scholarly journals Intellectual functioning and behavioural features associated with mosaicism in fragile X syndrome

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Emma K. Baker ◽  
Marta Arpone ◽  
Solange Aliaga Vera ◽  
Lesley Bretherton ◽  
Alexandra Ure ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Cognitive Abilities ◽  
Fragile X ◽  
Autism Diagnostic Observation Schedule ◽  
Intellectual Functioning ◽  
Autism Spectrum ◽  
Aberrant Behavior Checklist ◽  
Age Appropriate ◽  
Maladaptive Behaviours ◽  
Age And Sex

Abstract Background Fragile X syndrome (FXS) is a common cause of intellectual disability and autism spectrum disorder (ASD) usually associated with a CGG expansion, termed full mutation (FM: CGG ≥ 200), increased DNA methylation of the FMR1 promoter and silencing of the gene. Mosaicism for presence of cells with either methylated FM or smaller unmethylated pre-mutation (PM: CGG 55–199) alleles in the same individual have been associated with better cognitive functioning. This study compares age- and sex-matched FM-only and PM/FM mosaic individuals on intellectual functioning, ASD features and maladaptive behaviours. Methods This study comprised a large international cohort of 126 male and female participants with FXS (aged 1.15 to 43.17 years) separated into FM-only and PM/FM mosaic groups (90 males, 77.8% FM-only; 36 females, 77.8% FM-only). Intellectual functioning was assessed with age appropriate developmental or intelligence tests. The Autism Diagnostic Observation Schedule-2nd Edition was used to examine ASD features while the Aberrant Behavior Checklist-Community assessed maladaptive behaviours. Results Comparing males and females (FM-only + PM/FM mosaic), males had poorer intellectual functioning on all domains (p < 0.0001). Although females had less ASD features and less parent-reported maladaptive behaviours, these differences were no longer significant after controlling for intellectual functioning. Participants with PM/FM mosaicism, regardless of sex, presented with better intellectual functioning and less maladaptive behaviours compared with their age- and sex-matched FM-only counterparts (p < 0.05). ASD features were similar between FM-only and PM/FM mosaics within each sex, after controlling for overall intellectual functioning. Conclusions Males with FXS had significantly lower intellectual functioning than females with FXS. However, there were no significant differences in ASD features and maladaptive behaviours, after controlling for intellectual functioning, independent of the presence or absence of mosaicism. This suggests that interventions that primarily target cognitive abilities may in turn reduce the severity of maladaptive behaviours including ASD features in FXS.

scholarly journals “Are We Done Yet?” Question-Asking in Boys With Fragile X Syndrome and Idiopathic Autism Spectrum Disorder

2020 ◽  
Vol 63 (6) ◽  
pp. 1822-1834
Author(s):  
Laura Friedman ◽  
Emily Lorang ◽  
Elizabeth Hilvert ◽  
Audra Sterling
Keyword(s):  
Autism Spectrum Disorder ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Diagnostic Observation Schedule ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Frequency Function ◽  
Question Asking ◽  
Social Settings ◽  
New Information

Purpose Question-asking serves as a tool to learn new information and is important in both academic and social settings. Boys with idiopathic autism spectrum disorder (ASD) and boys with fragile X syndrome and comorbid ASD (FXS + ASD) have similar social communication deficits, which may have downstream effects on their question-asking ability. This study examined question-asking in school-age boys with idiopathic ASD and FXS + ASD, including the role of ASD severity, expressive grammatical complexity (measured by mean length of utterance [MLU]), and IQ. Method Twenty-five boys with FXS + ASD and 21 boys with idiopathic ASD (ages 9–16 years) were included in this study. Autism Diagnostic Observation Schedule assessments were transcribed and coded for the frequency, function, and appropriateness of spontaneous questions asked. We examined group differences in these aspects of question-asking and relationships between question-asking and ASD severity, MLU, and IQ within each group. Results Boys with FXS + ASD asked more questions than boys with idiopathic ASD, although boys with idiopathic ASD asked a higher proportion of appropriate questions. Boys with idiopathic ASD also asked the examiner more personal questions than the boys with FXS + ASD. ASD severity and MLU were related to the proportion of clarification questions in FXS + ASD, and ASD severity was also related to the proportion of personal questions in this group. For the boys with idiopathic ASD, ASD severity was related to the total number of questions asked. Conclusions Our findings highlight similarities and differences between boys with FXS + ASD and idiopathic ASD in their spontaneous question production and indicate that ASD severity and grammatical language are differentially important for question-asking. This study has implications for targeted treatment in question-asking skills for boys with FXS + ASD and ASD.

scholarly journals Impaired perceptual learning in Fragile X syndrome is mediated by parvalbumin neuron dysfunction in V1 and is reversible

