Serial control of phonology in speech production: a hierarchical model

A dynamic oscillator-based model of the sequencing of phonemes in speech production (OSCAR) is described. An analysis of phoneme movement errors (anticipations, perseverations, and exchanges) from a large naturalistic speech error corpus provides a new set of data suitable for quantitative modeling and is used to derive a set of constraints that any speech-production model must address. The new computational model is shown to account for error type proportions, movement error distance gradients, the syllable-position effect, and phonological similarity effects. The model provides an alternative to frame-based accounts, serial buffer accounts, and associative chaining theories of serial order processing in speech.     

Hyperactivity and the Fragile X Syndrome

Workers who have claimed an association between Fragile X [fra(x)] Syndrome and Hyperactivity and aggressive behavior have done so despite the lack of controlled studies using standard diagnostic criteria. Accordingly, we provided a controlled test of the hypothesis that individuals with the fra(x) Syndrome are more hyperactive and have more symptoms of aggression than other mentally retarded individuals. The test formed part of a study to assess autistic behavior in fra(x) individuals. A sample of fra(x) individuals was obtained from the register of a clinical genetics unit and individually matched for age, sex, and IQ with mentally retarded individuals selected from assessment centres. Fortyfive pairs of fra(x) cases and control individuals were compared on criteria which reflected DSM-III concepts of hyperactivity and on criteria reflecting aggressive behavior. The comparison failed to find a higher prevalence of these symptoms in the fra(x) group. An analysis of the study's statistical power suggested that it is unlikely that the investigation failed to detect a large to medium difference between fra(x) individuals and control individuals in the symptoms investigated.     

Modeling Family Dynamics in Children with Fragile X Syndrome

Few studies have examined the impact of children with genetic disorders and their unaffected siblings on family functioning. In this study, the reciprocal causal links between problem behaviors and maternal distress were investigated in 150 families containing a child with fragile X syndrome (FXS) and an unaffected sibling. Both children's behavior problems appeared to have strong, direct effects on maternal distress, but maternal distress did not appear to have any reciprocal causal effects on either child's behavior problems. Surprisingly, there were no significant differences in the effects of the two children's behavior problems on maternal distress. These data suggest that the problem behaviors of children with FXS, as well as their unaffected siblings, can have a substantial and additive impact on maternal depression and anxiety. Future research efforts should employ longitudinal research designs to confirm these findings.     

Language deficits in dyslexic children: speech perception, phonology, and morphology

We investigated the relationship between dyslexia and three aspects of language: speech perception, phonology, and morphology. Reading and language tasks were administered to dyslexics aged 8-9 years and to two normal reader groups (age-matched and reading-level matched). Three dyslexic groups were identified: phonological dyslexics (PD), developmentally language impaired (LI), and globally delayed (delay-type dyslexics). The LI and PD groups exhibited similar patterns of reading impairment, attributed to low phonological skills. However, only the LI group showed clear speech perception deficits, suggesting that such deficits affect only a subset of dyslexics. Results also indicated phonological impairments in children whose speech perception was normal. Both the LI and the PD groups showed inflectional morphology difficulties, with the impairment being more severe in the LI group. The delay group's reading and language skills closely matched those of younger normal readers, suggesting these children had a general delay in reading and language skills, rather than a specific phonological impairment. The results are discussed in terms of models of word recognition and dyslexia.     

Working Memory In Individuals With Fragile X Syndrome

The present research tests the hypothesis that fragile X syndrome (FXS) is associated with a deficit in working memory (WM) and the deficit is more pronounced the higher the control requirements of the task. To this purpose, 15 boys with FXS and 15 typically developing children, matched for mental age, assessed with Logical Operation Test, were tested with batteries of 4 verbal and 4 visuospatial WM tasks requiring different levels of control. Children with FXS showed a performance equal to controls, in WM tasks requiring low and medium-low control but significant impairment in correspondence with greater control requirements. Results show that boys with FXS present a WM deficit only when high control is required by the task, supporting the hypothesis that control can be a critical variable distinguishing WM functions and explaining intellectual differences. On the contrary the hypothesis that the FXS is associated with a visuospatial deficit was not supported.     

Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

Structural equation modeling (SEM) was used to examine the development of intellectual functioning in 145 school-age pairs of siblings. Each pair included one child with Fragile X syndrome (FXS) and one unaffected sibling. All pairs of children were evaluated on the Wechsler Intelligence Scale for Children-Third Edition (WISC-III) at time 1 and 80 pairs of children received a second evaluation at time 2 approximately 4 years later. Compared to their unaffected siblings, children with FXS obtained significantly lower percentage correct scores on all subtests of the WISC at both time points. During the time between the first and second assessments, the annual rate of intellectual development was approximately 2.2 times faster in the unaffected children compared to the children with FXS. Levels of the fragile X mental retardation protein (FMRP) were highly associated with intellectual ability scores of the children with FXS at both time points (r=0.55 and 0.64 respectively). However, when gender, age, and the time between assessments were included as covariates in the structural equation model, FMRP accounted for only 5% of the variance in intellectual ability scores at time 1 and 13% of the variance at time 2. The results of this study suggest that slower learning contributes to the low and declining standardized IQ scores observed in children with FXS.     

Fragile X mental retardation protein regulates heterosynaptic plasticity in the hippocampus

Silencing of a single gene, FMR1, is linked to a highly prevalent form of mental retardation, characterized by social and cognitive impairments, known as fragile X syndrome (FXS). The FMR1 gene encodes fragile X mental retardation protein (FMRP), which negatively regulates translation. Knockout of Fmr1 in mice results in enhanced long-term depression (LTD) induced by metabotropic glutamate receptor (mGluR) activation. Despite the evidence implicating FMRP in LTD, the role of FMRP in long-term potentiation (LTP) is less clear. Synaptic strength can be augmented heterosynaptically through the generation and sequestration of plasticity-related proteins, in a cell-wide manner. If heterosynaptic plasticity is altered in Fmr1 knockout (KO) mice, this may explain the cognitive deficits associated with FXS. We induced homosynaptic plasticity using the β-adrenergic receptor (β-AR) agonist, isoproterenol (ISO), which facilitated heterosynaptic LTP that was enhanced in Fmr1 KO mice relative to wild-type (WT) controls. To determine if enhanced heterosynaptic LTP in Fmr1 KO mouse hippocampus requires protein synthesis, we applied a translation inhibitor, emetine (EME). EME blocked homo- and heterosynaptic LTP in both genotypes. We also probed the roles of mTOR and ERK in boosting heterosynaptic LTP in Fmr1 KO mice. Although heterosynaptic LTP was blocked in both WT and KOs by inhibitors of mTOR and ERK, homosynaptic LTP was still enhanced following mTOR inhibition in slices from Fmr1 KO mice. Because mTOR will normally stimulate translation initiation, our results suggest that β-AR stimulation paired with derepression of translation results in enhanced heterosynaptic plasticity.     

Fragile X syndrome: Neural network models of sequencing and memory

A comparative framework of memory processes in males with fragile X syndrome (FXS) and typically developing (TYP) mental age-match children is presented. Results indicate a divergence in sequencing skills, such that males with FXS recall sequences similarly to TYP children around five and a half years of age, but the males with FXS recall significantly worse when compared to TYP children around seven and a half years of age. Performance on one working memory measure, an n-back Card Task, is modeled with a neural network. To date, no network models explicate the sequencing and memory processes in those with FXS. Noise was added to various levels (weight matrices) in the FXS model and outputs approximated human FXS performance. Three models were compared: (1) FXS; (2) younger mental age-TYP matches; (3) older reading level-TYP matches. Modeling can help to reify conceptualizations of deficits and to guide in the creation of more valid, science-based remediations. The FXS model suggested that the levels of phonological representation and sequencing in memory were candidates for targeted therapies in males with FXS.     

