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...
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.
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, Jan 13, 2017
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder af... more Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting approximately 45% of male and 16% of female carriers of the FMR1 premutation over the age of 50 years. Currently, no effective treatment is available. We performed an open-label intervention study to assess whether allopregnanolone, a neurosteroid promoting regeneration and repair, can improve clinical symptoms, brain activity, and magnetic resonance imaging (MRI) measurements in patients with FXTAS. Six patients underwent weekly intravenous infusions of allopregnanolone (2-6 mg over 30 min) for 12 weeks. All patients completed baseline and follow-up studies, though MRI scans were not collected from 1 patient because of MRI contraindications. The MRI scans from previous visits, along with scans from 8 age-matched male controls, were also included to establish patients' baseline condition as a reference. Functional outcomes included quantitative measurements of tremor and atax...
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...
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.
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, Jan 13, 2017
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder af... more Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting approximately 45% of male and 16% of female carriers of the FMR1 premutation over the age of 50 years. Currently, no effective treatment is available. We performed an open-label intervention study to assess whether allopregnanolone, a neurosteroid promoting regeneration and repair, can improve clinical symptoms, brain activity, and magnetic resonance imaging (MRI) measurements in patients with FXTAS. Six patients underwent weekly intravenous infusions of allopregnanolone (2-6 mg over 30 min) for 12 weeks. All patients completed baseline and follow-up studies, though MRI scans were not collected from 1 patient because of MRI contraindications. The MRI scans from previous visits, along with scans from 8 age-matched male controls, were also included to establish patients' baseline condition as a reference. Functional outcomes included quantitative measurements of tremor and atax...
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Papers by Susan Rivera