2017 ◽  
Author(s):  
Anubhuti Goel ◽  
Daniel A. Cantu ◽  
Janna Guilfoyle ◽  
Gunvant R. Chaudhari ◽  
Aditi Newadkar ◽  
...  
Keyword(s):  
Perceptual Learning ◽  
Fragile X Syndrome ◽  
Visual Discrimination ◽  
Fragile X ◽  
Human Subjects ◽  
Autistic Traits ◽  
Autism Spectrum ◽  
Orientation Tuning ◽  
Mechanistic Basis

Atypical sensory processing is a core characteristic in autism spectrum disorders1 that negatively impacts virtually all activities of daily living. Sensory symptoms are predictive of the subsequent appearance of impaired social behavior and other autistic traits2, 3. Thus, a better understanding of the changes in neural circuitry that disrupt perceptual learning in autism could shed light into the mechanistic basis and potential therapeutic avenues for a range of autistic symptoms2. Likewise, the lack of directly comparable behavioral paradigms in both humans and animal models currently limits the translational potential of discoveries in the latter. We adopted a symptom-to-circuit approach to uncover the circuit-level alterations in the Fmr1-/- mouse model of Fragile X syndrome (FXS) that underlie atypical visual discrimination in this disorder4, 5. Using a go/no-go task and in vivo 2-photon calcium imaging in primary visual cortex (V1), we find that impaired discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons, and a decrease in the activity of parvalbumin (PV) interneurons in V1. Restoring visually evoked activity in PV cells in Fmr1-/- mice with a chemogenetic (DREADD) strategy was sufficient to rescue their behavioral performance. Finally, we found that human subjects with FXS exhibit strikingly similar impairments in visual discrimination as Fmr1-/- mice. We conclude that manipulating orientation tuning in autism could improve visually guided behaviors that are critical for playing sports, driving or judging emotions.

Altered Behaviour Associated With Autism in a Mouse Model of Fragile X Syndrome Treated With Bacteroides Fragilis BF839

2020 ◽  
Author(s):  
Chu-Hui Lin ◽  
Ting Zeng ◽  
Jian-Hong Lin ◽  
Feng Xiao ◽  
Bing-Mei Li ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Escape Latency ◽  
Fragile X ◽  
Bacteroides Fragilis ◽  
Autism Spectrum ◽  
Cognitive Capacity ◽  
Surrounding Environment ◽  
Maze Test ◽  
Plus Maze ◽  
The Impact

Abstract Background: Fragile X syndrome (FXS), tightly related to the morbidity of Autism spectrum disorder (ASD), is a common hereditary syndrome often associated with retardation of intelligence. Some key symptoms of ASD such as anxiety, cognitive impairment and social anxiety disorder are also the predominant features in FXS. Children with ASD are often performed with gastrointestinal symptoms. According to the existing research, with the treatment with Bacteroides Fragilis BF839, mice with ASD will have better performance in communication and social behaviours with less anxiety and perceptual disorder. In this article, we have observed the impact of Bacteroides Fragilis BF839, a well-established Chinese bacteria strain with the human intestine origin, on mice with FXS and their behavioural disorders accordingly. Result: Based on the Open Field test, compared to the Fmr1KO group, mice treated with BF839 showed prolonged staying time in the center of the container. This finding suggests that BF839 can improve Fmr1KO mice's self-exploration behaviour and dented their anxiety. The Elevated Plus Maze test indicated BF839 treated mice presented more activities in entering open arms, prolonged time of staying and significantly less distance travelled at the plus-maze, along with less entering behaviours in the closed arms with less time of staying and more distance travelled. This result proved that with the treatment of BF839, Fmr1KO mice have improved ability in recognizing the surrounding environment and greater senses at detecting danger. Three-box Social Interaction test confirmed that BF839 strengthens the social novelty preference of the Fmr1KO mice, proven by their increasing duration and frequency in social interacting with the stranger mouse. The final experiment named the Pool Maze test presented the result that on the fourth day, BF839 treated mice have shown significantly shortened escape latency. Meanwhile, on Day 5, BF839 treated group performed increasing frequency in passing through the platform, which, along with the shortened escape latency, demonstrated BF839 has the function of improving Fmr1KO mice's cognitive capacity and their ability to extract information from the surrounding environment.Conclusion: Based on the outcome of each test performed, Bacteroides Fragilis BF839 can successfully improve Autism related abnormal behaviours in mice with FXS. Bacteroides Fragilis BF839 can be a potential intervention strategy in treating FXS and ASD safely and effectively.

scholarly journals Cascade Testing for Fragile X Syndrome in a Rural Setting in Cameroon (Sub-Saharan Africa)

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 136
Author(s):  
Karen Kengne Kamga ◽  
Séraphin Nguefack ◽  
Khuthala Minka ◽  
Edmond Wonkam Tingang ◽  
Alina Esterhuizen ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Sub Saharan Africa ◽  
Rural Setting ◽  
Premature Menopause ◽  
Molecular Testing ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Cgg Repeats

