Early socio-communicative forms and functions in typical Rett syndrome

Rett syndrome (RTT) is a severe neurological disorder characterized by a developmental regression in motor and speech-language domains. There is, however, limited research on socio-communicative development of affected children before the onset of regression. We analyzed audio–video recordings made by parents of six 9- to 12-month old girls later diagnosed with typical RTT, applying the Inventory of Potential Communicative Acts (IPCA) to identify early communicative forms and functions. Each girl used at least one communicative form (e.g., body movement, eye gaze, or vocalizations) to gain attention and answer, but none were observed to make choices or request information. Varying numbers of children were observed to perform other communicative functions according to the IPCA including social convention, rejecting or requesting an object. Non-verbal forms (e.g., reaching, moving closer, eye contact, smiling) were more common than non-linguistic verbal forms (e.g., unspecified vocalizations, pleasure vocalizations, crying). (Pre-)linguistic verbal forms (e.g., canonical or variegated babbling, proto-words) were not used for communicative purposes. These data suggest that atypical developmental patterns in the socio-communicative domain are evident prior to regression in young individuals later diagnosed with RTT.     

Epilepsy in fragile X syndrome

The occurrence of seizures in patients with fragile X syndrome (Fra-X) is reported. Among the 30 patients, six had epilepsy that was particularly severe and two also showed atypical facial dysmorphism that was different from that seen in classical Fra-X. From the study performed in this series of Fra-X patients the authors arrived at the following conclusions. (1) The occurrence of seizures in Fra-X population is around 20%, as reported in the literature. (2) The EEG pattern of benign childhood epilepsy with central-temporal spikes (BCECTS) was found in only three patients (10%). (3) According to the pattern of seizures and EEGs, four groups may be recognizable, the less frequent being the uncommon group characterized by severe epilepsy unresponsive to treatment. (4) In this group atypical facial dysmorphism (although not similar in the two patients and different from the classical facial pattern of Fra-X) was found. The authors maintain that additional genetic factors might influence the clinical course and neurological aspects of Fra-X syndrome.     

Status epilepticus in fragile X syndrome

Epilepsy is frequent in fragile X syndrome (FXS), the most common cause of inherited mental retardation. Status epilepticus (SE), however, seems exceptional in FXS, particularly as an initial epileptic manifestation. To our knowledge, SE was reported in only four FXS patients. We report the clinical features and electroencephalography (EEG) findings of five children with FXS, who presented with SE as their initial seizure.     

Uncovering the evidence for behavioral interventions with individuals with fragile X syndrome: A systematic review

Fragile X syndrome (FXS) is associated with a wide range of cognitive, emotional, and behavioral difficulties. Although there is considerable research on the behavioral phenotype of FXS, few empirical studies of behavioral interventions with this population have been identified. Through a hand search of 34 behavioral journals, we examined the evidence base for behavioral interventions with individuals with FXS and in light of the current state of knowledge regarding the FXS behavioral phenotype. Systematic review procedures were used to identify behavioral intervention studies that included at least one participant with FXS, extract and summarize the data on several relevant dimensions, and rate the methodological quality of the studies. Results revealed 31 intervention studies with a small number of participants with FXS. Overall, results suggest a behavioral approach to intervention with individuals with FXS shows promise. Future research focused on individuals with FXS will be necessary to continue to examine differences in response to intervention and interventions that specifically address phenotypic characteristics.     

Age-dependent cognitive changes in carriers of the fragile X syndrome

Fragile X syndrome is a neurodevelopmental disorder that is caused by the silencing of a single gene on the X chromosome, the fragile X mental retardation 1 (FMR1) gene. Affected individuals display a unique neurocognitive phenotype that includes significant impairment in inhibitory control, selective attention, working memory, and visual–spatial cognition. In contrast, little is known about the trajectory and specificity of any cognitive impairment associated with the fragile X premutation (i.e., “carrier status”) or its relationship with the recently identified neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). In the present study, we evaluated a broad sample of 40 premutation males (PM) aged 18–69 years matched on age and IQ to 67 unaffected comparison males (NC). Performance was compared across a range of cognitive domains known to be impaired in fragile X syndrome (i.e., “full mutation”). Tremor was also assessed using a self-report neurological questionnaire. PM displayed statistically significant deficits in their ability to inhibit prepotent responses, differentiating them from NC from age 30 onwards. With increasing age, the two groups follow different trajectories, with PM developing progressively more severe problems in inhibitory control. This deficit also has a strong co-occurrence in males displaying FXTAS-related symptomatology (p < .001). Selective attention was also impaired in PM but did not show any disproportionate aging effect. No other cognitive deficits were observed. We conclude that an inhibitory deficit and its impact across the lifespan are specifically associated with the fragile X premutation status, and may be a precursor for development of a more severe form of cognitive impairment or dementia, which has been reported in patients with the diagnosis of FXTAS.     

