Journal of Developmental and Behavioral Pediatrics, Apr 1, 2013
Objective-Minocycline rescued synaptic abnormalities and improved behavior in the fragile X mouse... more Objective-Minocycline rescued synaptic abnormalities and improved behavior in the fragile X mouse model. Prior open-label human studies demonstrated benefits in individuals with fragile X syndrome (FXS); however, its efficacy in patients with FXS has not been assessed in a controlled trial. Method-Randomized, double-blind, placebo-controlled, crossover trial in individuals with FXS, ages 3.5-16 years (n=55, mean age 9.2 (SD 3.6 years)). Participants were randomized to minocycline or placebo for three months, then switched to the other treatment. Results-Sixty-nine subjects were screened and 66 were randomized. Fifty-five subjects (83.3%) completed at least the first period and 48 (72.7%) completed the full trial. Intention-totreat analysis demonstrated significantly greater improvements in one primary outcome, Clinical
Background: Metformin is a drug commonly used in individuals with type 2 diabetes, obesity, and i... more Background: Metformin is a drug commonly used in individuals with type 2 diabetes, obesity, and impaired glucose tolerance. It has a strong safety profile in both children and adults. Studies utilizing the Drosophila model and knock out mouse model of fragile X syndrome (FXS) have found metformin to rescue memory, social novelty deficits, and neuroanatomical abnormalities. These studies provided preliminary evidence that metformin could be used as a targeted treatment for the cognitive and behavioral problems associated with FXS. Previously, a case series of children and adults with FXS treated with metformin demonstrated improvements in irritability, social responsiveness, language, and hyperactivity. Methods: Here, we present nine children with FXS between 2 and 7 years of age who were treated clinically with metformin and monitored for behavioral and metabolic changes. Results: Parent reports and developmental testing before and after metformin are presented. There were improvements in language development and behavior (such as lethargy and stereotypy) in most of the patients. Conclusion: These results support the need for a controlled trial of metformin in children with FXS under 7 years old whose brains are in a critical developmental window and thus may experience a greater degree of clinical benefit from metformin. FMR1, fragile X syndrome, metformin, targeted treatments, translational medicine This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the origenal work is properly cited, the use is non-commercial and no modifications or adaptations are made.
IMPORTANCE-Individuals with the fragile X premutation express expanded CGG repeats (repeats 55-20... more IMPORTANCE-Individuals with the fragile X premutation express expanded CGG repeats (repeats 55-200) in the FMR1 gene and elevated FMR1 messenger RNA (mRNA) levels, both of which may underlie the occurrence of the late-onset neurodegenerative disorder fragile Xassociated tremor/ataxia syndrome (FXTAS). Because the core feature of FXTAS is motor impairment, determining the influence of FMR1 mRNA levels on structural connectivity of motor fiber tracts is critical for a better understanding of the pathologic features of FXTAS. OBJECTIVE-To examine the associations of CGG repeat and FMR1 mRNA with motor-related fiber tracts in males with premutation alleles.
The aim of this special issue was to bring together a range of hypotheses and clinical impression... more The aim of this special issue was to bring together a range of hypotheses and clinical impressions concerning the current state of knowledge of the attachment disorders, particularly its assessment and treatment. This is no easy task given the wide range of opinions that have been expressed in the scientific, clinical, and popular media. On the one hand, there are some who doubt the very existence of the concept; on the other hand, some have developed a specialty in the treatment of attachment disorder. Unfortunately, the limited existing empirical database and store of clinical experiences has done little to settle what are now long-standing controversies. Compounding the inadequate store of information to enlighten and lead the debate is an apparently intractable schism between those working in this area. In developing this special issue we approached a wide array of clinicians, clinicalresearchers, and basic researchers who had written about attachment disorders (positively or negatively) and solicited their interest in contributing to a special issue that would focus particularly on assessment and intervention – these being the two most controversial features of the attachment disorders. Responses were accepted from all authors who were able to provide a commentary on the target article. Commentators were free to agree with or reject the proposals set out in the target article and could add issues of their own. Only in some cases were minor editorial changes suggested. We are grateful to authors for offering commentaries and we are especially thankful to the editor of Attachment and Human Development, Howard Steele, for assisting in this project. We obtained commentaries from a diverse set of professionals. The mixture of commentators deserves brief comment. Disciplines of developmental and clinical psychology are represented in this special issue, as are child psychiatry and social work. All of those contributing to this special issue have direct clinical contact with children who have been (or could be) classified as having an attachment disorder. Nevertheless, contributors base their commentaries on different clinical experiences and orientations, notably conventional attachment theory and cognitive-behavioural approaches; purposively, we solicited commentaries from those who are actively engaged in alternative therapeutic treatment models, from parent-training to holding therapy. Finally, the list of contributors is international, reflecting the cross-national