Emotional Reaction to Fragile X Premutation Carrier Tests Among Infertile Women

Female fragile X premutation carriers are at ∼10-fold increased risk of premature ovarian failure (follicle stimulating hormone >40 mIU/mL, amenorrhea, age <40). A milder degree of premature ovarian aging (diminished ovarian reserve, where follicle stimulating hormone levels are typically 10–20 mIU/mL) results in infertility. Approximately 10% of fertility clinic patients have this diagnosis. A cohort of 20 women diagnosed with diminished ovarian reserve provided a blood specimen (confidential results), and completed structured questionnaires that assessed emotional reactions to potentially being a premutation carrier (pretest questionnaire, n = 20) and the posttest known carrier status (3 month follow-up questionnaire, n = 18 non-carriers). Responses were measured using 9-point scales, and analyzed with Fisher exact and Wilcoxon exact tests. While most participants did not view fragile X premutations as a serious medical condition, perceptions of seriousness were positively correlated with anger and regret about not knowing sooner of the potential association of these premutations with infertility. Overall, when women (pretest) imagined themselves as carriers, their self-esteem and Health Orientation Scale responses were unchanged with the exception of feeling more afraid (p = 0.004). Despite strongly wishing for negative test results, they were glad to know there might be a medical explanation for their infertility. Financial Support: This work was financially supported by a University of Virginia School of Medicine Research & Development Award.     

Visual search in typically developing toddlers and toddlers with Fragile X or Williams syndrome

Visual selective attention is the ability to attend to relevant visual information and ignore irrelevant stimuli. Little is known about its typical and atypical development in early childhood Experiment 1 investigates typically developing toddlers' visual search for multiple targets on a touch-screen. Time to hit a target, distance between successively touched items, accuracy and error types revealed changes in 2- and 3-year-olds' vulnerability to manipulations of the search display. Experiment 2 examined search performance by toddlers with Fragile X syndrome (FXS) or Williams syndrome (WS). Both of these groups produced equivalent mean time and distance per touch as typically developing toddlers matched by chronological or mental age; but both produced a larger number of errors. Toddlers with WS confused distractors with targets more than the other groups; while toddlers with FXS perseverated on previously found targets. These findings provide information on how visual search typically develops in toddlers, and reveal distinct search deficits for atypically developing toddlers.     

Attitudes Toward Fragile X Mutation Carrier Testing from Women Identified in a General Population Survey

Fragile X syndrome is primarily due to a CGG repeat expansion found in the FMR1 X-linked gene. In a previous study, we conducted focus groups with women to assess their attitudes towards fragile X carrier screening. In this follow-up study, we conducted in-depth interviews of general population reproductive-age women who were identified as carriers. We explored their attitudes toward testing for carrier status of the fragile X mutation. These women underwent screening primarily to participate in a research project rather than in search of a diagnosis for specific symptoms. As such, these women were wholly unprepared for positive carrier results. Their responses about their results and carrier screening, in many cases, were being worked out over the course of the interview itself. The most salient finding of this work is the apparent lack of relevance of carrier status to these women. Many expressed that although the information could be relevant in the future, it is not relevant at this stage of their lives in terms of family planning (either with respect to having unaffected offspring or to premature ovarian failure) and personal relationships. Although issues of abortion seemed prominent in the focus groups, we found that carrier status did not have an apparent effect on women’s attitudes about termination. We hypothesize this may be related to the fact that women had not processed their new carrier status and had not related it to previously-formed personal opinions. The findings of this work have significant implications for genetic counseling and population screening. Genetic counselors should be mindful that general population women may not recognize the immediate importance of their carrier status even when literature is provided and discussed prior to providing a sample. As part of comprehensive genetic counseling, counselors should identify the reproductive life stage of the woman receiving the new information and help her identify when this information would be more meaningful in her life. Counselors can assist in setting up a personalized road map with specific types of services that will be more applicable to the woman as her carrier status becomes more relevant.     