Aging in fragile X syndrome

Many studies have focused on the behavior and cognitive problems in young patients with fragile X syndrome (FXS), but there are no studies about the problems in aging for those with FXS. The discovery of the fragile X-associated tremor ataxia syndrome (FXTAS), a neurodegenerative disorder related to elevated FMR1-mRNA, in elderly men and some women with the premutation, intensified the need for aging studies in FXS. Approximately 40% of males with FXS have repeat size mosaicism and as a result, some of these individuals also have elevated levels of FMR1-mRNA which theoretically puts them at risk for FXTAS. Here, we have surveyed all of the aging patients with FXS that we have followed over the years to clarify the medical complications of aging seen in those with FXS. Data was collected from 62 individuals with the FXS full mutation (44 males; 18 females) who were at least 40 years old at their most recent clinical examination. We found that the five most frequent medical problems in these patients were neurological problems (38.7%), gastrointestinal problems (30.6%), obesity (28.8%), hypertension (24.2%) and heart problems (24.2%). Movement disorders were significantly different between males and females (38.6% vs.10.2%, p = 0.029). We did not find any differences in medical problems between those with a full mutation and those with mosaicism. Identification of medical problems associated with aging in FXS is important to establish appropriate recommendations for medical screening and treatment considerations.     

Temperament factor structure in fragile X syndrome: The Children's Behavior Questionnaire

Early patterns of temperament lay the foundation for a variety of developmental constructs such as self-regulation, psychopathology, and resilience. Children with fragile X syndrome (FXS) display unique patterns of temperament compared to age-matched clinical and non-clinical samples, and early patterns of temperament have been associated with later anxiety in this population. Despite these unique patterns in FXS and recent reports of atypical factor structure of temperament questionnaires in Williams Syndrome (Leyfer, John, Woodruff-Borden, & Mervis, 2012), no studies have examined the latent factor structure of temperament scales in FXS to ensure measurement validity in this sample. The present study used confirmatory factor analysis to examine the factor structure of a well-validated parent-reported temperament questionnaire, the Children's Behavior Questionnaire (Rothbart, Ahadi, Hershey, & Fisher, 2001), in a sample of 90 males with FXS ages 3–9 years. Our data produced a similar, but not identical, three-factor model that retained the original CBQ factors of negative affectivity, effortful control, and extraversion/surgency. In particular, our FXS sample demonstrated stronger factor loadings for fear and shyness than previously reported loadings in non-clinical samples, consistent with reports of poor social approach and elevated anxiety in this population. Although the original factor structure of the Children's Behavior Questionnaire is largely retained in children with FXS, differences in factor loading magnitudes may reflect phenotypic characteristics of the syndrome. These findings may inform future developmental and translational research efforts.     

Effects of computerized match-to-sample training on emergent fraction-decimal relations in individuals with fragile X syndrome

Individuals diagnosed with fragile X syndrome (FXS), the most common known form of inherited intellectual disability, are reported to exhibit considerable deficits in mathematical skills that are often attributed to brain-based abnormalities associated with the syndrome. We examined whether participants with FXS would display emergent fraction-decimal relations following brief, intensive match-to-sample training on baseline relations. The performance profiles on tests of symmetry and transitivity/equivalence of 11 participants with FXS, aged 10-23 years, following baseline match-to-sample training were compared to those of 11 age- and IQ-matched controls with idiopathic developmental disability. The results showed that both groups of participants showed significant improvements in the baseline (trained) relations, as expected. However, participants with FXS failed to show significant improvements in the (untrained) symmetry and transitivity/equivalence relations compared to those in the control group. A categorical analysis of the data indicated that five participants with FXS and eight controls showed at least “intermediate” emergence of symmetry relations, whereas one individual with FXS and three controls showed at least intermediate emergence of transitivity/equivalence relations. A correlation analysis of the data indicated that improvements in the symmetry relations were significantly associated with improvements in the transitivity/equivalence relations in the control group (r = .69, p = .018), but this was not the case in the FXS group (r = .34, p > .05). Participant IQ was significantly associated with improvements in the symmetry relations in individuals with FXS (r = .60, p = .049), but not in controls (r = .21, p > .05). Taken together, these results suggest that brief, computerized match-to-sample training may produce emergent mathematical relations for a subset of children with FXS and developmental disabilities. However, the ability of individuals with FXS to form transitivity/equivalence relations may be impaired relative to those with idiopathic developmental disabilities, which may be attributed to neurodevelopmental variables associated with the syndrome.     

