Enlarged perivascular spaces and their association with motor, cognition, MRI markers and cerebrovascular risk factors in male fragile X premutation carriers.

FMR1 premutation carriers (55-200 CGG repeats) are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder associated with motor and cognitive impairment. Bilateral hyperintensities of the middle cerebellar peduncles (MCP sign) are the major radiological hallmarks of FXTAS. In the general population, enlarged perivascular spaces (PVS) are biomarkers of small vessel disease and glymphatic dysfunction and are associated with cognitive decline. Our aim was to determine if premutation carriers show higher ratings of PVS than controls and whether enlarged PVS are associated with motor and cognitive impairment, MRI features of neurodegeneration, cerebrovascular risk factors and CGG repeat length. We evaluated 655 MRIs (1-10 visits/participant) from 229 carriers (164 with FXTAS and 65 without FXTAS) and 133 controls. PVS in the basal ganglia (BG-EPVS), centrum semiovale, and midbrain were evaluated with a semiquantitative scale. Mixed-effects models were used for statistical analysis adjusting for age. In carriers with FXTAS, we revealed that (1) BG-PVS ratings were higher than those of controls and carriers without FXTAS; (2) BG-PVS severity was associated with brain atrophy, white matter hyperintensities, enlarged ventricles, FXTAS stage and abnormal gait; (3) age-related increase in BG-PVS was associated with cognitive dysfunction; and (4) PVS ratings of all three regions showed robust associations with CGG repeat length and were higher in carriers with the MCP sign than carriers without the sign. This study demonstrates clinical relevance of PVS in FXTAS especially in the basal ganglia region and suggests microangiopathy and dysfunctional cerebrospinal fluid circulation in FXTAS physiopathology.

Motor Control Adherence to the Two-thirds Power Law Differs in Autistic Development.

Autistic individuals often exhibit motor atypicalities, which may relate to difficulties in social communication. This study utilized a smart tablet activity to computationally characterize motor control by testing adherence to the two-thirds power law (2/3 PL), which captures a systematic covariation between velocity and curvature in motor execution and governs many forms of human movement. Children aged 4-8 years old participated in this study, including 24 autistic children and 33 typically developing children. Participants drew and traced ellipses on an iPad. We extracted data from finger movements on the screen, and computed adherence to the 2/3 PL and other kinematic metrics. Measures of cognitive and motor functioning were also collected. In comparison to the typically developing group, the autistic group demonstrated greater velocity modulation between curved and straight sections of movement, increased levels of acceleration and jerk, and greater intra- and inter-individual variability across several kinematic variables. Further, significant motor control development was observed in typically developing children, but not in those with autism. This study is the first to examine motor control adherence to the 2/3 PL in autistic children, revealing overall diminished motor control. Less smooth, more varied movement and an indication of developmental stasis in autistic children were observed. This study offers a novel tool for computational characterization of the autism motor signature in children's development, demonstrating how smart tablet technology enables accessible assessment of children's motor performance in an objective, quantifiable and scalable manner.

FMR1 Carriers Report Executive Function Changes Prior to Fragile X-Associated Tremor/Ataxia Syndrome: A Longitudinal Study.

BACKGROUND: Men with fragile X-associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross-sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies has made it difficult to address this hypothesis. OBJECTIVE: To determine whether executive function deterioration experienced by premutation carriers (PC) in daily life precedes and predicts FXTAS. METHODS: This study included 66 FMR1 PC ranging from 40 to 78 years (mean, 59.5) and 31 well-matched healthy controls (HC) ages 40 to 75 (mean, 57.7) at baseline. Eighty-four participants returned for 2 to 5 follow up visits over a duration of 1 to 9 years (mean, 4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was completed by participants and their spouses/partners at each visit. RESULTS: Longitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self-initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, increased self-report executive function problems at baseline significantly predicted later development of FXTAS. CONCLUSIONS: Executive function changes experienced by male PC represent a prodrome of the later movement disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS.