Diagnosis of Fragile X Syndrome: A Qualitative Study of African American Families

Fragile X syndrome (FXS) is an inherited genetic condition with critical consequences to the proband and family members at all levels in the generations. Although evidence demonstrates that the rates of diagnosis for FXS are the same in all racial groups, age of diagnosis in African American children has been reported to occur later than in Caucasian children. Additionally, African American families are seriously under-represented in existing FXS research studies. As such, it is important to understand the possible disparities in the underlying factors to receiving a diagnosis in African American families with FXS. Herein, a qualitative approach was adopted to describe the overall FXS diagnosis experiences (pre-diagnosis, diagnosis, and post-diagnosis stages) of a convenience sample of 10 African American mothers. We identified three major findings among our participants: (1) FXS testing is not ordered immediately once a parent expresses concerns of developmental delays to the pediatricians, (2) the diagnosis is sometimes delivered in an insensitive manner with information often being outdated and unbalanced towards negative aspects, (3) communication issues among family members exists once the diagnosis is discovered. Although these qualitative data may not be representative of the whole group, these findings have significant implications for genetic counseling and our understanding in providing support and advocacy for African American families with FXS.     

Duty to Re-Contact: A Study of Families at Risk for Fragile X

DNA testing for Fragile X syndrome is now routinely available through a large number of diagnostic laboratories. We have surveyed individuals from British Columbia Fragile X families identified prior to the availability of DNA testing for FMR1 to determine if they are subsequently receiving information about DNA testing. Of the 78 individuals first seen before the cloning of the FMR1 gene, 39 (50%) had not been seen in the clinic to discuss DNA testing. We initiated a contact program with these 39 patients to determine their interest in DNA testing. Contact was made with 28 individuals, 20 of whom stated interest in testing either for themselves or for a relative. Patient opinions about DNA testing were assessed through questionnaires. In those individuals who stated an interest in DNA testing, the most common reason for wishing testing was to provide information to children or grandchildren. The most common disadvantages of testing indicated by this group were that they had finished their families and that they felt the test would not have a direct impact. The most common reasons individuals were not interested in DNA testing were that there were no family members appropriate to test and that the respondent had completed his or her family. DNA testing has been performed for 13 of the 28 (46%) contacted individuals and/or at least one relative. In view of the high level of interest for testing in families who had not been seen since the cloning of the FMR1 gene, we feel that FMR1 screening programs should include actively contacting previously seen individuals.     

Reading without phonology?

Responses to items such as brane are slower and/or more error prone than responses to items such as slint in lexical decision (is this string spelt like a real word?). The received view is that this “pseudohomophone” effect is attributable to phonological receding. Taft (1982) has challenged this view, offering instead a grapheme-grapheme account which assumes that graphemes that map onto a common phoneme develop the ability to activate each other without reference to phonological mediation.

Taft's grapheme-grapheme account is tested in two experiments. Experiment 1 shows that the presentation of a pseudohomophone facilitates the response to a subsequently presented word (e.g., groce-gross). Experiment 2 shows that nonword letter strings that are translatable into words by the application of putative grapheme-grapheme rules (e.g., gloce-gloss) produce no facilitation. These results are consistent with the notion of a phonological influence but inconsistent with the grapheme-grapheme account. Loci for this pseudohomophone priming effect are discussed.     

Longitudinal Interviews of Couples Diagnosed with Diminished Ovarian Reserve Undergoing Fragile X Premutation Testing