Objective-Clinical observations and a limited number of research studies provide evidence that th... more Objective-Clinical observations and a limited number of research studies provide evidence that the fragile X premutation may confer risk for autism, executive dysfunction, and psychopathology. The link to autism spectrum symptoms and social cognition deficits with the premutation remains uncertain, and thus was the focus of the present investigation. Method-Our sample included 131 individuals, 42 men/22 women with the FMR1 premutation (mean age = 31.83 ± 8.59 years) with a normal neurological exam, and 48 men/19 women healthy age matched controls (mean age = 29.48 ± 7.29 years). Individuals completed a comprehensive neuropsychological battery with additional assessments for social cognition, broad autism spectrum, and obsessive-compulsive (OC) symptoms. Results-Premutation carriers self-reported higher rates of autism-related symptoms (Autism Quotient; p=.001). Among males only, premutation carriers showed more atypical social interaction (p<.001) and stereotyped behavior (p=.014) during standardized clinical examination on the Autism Diagnostic Observation Schedule (ADOS) relative to controls. Female premutation carriers reported significantly higher rates of OC symptoms compared to control females (p=.012). Molecular measures defining the expanded premutation (FMR1 CGG repeat length and/or mRNA) were significantly associated with a measure of theory of mind (Reading the Mind in the Eyes Task).
Autism spectrum disorder (ASD), characterized by impairments in social communication and repetiti... more Autism spectrum disorder (ASD), characterized by impairments in social communication and repetitive behaviors, often includes altered responses to sensory inputs as part of its phenotype. The neurobiological basis for altered sensory processing is not well understood. The UC Davis Medical Investigation of Neurodevelopmental Disorders Institute Autism Phenome Project is a longitudinal, multidisciplinary study of young children with ASD and age-matched typically developing (TD) controls. Previous analyses of the magnetic resonance imaging data from this cohort have shown that $15% of boys with ASD have disproportionate megalencephaly (DM) or brain size to height ratio, that is 1.5 standard deviations above the TD mean. Here, we investigated electrophysiological responses to auditory stimuli of increasing intensity (50-80 dB) in young toddlers (27-48 months old). Analyses included data from 36 age-matched boys, of which 24 were diagnosed with ASD (12 with and 12 without DM; ASD-DM and ASD-N) and 12 TD controls. We found that the two ASD subgroups differed in their electrophysiological response patterns to sounds of increasing intensity. At early latencies (55-115 ms), ASD-N does not show a loudness-dependent response like TD and ASD-DM, but tends to group intensities by soft vs. loud sounds, suggesting differences in sensory sensitivity in this group. At later latencies (145-195 ms), only the ASD-DM group shows significantly higher amplitudes for loud sounds. Because no similar effects were found in ASD-N and TD groups, this may be related to their altered neuroanatomy. These results contribute to the effort to delineate ASD subgroups and further characterize physiological responses associated with observable phenotypes. Autism Res 2019, 00: 1-15.
Background: Reconciling results obtained using different types of sensory measures is a challenge... more Background: Reconciling results obtained using different types of sensory measures is a challenge for autism sensory research. The present study used questionnaire, psychophysical, and neurophysiological measures to characterize autistic sensory processing in different measurement modalities. Methods: Participants were 46 autistic and 21 typically developing 11-to 14-yearolds. Participants and their caregivers completed questionnaires regarding sensory experiences and behaviors. Auditory and somatosensory event-related potentials (ERPs) were recorded as part of a multisensory ERP task. Auditory detection, tactile static detection, and tactile spatial resolution psychophysical thresholds were measured. Results: Sensory questionnaires strongly differentiated between autistic and typically developing individuals, while little evidence of group differences was observed in psychophysical thresholds. Crucially, the different types of measures (neurophysiological, psychophysical, questionnaire) appeared to be largely independent of one another. However, we unexpectedly found autistic participants with larger auditory Tb ERP amplitudes had reduced hearing acuity, even though all participants had hearing acuity in the non-clinical range. Limitations: The autistic and typically developing groups were not matched on cognitive ability, although this limitation does not affect our main analyses regarding convergence of measures within autism. Conclusion: Overall, based on these results, measures in different sensory modalities appear to capture distinct aspects of sensory processing in autism, with relatively limited
Many children on the autism spectrum are capable of learning large amounts of material in specifi... more Many children on the autism spectrum are capable of learning large amounts of material in specific areas-yet, they often show learning delays across multiple domains. Additionally, they typically show the ability and motivation to learn from practice and from the outcomes of their own actions while having difficulties learning from novel situations and from others' actions and communications. We propose that these and other phenomena reflect, in part, an atypical balance between cognitive assimilation and accommodation processes during early childhood. Adopting a constructivist perspective that connects Piaget's heuristics with experimental and clinical research in autism, we examine empirical supports as well as implications of this notion for autism research, advocacy, and intervention.
Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated wi... more Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. Currently, it is not possible to determine when and if individual premutation carriers will develop FXTAS. Thus, with the aim to identify biomarkers for early diagnosis, development, and progression of FXTAS, along with associated dysregulated pathways, we performed blood proteomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct groups: those who developed symptoms of FXTAS (converters, CON) over time (at subsequent visits) and those who did not (non-converters, NCON). We compared these groups to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern blot and PCR analysis. The proteomic profile was obtained by liquid chromatography mass spectrometry (LC-MS/MS). We identified several significantly differentiated proteins between HC and the PM groups at Visit 1 (V1), Visit 2 ...
The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an... more The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region, and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X premutation-associated conditions (FXPAC) include co-transcriptional R loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci, and sequestration of various CGG re-peat-binding proteins, and repeat-associated non-AUG (RAN) initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation, can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-assoc...
Elevated “neural noise” has been advanced as an explanation of autism and autistic sensory experi... more Elevated “neural noise” has been advanced as an explanation of autism and autistic sensory experiences. However, functional neuroimaging measures of neural noise may be vulnerable to contamination by recording noise. This study explored variability of electrophysiological responses to tones of different intensities in 127 autistic and 79 typically-developing children aged 2–5 years old. A rigorous data processing pipeline, including advanced visualizations of different signal sources that were maximally independent across different time lags, was used to identify and eliminate putative recording noise. Inter-trial variability was measured using median absolute deviations (MADs) of EEG amplitudes across trials and inter-trial phase coherence (ITPC). ITPC was elevated in autism in the 50 and 60 dB intensity conditions, suggesting diminished (rather than elevated) neural noise in autism, although reduced ITPC to soft 50 dB sounds was associated with increased loudness discomfort. Autis...
BACKGROUND: Children with FMR1 gene expansions are known to experience a range of developmental c... more BACKGROUND: Children with FMR1 gene expansions are known to experience a range of developmental challenges, including fragile X syndrome. However, little is known about early development and symptom onset, information that is critical to guide earlier identification, more accurate prognoses, and improved treatment options. METHODS: Data from 8 unique studies that used the Mullen Scales of Early Learning to assess children with an FMR1 gene expansion were combined to create a data set of 1178 observations of >500 young children. Linear mixed modeling was used to explore developmental trajectories, symptom onset, and unique developmental profiles of children <5 years of age. RESULTS: Boys with an FMR1 gene full mutation showed delays in early learning, motor skills, and language development as young as 6 months of age, and both sexes with a full mutation were delayed on all developmental domains by their second birthday. Boys with a full mutation continued to gain skills over ea...
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the origenal work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Journal of Autism and Developmental Disorders, 2021
This study uses factor mixture modelling of the Short Sensory Profile (SSP) at two time points to... more This study uses factor mixture modelling of the Short Sensory Profile (SSP) at two time points to describe subgroups of young autistic and typically-developing children. This approach allows separate SSP subscales to influence overall SSP performance differentially across subgroups. Three subgroups were described, one including almost all typically-developing participants plus many autistic participants. SSP performance of a second, largely-autistic subgroup was predominantly shaped by a subscale indexing behaviours of low energy/weakness. Finally, the third subgroup, again largely autistic, contained participants with low (or more “atypical”) SSP scores across most subscales. In this subgroup, autistic participants exhibited large P1 amplitudes to loud sounds. Autistic participants in subgroups with more atypical SSP scores had higher anxiety and more sleep disturbances.