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 (V2), and between the visits. We further reported the dysregulated protein pathways, including sphingolipid and amino acid metabolism. Our findings are in agreement with previous studies showing that pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered and appear to contribute to the development of FXTAS. Lastly, we compared the blood proteome of the PM who developed FXTAS over time with the CSF proteome of the FXTAS patients recently reported and found eight significantly differentially expressed proteins in common. To our knowledge, this is the first report of longitudinal proteomic profiling and the identification of unique biomarkers and dysregulated protein pathways in FXTAS.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation.

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 cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the 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-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

A Longitudinal Study of Executive Function in Daily Life in Male Fragile X Premutation Carriers and Association with FXTAS Conversion.

Background: Men with fragile X-associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross-sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies have made it difficult to address this hypothesis. Methods: This study included 66 FMR1 premutation carriers (PC) ranging from 40-78 years (Mean=59.5) and 31 well-matched healthy controls (HC) ages 40-75 (Mean 57.7) at baseline. Eighty-four participants returned for 2-5 follow up visits over a duration of 1 to 9 years (Mean=4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was completed by participants and their spouses/partners at each visit. Results: Longitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self-initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, BRIEF-A executive function problems at baseline significantly predicted later development of FXTAS. Conclusions: These findings suggest that executive function changes represent a prodrome of the later movement disorder.

Habituation of auditory responses in young autistic and neurotypical children.

Prior studies suggest that habituation of sensory responses is reduced in autism and that diminished habituation could be related to atypical autistic sensory experiences, for example, by causing brain responses to aversive stimuli to remain strong over time instead of being suppressed. While many prior studies exploring habituation in autism have repeatedly presented identical stimuli, other studies suggest group differences can still be observed in habituation to intermittent stimuli. The present study explored habituation of electrophysiological responses to auditory complex tones of varying intensities (50-80 dB SPL), presented passively in an interleaved manner, in a well-characterized sample of 127 autistic (MDQ = 65.41, SD = 20.54) and 79 typically developing (MDQ = 106.02, SD = 11.50) children between 2 and 5 years old. Habituation was quantified as changes in the amplitudes of single-trial responses to tones of each intensity over the course of the experiment. Habituation of the auditory N2 response was substantially reduced in autistic participants as compared to typically developing controls, although diagnostic groups did not clearly differ in habituation of the P1 response. Interestingly, the P1 habituated less to loud 80 dB sounds than softer sounds, whereas the N2 habituated less to soft 50 dB sounds than louder sounds. No associations were found between electrophysiological habituation and cognitive ability or participants' caregiver-reported sound tolerance (Sensory Profile Hyperacusis Index). The results present study results extend prior research suggesting habituation of certain sensory responses is reduced in autism; however, they also suggest that habituation differences observed using this study's paradigm might not be a primary driver of autistic participants' real-world sound intolerance.

Tophaceous gout of the nose in a male FMR1 premutation carrier.

Premutation alleles with 55-200 CGG repeats in FMR1 can lead to fragile X-associated tremor/ataxia syndrome (FXTAS). In this case study, we report uncontrolled gout in a 68-year-old male with FXTAS with multiple sites of involvement including a rare gouty tophus in the nasal region.

"Neural Noise" in Auditory Responses in Young Autistic and Neurotypical Children.

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. Autistic and non-autistic participants did not differ in MADs, and indeed, the vast majority of the statistical tests examined in this study yielded no significant effects. These results appear inconsistent with the neural noise account.

Multisensory integration and interactions across vision, hearing, and somatosensation in autism spectrum development and typical development.

Most prior studies of multisensory integration (MSI) in autism have measured MSI in only a single combination of modalities - typically audiovisual integration. The present study used onset reaction times (RTs) and 125-channel electroencephalography (EEG) to examine different forms of bimodal and trimodal MSI based on combinations of auditory (noise burst), somatosensory (finger tap), and visual (flash) stimuli presented in a spatially-aligned manner using a custom desktop apparatus. A total of 36 autistic and 19 non-autistic adolescents between the ages of 11-14 participated. Significant RT multisensory facilitation relative to summed unisensory RT was observed in both groups, as were significant differences between summed unisensory and multisensory ERPs. Although the present study's statistical approach was not intended to test effect latencies, these interactions may have begun as early as ∼45 ms, constituting "early" (<100 ms) MSI. RT and ERP measurements of MSI appeared independent of one another. Groups did not significantly differ in multisensory RT facilitation, but we found exploratory evidence of group differences in the magnitude of audiovisual interactions in ERPs. Future research should make greater efforts to explore MSI in under-represented populations, especially autistic people with intellectual disabilities and nonspeaking/minimally-verbal autistic people.