About 10 % of infertile/subfertile women are diagnosed with diminished ovarian reserve (DOR), of which?<?5 % will become pregnant spontaneously. Fragile X (FMR1) genetic testing may provide a reason for her early ovarian aging and/or have reproductive implications. Seven women with DOR (genetic study subset) and the male partners of six of these women were separately interviewed about the experience of being asked to undergo this unanticipated genetic test. Three interviews were conducted (before, within 1 week after, and 3 months after learning the test results). None of the participants carried the FMR1 premutation (largest FMR1 allele 27–50 CGG repeats). For women, their pregnancy-seeking journey was long and exhausting. Women understood the reproductive implications of carrying the FMR1 premutation, and hoped for a negative result. Being offered a genetic test caused women to pause and re-think their future reproductive plans. Husbands viewed the infertility journey as filled with unknowns, of which the genetic test results would be one more puzzle piece. The expense of fertility testing/treatment was mentioned by both spouses, though more notably by husbands. The introduction of a possible genetic cause of infertility, with additional potential health consequences for future biological children, caused women to re-think their quest for pregnancy. In contrast, the genetic test was viewed as an additional source of information for their husbands as opposed to raising concern regarding potential reproductive ramifications.     

Early Negative Affect Predicts Anxiety, not Autism, in Preschool Boys with Fragile X Syndrome

Children with fragile X syndrome (FXS) face high risk for anxiety disorders, yet no studies have explored FXS as a high-risk sample for investigating early manifestations of anxiety outcomes. Negative affect is one of the most salient predictors of problem behaviors and has been associated with both anxiety and autistic outcomes in clinical and non-clinical pediatric samples. In light of the high comorbidity between autism and anxiety within FXS, the present study investigates the relationship between longitudinal trajectories of negative affect (between 8 and 71 months) and severity of anxiety and autistic outcomes in young males with FXS (n?=?25). Multilevel models indicated associations between elevated anxiety and higher fear and sadness, lower soothability, and steeper longitudinal increases in approach. Autistic outcomes were unrelated to negative affect. These findings suggest early negative affect differentially predicts anxiety, not autistic symptoms, within FXS. Future research is warranted to determine the specificity of the relationship between negative affect and anxiety, as well as to explore potential moderators. Characterizing the relationship between early negative affect and anxiety within FXS may inform etiology and treatment considerations specific to children with FXS, as well as lend insight into precursors of anxiety disorders in other clinical groups and community samples.     

Genetic Counseling for Fragile X Syndrome: Recommendations of the National Society of Genetic Counselors

The National Society of Genetic Counselors' (NSGC) recommendations for fragile X syndrome (FXS) genetic counseling are intended to assist health care professionals who provide genetic counseling for individuals and families in whom the diagnosis of FXS is strongly suspected or has been made. The recommendations are the opinions of genetic counselors with expertise in FXS counseling and are based on clinical experience, a review of pertinent English language medical articles, and reports of expert committees. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of a particular client.     

The search for phonology in other species

Human language draws on a complex set of cognitive, motor and auditory skills. Some of these are found in other species but others are thought to be absent. There has been a burst of research in this area over the past five years, both in examining natural communication systems and also in the laboratory, exposing animals to human language. Most of the work has focused on analogies to syntax. Although many of the fundamental building blocks for basic phonological skills might be found outside humans, most aspects of core phonology have never been investigated.     

Genetic Counseling for Fragile X Syndrome: Updated Recommendations of the National Society of Genetic Counselors

These recommendations describe the minimum standard criteria for genetic counseling and testing of individuals and families with fragile X syndrome, as well as carriers and potential carriers of a fragile X mutation. The original guidelines (published in 2000) have been revised, replacing a stratified pre- and full mutation model of fragile X syndrome with one based on a continuum of gene effects across the full spectrum of FMR1 CGG trinucleotide repeat expansion. This document reviews the molecular genetics of fragile X syndrome, clinical phenotype (including the spectrum of premature ovarian failure and fragile X-associated tremor-ataxia syndrome), indications for genetic testing and interpretation of results, risks of transmission, family planning options, psychosocial issues, and references for professional and patient resources. These recommendations are the opinions of a multicenter working group of genetic counselors with expertise in fragile X syndrome genetic counseling, and they are based on clinical experience, review of pertinent English language articles, and reports of expert committees. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. The professional judgment of a health care provider, familiar with the facts and circumstances of a specific case, will always supersede these recommendations.