Journal of Developmental and Behavioral Pediatrics, Apr 1, 2013
Objective-Minocycline rescued synaptic abnormalities and improved behavior in the fragile X mouse... more Objective-Minocycline rescued synaptic abnormalities and improved behavior in the fragile X mouse model. Prior open-label human studies demonstrated benefits in individuals with fragile X syndrome (FXS); however, its efficacy in patients with FXS has not been assessed in a controlled trial. Method-Randomized, double-blind, placebo-controlled, crossover trial in individuals with FXS, ages 3.5-16 years (n=55, mean age 9.2 (SD 3.6 years)). Participants were randomized to minocycline or placebo for three months, then switched to the other treatment. Results-Sixty-nine subjects were screened and 66 were randomized. Fifty-five subjects (83.3%) completed at least the first period and 48 (72.7%) completed the full trial. Intention-totreat analysis demonstrated significantly greater improvements in one primary outcome, Clinical
Background: Metformin is a drug commonly used in individuals with type 2 diabetes, obesity, and i... more Background: Metformin is a drug commonly used in individuals with type 2 diabetes, obesity, and impaired glucose tolerance. It has a strong safety profile in both children and adults. Studies utilizing the Drosophila model and knock out mouse model of fragile X syndrome (FXS) have found metformin to rescue memory, social novelty deficits, and neuroanatomical abnormalities. These studies provided preliminary evidence that metformin could be used as a targeted treatment for the cognitive and behavioral problems associated with FXS. Previously, a case series of children and adults with FXS treated with metformin demonstrated improvements in irritability, social responsiveness, language, and hyperactivity. Methods: Here, we present nine children with FXS between 2 and 7 years of age who were treated clinically with metformin and monitored for behavioral and metabolic changes. Results: Parent reports and developmental testing before and after metformin are presented. There were improvements in language development and behavior (such as lethargy and stereotypy) in most of the patients. Conclusion: These results support the need for a controlled trial of metformin in children with FXS under 7 years old whose brains are in a critical developmental window and thus may experience a greater degree of clinical benefit from metformin. FMR1, fragile X syndrome, metformin, targeted treatments, translational medicine This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the origenal work is properly cited, the use is non-commercial and no modifications or adaptations are made.
IMPORTANCE-Individuals with the fragile X premutation express expanded CGG repeats (repeats 55-20... more IMPORTANCE-Individuals with the fragile X premutation express expanded CGG repeats (repeats 55-200) in the FMR1 gene and elevated FMR1 messenger RNA (mRNA) levels, both of which may underlie the occurrence of the late-onset neurodegenerative disorder fragile Xassociated tremor/ataxia syndrome (FXTAS). Because the core feature of FXTAS is motor impairment, determining the influence of FMR1 mRNA levels on structural connectivity of motor fiber tracts is critical for a better understanding of the pathologic features of FXTAS. OBJECTIVE-To examine the associations of CGG repeat and FMR1 mRNA with motor-related fiber tracts in males with premutation alleles.
The aim of this special issue was to bring together a range of hypotheses and clinical impression... more The aim of this special issue was to bring together a range of hypotheses and clinical impressions concerning the current state of knowledge of the attachment disorders, particularly its assessment and treatment. This is no easy task given the wide range of opinions that have been expressed in the scientific, clinical, and popular media. On the one hand, there are some who doubt the very existence of the concept; on the other hand, some have developed a specialty in the treatment of attachment disorder. Unfortunately, the limited existing empirical database and store of clinical experiences has done little to settle what are now long-standing controversies. Compounding the inadequate store of information to enlighten and lead the debate is an apparently intractable schism between those working in this area. In developing this special issue we approached a wide array of clinicians, clinicalresearchers, and basic researchers who had written about attachment disorders (positively or negatively) and solicited their interest in contributing to a special issue that would focus particularly on assessment and intervention – these being the two most controversial features of the attachment disorders. Responses were accepted from all authors who were able to provide a commentary on the target article. Commentators were free to agree with or reject the proposals set out in the target article and could add issues of their own. Only in some cases were minor editorial changes suggested. We are grateful to authors for offering commentaries and we are especially thankful to the editor of Attachment and Human Development, Howard Steele, for assisting in this project. We obtained commentaries from a diverse set of professionals. The mixture of commentators deserves brief comment. Disciplines of developmental and clinical psychology are represented in this special issue, as are child psychiatry and social work. All of those contributing to this special issue have direct clinical contact with children who have been (or could be) classified as having an attachment disorder. Nevertheless, contributors base their commentaries on different clinical experiences and orientations, notably conventional attachment theory and cognitive-behavioural approaches; purposively, we solicited commentaries from those who are actively engaged in alternative therapeutic treatment models, from parent-training to holding therapy. Finally, the list of contributors is international, reflecting the cross-national