A Multidimensional Investigation of Sensory Processing in Autism: Parent- and Self-Report Questionnaires, Psychophysical Thresholds, and Event-Related Potentials in the Auditory and Somatosensory Modalities.

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-year-olds. 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 convergence between questionnaires and laboratory-based tasks. Generally, this might reflect the reality that laboratory tasks are often carried out in controlled environments without background stimuli to compete for attention, a context which may not closely resemble the busier and more complex environments in which autistic people's atypical sensory experiences commonly occur. Sensory questionnaires and more naturalistic laboratory tasks may be better suited to explore autistic people's real-world sensory challenges. Further research is needed to replicate and investigate the drivers of the unexpected association we observed between auditory Tb ERP amplitudes and hearing acuity, which could represent an important confound for ERP researchers to consider in their studies.

Prosaccade and Antisaccade Behavior in Fragile X-Associated Tremor/Ataxia Syndrome Progression.

Background: Quantitative measurement of eye movements can reveal subtle progression in neurodegenerative diseases. Objective: To determine if quantitative measurements of eye movements may reveal subtle progression of fragile X-associated tremor and ataxia (FXTAS). Methods: Prosaccade (PS) and antisaccade (AS) behavior was analyzed in 25 controls, 57 non-FXTAS carriers, and 46 carriers with FXTAS. Results: Symptomatic individuals with FXTAS had longer AS latencies, increased rates of AS errors, and increased AS dysmetria relative to non-FXTAS carriers and controls. These deficits, along with PS latency and velocity, were greater in advanced FXTAS stages. Conclusion: AS deficits differentiated FXTAS from non-FXTAS premutation carriers implicating top-down control and frontostriatal deterioration. However, the absence of group differences between non-FXTAS carriers and controls in AS and PS markers suggests saccade performance may not be a sensitive enough measure for detecting conversion to FXTAS, but instead more helpful as translational biomarkers of FXTAS progression.

Neuropsychological changes in FMR1 premutation carriers and onset of fragile X-associated tremor/ataxia syndrome.

BACKGROUND: Carriers of the FMR1 premutation are at increased risk of developing a late-onset progressive neurodegenerative disease, fragile X-associated tremor/ataxia syndrome (FXTAS), characterized by intention tremor, gait ataxia, and cognitive decline. Cross-sectional studies to date have provided evidence that neuropsychological changes, such as executive function alterations, or subtle motor changes, may precede the onset of formal FXTAS, perhaps characterizing a prodromal state. However, the lack of longitudinal data has prevented the field from forming a clear picture of progression over time within individuals, and we lack consensus regarding early markers of risk and measures that may be used to track response to intervention. METHODS: This was a longitudinal study of 64 male FMR1 premutation carriers (Pm) without FXTAS at study entry and 30 normal controls (Nc), aged 40 to 80 years (Pm M = 60.0 years; Nc M = 57.4 years). Fifty of the Pm and 22 of the Nc were re-assessed after an average of 2.33 years, and 37 Pm and 20 Nc were re-assessed a third time after an average of another 2.15 years. Eighteen of 64 carriers (28%) converted to FXTAS during the study to date. Neuropsychological assessments at each time point, including components of the Cambridge Neuropsychological Test Automated Battery (CANTAB), tapped domains of episodic and working memory, inhibitory control, visual attention, planning, executive control of movement, and manual speed and dexterity. Age-based mixed models were used to examine group differences in change over time on the outcomes in the full sample, and differences were further evaluated in 15 trios (n = 45; 15 Pm "converters," 15 Pm "nonconverters," 15 Nc) that were one-one matched on age, education, and socioeconomic status. RESULTS: Compared to Nc, Pm showed significantly greater rates of change over time in visual working memory, motor dexterity, inhibitory control, and manual movement speed. After multiple comparison correction, significant effects remained for motor dexterity. Worsening inhibitory control and slower manual movements were related to progression in FXTAS stage, but these effects became statistically non-significant after correcting for multiple comparisons. Higher FMR1 mRNA correlated with worsening manual reaction time but did not survive multiple comparisons and no other molecular measures correlated with neuropsychological changes. Finally, trio comparisons revealed greater rate of decline in planning and manual movement speed in Pm converters compared to Pm nonconverters. CONCLUSIONS: Accelerated decline in executive function and subtle motor changes, likely mediated by frontocerebellar circuits, may precede, and then track with the emergence of formal FXTAS symptoms. Further research to develop and harmonize clinical assessment of FMR1 carriers across centers is needed to prepare for future prophylactic and treatment trials for this disorder.