Three different profiles: Early socio-communicative capacities in typical Rett syndrome,the preserved speech variant and normal development

Background and aims: This is the first study aiming to compare pre-diagnostic socio-communicative development of a female with typical Rett syndrome (RTT), a female with the preserved speech variant of RTT (PSV) and a control toddler.

Methods: We analysed 1275?min of family videos at the participants’ age between 9 and 24 months and used the Inventory of Potential Communicative Acts (IPCA) to delineate their repertoires of communicative forms and functions.

Results: The results revealed different profiles for the three different conditions. The repertoire of communicative gestures and (pre)linguistic vocalizations was most comprehensive in the control toddler, followed by the female with PSV and the female with RTT.

Conclusion: These findings contribute to the growing knowledge about early developmental abnormalities in RTT. In order to define distinctive profiles for typical and atypical RTT and evaluate their specificity, a larger body of evidence is needed.     

Decreased expression of the GABAA receptor in fragile X syndrome

After our initial discovery of under expression of the GABA(A) receptor delta subunit in a genome wide screening for differentially expressed mRNAs in brain of fragile X mice, a validated model for fragile X mental retardation syndrome, we analyzed expression of the 17 remaining subunits of the GABA(A) receptor using real-time PCR. We confirmed nearly 50% under expression of the delta subunit and found a significant 35%-50% reduction in expression of 7 additional subunit mRNAs, namely alpha(1), alpha(3), and alpha(4), beta(1) and beta(2) and gamma(1) and gamma(2), in fragile X mice compared to wild-type littermates. In concordance with previous results, under expression was found in cortex, but not in cerebellum. Moreover, decreased expression of specific GABA(A) receptor subunits in fragile X syndrome seems to be an evolutionary conserved hallmark since in the fragile X fly (Drosophila melanogaster) model we also found almost 50% under expression of all 3 subunits which make up the invertebrate GABA receptor, namely Grd, Rdl and Lcch3. In addition, we demonstrated a direct correlation between the amount of dFmrp and the expression of the GABA receptor subunits Rdl and Grd. Our results add evidence to previous observations of an altered GABAergic system in fragile X syndrome. Because GABA(A) receptors are the major inhibitory receptors in brain, involved in anxiety, depression, insomnia, learning and memory and epilepsy, processes also disturbed in fragile X patients, the well described GABA(A) receptor pharmacology might open new powerful opportunities for treatment of the behavioral and epileptic phenotype associated with fragile X syndrome.     

Examining the operant function of challenging behavior in young males with fragile X syndrome: A summary of 12 cases

This study used experimental functional analyses to examine the operant function of challenging behaviors exhibited by 12 males (ages 27–51 months) with fragile X syndrome (FXS). Eight children met criteria for negatively reinforced challenging behavior in the form of escape from demands and/or escape from social interactions. Nine children met criteria for positively reinforced challenging behavior in the form of obtaining access to highly preferred items. Attention was identified as a maintaining consequence for three children. The functional analysis was inconclusive for one child. Results suggest that, for young males with FXS, challenging behaviors may more likely be tangibly and escape maintained than attention maintained. Our findings affirm past research suggesting a unique behavioral phenotype for this population.     

脆性X综合征26例儿童临床特征

目的 分析脆性X综合征(fragile X syndrome,FXS)儿童的临床资料以探讨利于尽早进行实验室确诊的临床线索.方法 对26例2～14岁首次确诊FXS的儿童详细临床资料进行回顾分析.结果 首诊主诉主要为语言障碍和行为问题;症状行为发生率较高的有语言障碍、智力差、孤独症样行为:12例(46.2%)有特殊面容和(或)体征;15例(57.7%)和11例(42.3%)首诊诊断分别为精神发育迟缓、孤独症;总智商从重度智力低下至边缘智力,平均(45.1±17.1),男女智商无统计学差异(t=1.16,P>0.05);均无癫痫发作.1例脑电图显示痫性放电.结论 临床中应重视行为问题等病史询问及重视特殊体征的发现以减少漏诊.孤独症儿童可考虑常规进行FXS筛查.     

