in the FMR1 gene. We performed, for the first time, screening in 247 Ecuadorian male individuals with clinical criteria to discard FXS. Analysis was carried out by the Genetics Service of the Hospital de Especialidades No. 1 de las Fuerzas Armadas (HE-1), Ecuador. The analysis was performed using endpoint PCR for CGG fragment expansion analysis of the FMR1 gene. Twenty-two affected males were identified as potentially carrying the full mutation in FMR1 and thus diagnosed with FXS that is 8.1% of the sample studied. The average age at diagnosis of the positive cases was 13 years of age, with most cases from the geographical area of Pichincha (63.63%). We confirmed the familial nature of the disease in four cases. The range of CGG variation in the population was 12–43 and followed a modal distribution of 27 repeats. Our results were similar to those reported in the literature; however, since it was not possible to differentiate between premutation and mutation cases, we can only establish a molecular screening approach to identify an expanded CGG repeat, which makes it necessary to generate national strategies to optimize molecular tests and establish proper protocols for the diagnosis, management, and follow-up of patients, families, and communities at risk of presenting FXS.

Glycogen Synthase Kinase-3 Inhibitors Reverse Deficits in Long-term Potentiation and Cognition in Fragile X Mice

Background: Intellectual disability (ID) is a major public health problem because the defect, treatment and rehabilitation require long life both medical and socio-economic assessment. Fragile X syndrome (FXS) is the most common cause of inherited X-linked intellectual disabilities (ID) with reduced penetrance. With regards to behavioral and emotional phenotype, FXS commonly mixed up with idiopathic autism. The prevalence is found higher in males compared to females. In accordance with rapid development of diagnosis technique, the prevalence of FXS is defining worldwide including Indonesia using, currently, simple molecular method.Objectives: This study was aimed to diagnose genetic cause of ID and to establish the prevalence of FXS among ID population in Central Java, and Yogyakarta Province.Method: Screening has been performed since 1994 continuously in high risk population (special school with and without autism) using clinical, cytogenetic, and FMR1 gene PCR-based molecular approach. Cascade testing was subjected to the family members with positive result of FXS and many new cases were disclosed in our cohort study.Results: The prevalence of FXS among ID population was calculated to be 1.9% (5/262) in 1994 and 1.7% (9/527) in 2011. Among autism population it was determined to be 6.15% (4/65). Trisomy 21 was found in 14% (74/527) as a major cause of ID.Conclusion: The prevalence of FXS among screened ID population overtime is comparable.

2012 National Society of Genetic Counselors Presidential Address: Maintaining Our Professional Identity in an Ever‐Expanding Genetics Universe

Awareness and knowledge of pediatricians regarding genetic testing for Fragile X syndrome in Japan: A National Survey of Pediatricians Managing Developmental Delay/Intellectual disability.

Fragile X syndrome (FXS) is an x-linked genetic disorder that represents the most common hereditary cause of Intellectual Disability (ID). Very specific behavioural features (e.g. attention deficit hyperactivity disorder and stereotyped behaviour) are associated with FXS in adolescents and adults, yet research on temperament and behavioural characteristics in young children with FXS has been more limited and less conclusive. This study investigated temperament differences in young boys (3-7 years old) with FXS (N = 26) recruited from a national FXS centre and controls (N = 26) matched on age, gender and race. Compared with controls, boys with FXS exhibited less overall surgency/extraversion and effortful control. Boys with FXS also displayed significantly greater activity and shyness and less attentional focusing, inhibitory control, soothability and high intensity pleasure (tendency to enjoy intense/complex activities), relative to comparison children. A significant interaction between age and diagnosis (FXS or control) was observed for negative affectivity only. Attention difficulties commonly found in adolescents and adults with FXS appear to also be characteristic of young boys with FXS, as reflected by lower effortful control. Age-related findings concerning negative affectivity may be particularly significant, leading to improved intervention/preventative efforts.