Clinical and Molecular Correlates of Abnormal Changes in the Cerebellum and Globus Pallidus in Fragile X Premutation.

BACKGROUND: Fragile X premutation carriers (55-200 CGG triplets) may develop a progressive neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), after the age of 50. The neuroradiologic markers of FXTAS are hyperintense T2-signals in the middle cerebellar peduncle-the MCP sign. We recently noticed abnormal T2-signals in the globus pallidus in male premutation carriers and controls but the prevalence and clinical significance were unknown. METHODS: We estimated the prevalence of the MCP sign and pallidal T2-abnormalities in 230 male premutation carriers and 144 controls (aged 8-86), and examined the associations with FXTAS symptoms, CGG repeat length, and iron content in the cerebellar dentate nucleus and globus pallidus. RESULTS: Among participants aged ≥45 years (175 premutation carriers and 82 controls), MCP sign was observed only in premutation carriers (52 vs. 0%) whereas the prevalence of pallidal T2-abnormalities approached significance in premutation carriers compared with controls after age-adjustment (25.1 vs. 13.4%, p = 0.069). MCP sign was associated with impaired motor and executive functioning, and the additional presence of pallidal T2-abnormalities was associated with greater impaired executive functioning. Among premutation carriers, significant iron accumulation was observed in the dentate nucleus, and neither pallidal or MCP T2-abnormalities affected measures of the dentate nucleus. While the MCP sign was associated with CGG repeat length >75 and dentate nucleus volume correlated negatively with CGG repeat length, pallidal T2-abnormalities did not correlate with CGG repeat length. However, pallidal signal changes were associated with age-related accelerated iron depletion and variability and having both MCP and pallidal signs further increased iron variability in the globus pallidus. CONCLUSIONS: Only the MCP sign, not pallidal abnormalities, revealed independent associations with motor and cognitive impairment; however, the occurrence of combined MCP and pallidal T2-abnormalities may present a risk for greater cognitive impairment and increased iron variability in the globus pallidus.

Exploring Sensory Subgroups in Typical Development and Autism Spectrum Development Using Factor Mixture Modelling.

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.

Metabolomic Biomarkers Are Associated With Area of the Pons in Fragile X Premutation Carriers at Risk for Developing FXTAS.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder that affects movement and cognition in male and female carriers of a premutation allele (55-200 CGG repeats; PM) in the fragile X mental retardation (FMR1) gene. It is currently unknown how the observed brain changes are associated with metabolic signatures in individuals who develop the disorder over time. The primary objective of this study was to investigate the correlation between longitudinal changes in the brain (area of the pons, midbrain, and MCP width) and the changes in the expression level of metabolic biomarkers of early diagnosis and progression of FXTAS in PM who, as part of an ongoing longitudinal study, emerged into two distinct categories. These included those who developed symptoms of FXTAS (converters, CON) at subsequent visits and those who did not meet the criteria of diagnosis (non-converters, NCON) and were compared to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern Blot and PCR analysis. Magnetic Resonance Imaging (MRIs) acquisition was obtained on a 3T Siemens Trio scanner and metabolomic profile was obtained by ultra-performance liquid chromatography, accurate mass spectrometer, and an Orbitrap mass analyzer. Our findings indicate that differential metabolite levels are linked with the area of the pons between healthy control and premutation groups. More specifically, we observed a significant association of ceramides and mannonate metabolites with a decreased area of the pons, both at visit 1 (V1) and visit 2 (V2) only in the CON as compared to the NCON group suggesting their potential role in the development of the disorder. In addition, we found a significant correlation of these metabolic signatures with the FXTAS stage at V2 indicating their contribution to the progression and pathogenesis of FXTAS. Interestingly, these metabolites, as part of lipid and sphingolipid lipids pathways, provide evidence of the role that their dysregulation plays in the development of FXTAS and inform us as potential targets for personalized therapeutic development.