Behavioral assessment of social anxiety in females with Turner or fragile X syndrome

Social skills impairment in children with Turner or fragile X syndrome has been documented using parental reports. Anxiety, shyness, and difficulty understanding social cues have been reported for females with Turner syndrome; whereas social withdrawal, avoidance of social interactions, and anxiety are often reported for females with fragile X syndrome. Social interaction anxiety in these two populations may be a framework for understanding the difficulty these children experience in social situations. In the present study, 29 females with Turner syndrome and 21 females with fragile X syndrome ages 6–22 years were compared to females in a comparison group, on a videotaped role-play interaction. Behavioral indices examined included eye-contact maintenance, duration of speech, and body discomfort as observed during the brief interaction. Three of eight such behavioral measures of social skills differentiated the participant groups from each other. Specifically, participants with fragile X required more time to initiate interactions than did participants in either of the remaining groups; and females with Turner syndrome made fewer facial movements than did females in the fragile X or comparison group. Self-report and parental ratings did not suggest higher levels of anxiety in females with Turner or fragile X syndrome, but did reflect higher levels of social difficulty. The authors discuss these findings in terms of understanding the nature of social dysfunction in females with Turner or fragile X syndrome.     

The acquisition of stimulus equivalence in individuals with fragile X syndrome

Background Few studies have employed stimulus equivalence procedures to teach individuals with intellectual disabilities (IDs) new skills. To date, no studies of stimulus equivalence have been conducted in individuals with fragile X syndrome (FXS), the most common known cause of inherited ID. Method Five adolescents with FXS were taught basic math and geography skills by using a computerized stimulus equivalence training programme administered over 2 days in 2‐h sessions. Results Four of the five participants learned the math relations, with one participant demonstrating stimulus equivalence at post‐test. Three of the five participants learned the geography relations, with all three of these participants demonstrating stimulus equivalence at post‐test. Conclusions These data indicate that computerized stimulus equivalence procedures, conducted in time‐limited sessions, may help individuals with FXS learn new skills. Hypotheses concerning the failure of some participants to learn the training relations and to demonstrate stimulus equivalence at post‐test are discussed.     

The neural basis of auditory temporal discrimination in girls with fragile X syndrome

Fragile X syndrome (FXS) is a common genetic disorder in which temporal processing may be impaired. To our knowledge however, no studies have examined the neural basis of temporal discrimination in individuals with FXS using functional magnetic resonance imaging (fMRI). Ten girls with fragile X syndrome and ten developmental age-matched typically developing controls performed an auditory temporal discrimination task in a 3T scanner. Girls with FXS showed significantly greater brain activation in a left-lateralized network, comprising left medial frontal gyrus, left superior and middle temporal gyrus, left cerebellum, and left brainstem (pons), when compared to a developmental age-matched typically developing group of subjects who had similar in-scanner task performance. There were no regions that showed significantly greater brain activation in the control group compared to individuals with FXS. These data indicate that networks of brain regions involved in auditory temporal processing may be dysfunctional in FXS. In particular, it is possible that girls with FXS employ left hemispheric resources to overcompensate for relative right hemispheric dysfunction.     

Maternal well-being and child behavior in families with fragile X syndrome

The purpose of this study was to examine the bidirectional relationships relationship between maternal mental health status, maternal stress, family environment and behavioral functioning of children with fragile X syndrome (FXS), the leading cause of inherited intellectual disability. Children with FXS commonly demonstrate challenging behavior related to anxiety, attention, and aggression, whereas mothers of children with FXS have been identified as susceptible to mental health challenges due to their status as genetic carriers of the FXS premutation, as well as the environmental stressors of raising children with special needs. The longitudinal design of this study builds upon prior work that established a concurrent relationship among these factors in families of children with other intellectual disorders. Findings indicated that maternal mental health status was not significantly related to changes in levels of child challenging behavior, heightened child challenging behavior was related to improvements in maternal depression over time, and heightened levels of child challenging behavior was related to increased feelings of maternal closeness toward the child over time. The unexpected nature of the results regarding maternal depression and closeness provides new and more complex hypotheses about how mothers of special needs children demonstrate adaptation and resilience. The findings have implications for maternal and familial mental health treatment as well as future research.     