Fragile X Syndrome (FXS), an X-linked dominant monogenic condition, is the main genetic cause of intellectual disability (ID) and autism spectrum disorder (ASD). FXS is associated with an expansion of CGG repeat sequence in the Fragile X Mental Retardation gene 1 (FMR1) on chromosome X. Following a neuropediatric assessment of two male siblings who presented with signs of FXS that was confirmed with molecular testing, we provided cascade counselling and testing to the extended family. A total of 46 individuals were tested for FXS; among them, 58.70% (n = 27) were females. The mean age was 9.4 (±5) years for children and 45.9 (±15.9) years for adults. Pedigree analysis suggested that the founder of these families was likely a normal transmitting male. Four out of 19 males with clinical ID were confirmed to have a full mutation for FXS, while 14/27 females had a pathologic CGG expansion (>56 CGG repeats) on one of their X chromosomes. Two women with premature menopause were confirmed of being carriers of premutation (91 and 101 CGG repeats). We also identified maternal alleles (91 and 126 CGG repeats) which expanded to a full mutation in their offspring (>200 CGG repeats). This study is a rare report on FXS from Africa and illustrates the case scenario of implementing genetic medicine for a neurogenetic condition in a rural setting.

scholarly journals Towards Mechanism-Based Treatments for Fragile X Syndrome

2019 ◽  
Vol 9 (8) ◽  
pp. 202
Author(s):  
Daman Kumari ◽  
Inbal Gazy
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Spectrum Disorder

Fragile X syndrome (FXS) is the most common heritable form of intellectual disability, as well as the most common known monogenic cause of autism spectrum disorder (ASD), affecting 1 in 4000–8000 people worldwide [...]

scholarly journals Abnormal development of auditory responses in the inferior colliculus of a mouse model of Fragile X Syndrome

2020 ◽  
Vol 123 (6) ◽  
pp. 2101-2121 ◽  
Author(s):  
Anna O. Nguyen ◽  
Devin K. Binder ◽  
Iryna M. Ethell ◽  
Khaleel A. Razak
Keyword(s):  
Mouse Model ◽  
Inferior Colliculus ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Abnormal Development ◽  
Sensory Sensitivity ◽  
Auditory Responses ◽  
Underlying Mechanisms ◽  
Early Developmental

Autism spectrum disorders (ASD) are commonly associated with sensory sensitivity issues, but the underlying mechanisms are unclear. This study presents novel evidence for neural correlates of auditory hypersensitivity in the developing inferior colliculus (IC) in the Fmr1 knockout (KO) mouse, a mouse model of Fragile X Syndrome (FXS), a leading genetic cause of ASD. Responses begin to show genotype differences between postnatal days 14 and 21, suggesting an early developmental treatment window.

Autism severity, co-occurring psychopathology, and intellectual functioning predict supportive school services for youth with autism spectrum disorder

Autism ◽  
2019 ◽  
Vol 23 (7) ◽  
pp. 1805-1816 ◽  
Author(s):  
Tamara E Rosen ◽  
Christine J Spaulding ◽  
Jacquelyn A Gates ◽  
Matthew D Lerner
Keyword(s):  
Autism Spectrum Disorder ◽  
Internalizing Symptoms ◽  
Psychiatric Symptoms ◽  
Skills Training ◽  
Autism Diagnostic Observation Schedule ◽  
Intellectual Functioning ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Multiple Sources ◽  
School Services

Supportive school services are a primary service modality for youth with autism spectrum disorder. Autism spectrum disorder, as well as co-occurring psychiatric symptoms and low intellectual abilities, interfere with academic achievement and therefore influence decisions about school services. Therefore, we examined the association of parent, teacher, and clinician ratings of autism spectrum disorder and co-occurring psychiatric symptom severity and intellectual functioning with school services. In total, 283 youth with autism spectrum disorder were assessed with clinical evaluation via the Autism Diagnostic Observation Schedule and parent and teacher versions of the CASI-4R ( Child and Adolescent Symptom Inventory). Full Scale Intelligence Quotient scores were obtained from case records. Clinical and teacher evaluations of autism spectrum disorder severity predicted services and were more strongly associated with school services than parent ratings. Teacher ratings were only associated with common school services (e.g. speech/language therapy, occupational therapy, and/or social skills training) frequency at medium and high levels of clinician-rated autism spectrum disorder severity. Higher IQ and parent-rated externalizing symptoms predicted lower likelihood of receiving school services, whereas internalizing symptoms were not predictive of school services. Autism spectrum disorder symptoms may overshadow externalizing and internalizing symptoms when considering school service supports. Results highlight the importance of evaluating autism spectrum disorder severity via multiple sources, especially in cases of unclear symptom presentation, when examining correlates of school services for youth with autism spectrum disorder.

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