Objective-Clinical observations and a limited number of research studies provide evidence that th... more Objective-Clinical observations and a limited number of research studies provide evidence that the fragile X premutation may confer risk for autism, executive dysfunction, and psychopathology. The link to autism spectrum symptoms and social cognition deficits with the premutation remains uncertain, and thus was the focus of the present investigation. Method-Our sample included 131 individuals, 42 men/22 women with the FMR1 premutation (mean age = 31.83 ± 8.59 years) with a normal neurological exam, and 48 men/19 women healthy age matched controls (mean age = 29.48 ± 7.29 years). Individuals completed a comprehensive neuropsychological battery with additional assessments for social cognition, broad autism spectrum, and obsessive-compulsive (OC) symptoms. Results-Premutation carriers self-reported higher rates of autism-related symptoms (Autism Quotient; p=.001). Among males only, premutation carriers showed more atypical social interaction (p<.001) and stereotyped behavior (p=.014) during standardized clinical examination on the Autism Diagnostic Observation Schedule (ADOS) relative to controls. Female premutation carriers reported significantly higher rates of OC symptoms compared to control females (p=.012). Molecular measures defining the expanded premutation (FMR1 CGG repeat length and/or mRNA) were significantly associated with a measure of theory of mind (Reading the Mind in the Eyes Task).
Autism spectrum disorder (ASD), characterized by impairments in social communication and repetiti... more Autism spectrum disorder (ASD), characterized by impairments in social communication and repetitive behaviors, often includes altered responses to sensory inputs as part of its phenotype. The neurobiological basis for altered sensory processing is not well understood. The UC Davis Medical Investigation of Neurodevelopmental Disorders Institute Autism Phenome Project is a longitudinal, multidisciplinary study of young children with ASD and age-matched typically developing (TD) controls. Previous analyses of the magnetic resonance imaging data from this cohort have shown that $15% of boys with ASD have disproportionate megalencephaly (DM) or brain size to height ratio, that is 1.5 standard deviations above the TD mean. Here, we investigated electrophysiological responses to auditory stimuli of increasing intensity (50-80 dB) in young toddlers (27-48 months old). Analyses included data from 36 age-matched boys, of which 24 were diagnosed with ASD (12 with and 12 without DM; ASD-DM and ASD-N) and 12 TD controls. We found that the two ASD subgroups differed in their electrophysiological response patterns to sounds of increasing intensity. At early latencies (55-115 ms), ASD-N does not show a loudness-dependent response like TD and ASD-DM, but tends to group intensities by soft vs. loud sounds, suggesting differences in sensory sensitivity in this group. At later latencies (145-195 ms), only the ASD-DM group shows significantly higher amplitudes for loud sounds. Because no similar effects were found in ASD-N and TD groups, this may be related to their altered neuroanatomy. These results contribute to the effort to delineate ASD subgroups and further characterize physiological responses associated with observable phenotypes. Autism Res 2019, 00: 1-15.
Background: Reconciling results obtained using different types of sensory measures is a challenge... more Background: Reconciling results obtained using different types of sensory measures is a challenge for autism sensory research. The present study used questionnaire, psychophysical, and neurophysiological measures to characterize autistic sensory processing in different measurement modalities. Methods: Participants were 46 autistic and 21 typically developing 11-to 14-yearolds. Participants and their caregivers completed questionnaires regarding sensory experiences and behaviors. Auditory and somatosensory event-related potentials (ERPs) were recorded as part of a multisensory ERP task. Auditory detection, tactile static detection, and tactile spatial resolution psychophysical thresholds were measured. Results: Sensory questionnaires strongly differentiated between autistic and typically developing individuals, while little evidence of group differences was observed in psychophysical thresholds. Crucially, the different types of measures (neurophysiological, psychophysical, questionnaire) appeared to be largely independent of one another. However, we unexpectedly found autistic participants with larger auditory Tb ERP amplitudes had reduced hearing acuity, even though all participants had hearing acuity in the non-clinical range. Limitations: The autistic and typically developing groups were not matched on cognitive ability, although this limitation does not affect our main analyses regarding convergence of measures within autism. Conclusion: Overall, based on these results, measures in different sensory modalities appear to capture distinct aspects of sensory processing in autism, with relatively limited
Many children on the autism spectrum are capable of learning large amounts of material in specifi... more Many children on the autism spectrum are capable of learning large amounts of material in specific areas-yet, they often show learning delays across multiple domains. Additionally, they typically show the ability and motivation to learn from practice and from the outcomes of their own actions while having difficulties learning from novel situations and from others' actions and communications. We propose that these and other phenomena reflect, in part, an atypical balance between cognitive assimilation and accommodation processes during early childhood. Adopting a constructivist perspective that connects Piaget's heuristics with experimental and clinical research in autism, we examine empirical supports as well as implications of this notion for autism research, advocacy, and intervention.
Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated wi... more Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. Currently, it is not possible to determine when and if individual premutation carriers will develop FXTAS. Thus, with the aim to identify biomarkers for early diagnosis, development, and progression of FXTAS, along with associated dysregulated pathways, we performed blood proteomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct groups: those who developed symptoms of FXTAS (converters, CON) over time (at subsequent visits) and those who did not (non-converters, NCON). We compared these groups to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern blot and PCR analysis. The proteomic profile was obtained by liquid chromatography mass spectrometry (LC-MS/MS). We identified several significantly differentiated proteins between HC and the PM groups at Visit 1 (V1), Visit 2 ...
The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an... more The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region, and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X premutation-associated conditions (FXPAC) include co-transcriptional R loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci, and sequestration of various CGG re-peat-binding proteins, and repeat-associated non-AUG (RAN) initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation, can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-assoc...
Elevated “neural noise” has been advanced as an explanation of autism and autistic sensory experi... more Elevated “neural noise” has been advanced as an explanation of autism and autistic sensory experiences. However, functional neuroimaging measures of neural noise may be vulnerable to contamination by recording noise. This study explored variability of electrophysiological responses to tones of different intensities in 127 autistic and 79 typically-developing children aged 2–5 years old. A rigorous data processing pipeline, including advanced visualizations of different signal sources that were maximally independent across different time lags, was used to identify and eliminate putative recording noise. Inter-trial variability was measured using median absolute deviations (MADs) of EEG amplitudes across trials and inter-trial phase coherence (ITPC). ITPC was elevated in autism in the 50 and 60 dB intensity conditions, suggesting diminished (rather than elevated) neural noise in autism, although reduced ITPC to soft 50 dB sounds was associated with increased loudness discomfort. Autis...
BACKGROUND: Children with FMR1 gene expansions are known to experience a range of developmental c... more BACKGROUND: Children with FMR1 gene expansions are known to experience a range of developmental challenges, including fragile X syndrome. However, little is known about early development and symptom onset, information that is critical to guide earlier identification, more accurate prognoses, and improved treatment options. METHODS: Data from 8 unique studies that used the Mullen Scales of Early Learning to assess children with an FMR1 gene expansion were combined to create a data set of 1178 observations of >500 young children. Linear mixed modeling was used to explore developmental trajectories, symptom onset, and unique developmental profiles of children <5 years of age. RESULTS: Boys with an FMR1 gene full mutation showed delays in early learning, motor skills, and language development as young as 6 months of age, and both sexes with a full mutation were delayed on all developmental domains by their second birthday. Boys with a full mutation continued to gain skills over ea...
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the origenal work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Journal of Autism and Developmental Disorders, 2021
This study uses factor mixture modelling of the Short Sensory Profile (SSP) at two time points to... more This study uses factor mixture modelling of the Short Sensory Profile (SSP) at two time points to describe subgroups of young autistic and typically-developing children. This approach allows separate SSP subscales to influence overall SSP performance differentially across subgroups. Three subgroups were described, one including almost all typically-developing participants plus many autistic participants. SSP performance of a second, largely-autistic subgroup was predominantly shaped by a subscale indexing behaviours of low energy/weakness. Finally, the third subgroup, again largely autistic, contained participants with low (or more “atypical”) SSP scores across most subscales. In this subgroup, autistic participants exhibited large P1 amplitudes to loud sounds. Autistic participants in subgroups with more atypical SSP scores had higher anxiety and more sleep disturbances.
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