Longitudinal trajectories of aberrant behavior in fragile X syndrome

The Aberrant Behavior Checklist-Community (ABC-C; Aman et al., 1995) has been increasingly adopted as a primary tool for measuring behavioral change in clinical trials for individuals with fragile X syndrome (FXS). To our knowledge, however, no study has documented the longitudinal trajectory of aberrant behaviors in individuals with FXS using the ABC-C. As part of a larger longitudinal study, we examined scores obtained on the ABC-C subscales for 124 children and adolescents (64 males, 60 females) with FXS who had two or more assessments (average interval between assessments was approximately 4 years). Concomitant changes in age-equivalent scores on the Vineland Adaptive Behavior Scales (VABS) were also examined. As expected for an X-linked genetic disorder, males with FXS obtained significantly higher scores on all subscales of the ABC-C and significantly lower age-equivalent scores on the VABS than females with FXS. In both males and females with FXS, scores on the Irritability/Agitation and Hyperactivity/Noncompliance subscales of the ABC-C decreased significantly with age, with little to no change occurring over time on the Lethargy/Social Withdrawal, Stereotypic Behavior, and Inappropriate Speech subscales. The decrease in scores on the Hyperactivity/Noncompliance domain was significantly greater for males than for females. In both males and females, age-equivalent scores on the VABS increased significantly over this developmental period. These results establish a basis upon which to evaluate long-term outcomes from intervention-based research. However, longitudinal direct observational studies are needed to establish whether the severity of problem behavior actually decreases over time in this population.     

Audiogenic seizures susceptibility in transgenic mice with fragile X syndrome

PURPOSE: To evaluate their susceptibility to audiogenic seizures, five groups of knockout mice with various forms of fragile X genetic involvement [hemizygous males (n = 46), and homozygous (n = 38) and heterozygous females (n = 45), and their normal male (n = 45) and female (n = 52) littermates] were studied. METHODS: All mouse groups were tested at ages 17, 22, 35, and 45 days. Audiogenic seizure susceptibility was scored, and the analysis of variance was used for the evaluation of the effects of age and genetic condition on seizure severity score (SSS). RESULTS: All groups of knockout fragile X mice exhibited SSSs significantly higher than those observed in their wild-type littermates; among knockout mice, hemizygous males and homozygous females showed the highest SSSs. Hemizygous males showed higher SSSs with increasing age, from 17 to 45 days; homozygous females showed a peak at age 22 days, followed by a decrease; finally, heterozygous females had their highest SSSs at age 17 days. CONCLUSIONS: This study demonstrates that an increased susceptibility to audiogenic seizures is present in fragile X knockout mice at all the ages tested. These results support the validity of this animal model also for epilepsy and seizures in the human fragile X syndrome.     

Developmental trajectories of attentional control in preschool males with fragile X syndrome

Attention problems are among the most impairing features associated with fragile X syndrome (FXS). However, few studies have examined behavioral development of inhibitory control in very young children with FXS. We examined attentional control in 3–6 year boys with FXS using both an experimental inhibitory control paradigm and parent-report of attention problems. Study 1 examined attentional control in FXS compared to comparison groups matched on chronological and mental age. To determine the stability of impairments over time in FXS, Study 2 examined patterns of developmental change in an expanded longitudinal sample. Across studies, males with FXS demonstrated persistent impairments in inhibitory control and parent-reported attention problems. Inhibitory control was related to, but not solely driven by, lower mental age. Although parent-rated attention problems remained stable across ages, inhibitory control improved with time. Children with more severe attention problems often displayed initially poorer inhibitory control. However, these trajectories also improved more rapidly with age. Our findings indicate that despite persistent deficits in attentional control in young children with FXS, multi-method assessment can be used to capture developmental growth that should be further supported through early, targeted intervention.     

脆性X染色体综合征临床与脑电图的研究

目的研究青春期前脆性Ｘ染色体综合征临床和ＥＥＧ表现特点。方法对３０例该综合征患儿的临床表现、脑电图及其与脆性Ｘ细胞表达率的关系进行研究。结果智力低下、语言障碍及行为异常十分常见，但特殊面容和巨睾出现率低。４６．７％的患儿有癫痫发作，且发作有无与脆性Ｘ表达率相关。ＥＥＧ有癫痫放电者９／２１，但仅１例局限于双颞区。结论特殊面容及巨睾不应作为青春期前脆性Ｘ染色体综合征患儿筛选和诊断的依据。癫痫的发生可能与脆性Ｘ位点有关。