Using Clustering to Examine Inter-individual Variability in Topography of Auditory Event-Related Potentials in Autism and Typical Development.

Although prior studies have compared sensory event-related potential (ERP) responses between groups of autistic and typically-developing participants, it is unclear how heterogeneity contributes to the results of these studies. The present study used examined individual differences in these responses. 130 autistic children and 81 typically-developing children, aged between 2 and 5 years, listened to tones at four identity levels while 61-channel electroencephalography was recorded. Hierarchical clustering was used to group participants based on rescaled ERP topographies between 51 and 350 ms. The hierarchical clustering analysis revealed substantial heterogeneity. Some of the seven clusters defined in this analysis were characterized by prolonged fronto-central positivities and/or weak or absent N2 negativities. However, many other participants fell into clusters in which N2 responses were present at varying latencies. Atypical response morphologies such as absent N2 responses and/or prolonged positive-going responses found in some autistic participants may account for prior research findings of attenuated N2 amplitudes in autism. However, there was also considerable overlap between groups, with participants of both groups appearing in all clusters. These results emphasize the utility of using clustering to explore individual differences in brain responses, which can expand on and clarify the results of analyses of group mean differences.

Emergence of Developmental Delay in Infants and Toddlers With an FMR1 Mutation.

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 early childhood at around half the rate of their typically developing peers; girls with a full mutation showed growth at around three-quarters of the rate of their typically developing peers. Although children with a premutation were mostly typical in their developmental profiles and trajectories, mild but significant delays in fine motor skills by 18 months were detected. CONCLUSIONS: Children with the FMR1 gene full mutation demonstrate significant developmental challenges within the first 2 years of life, suggesting that earlier identification is needed to facilitate earlier implementation of interventions and therapeutics to maximize effectiveness.

Effects of age on loudness-dependent auditory ERPs in young autistic and typically-developing children.

Limited research has investigated the development of auditory ERPs in young children, and particularly how stimulus intensity may affect these auditory ERPs. Previous research has also yielded inconsistent findings regarding differences in the development of auditory ERPs in autism and typical development. Furthermore, stimulus intensity may be of particular interest in autism insofar as autistic people may have atypical experiences of sound intensity (e.g., hyperacusis). Therefore, the present study examined associations between age and ERPs evoked by tones of differing intensities (50, 60, 70, and 80 dB SPL) in a large sample of young children (2-5 years) with and without an autism diagnosis. Correlations between age and P1 latencies were examined, while cluster-based permutation testing was used to examine associations between age and neural response amplitudes, as well as group differences in amplitude, over all electrode sites in the longer time window of 1-350 ms. Older autistic participants had faster P1 latencies, but these effects only attained significance over the right hemisphere in response to soft 50 dB sounds. Autistic participants had slower P1 responses to 80 dB sounds over the right hemisphere. Over the scalp regions associated with the later N2 response, more negative response amplitudes (that is, larger N2 responses) were observed in typically-developing than autistic participants. Furthermore, continuous associations between response amplitudes and age suggested that older typically-developing participants exhibited stronger N2 responses to all intensities, though this effect may have at least in part reflected the absence of small positive voltage deflections in the N2 latency window. Age was associated with amplitudes of responses to 50 dB through 70 dB sounds in autism, but in contrast to Typical Development (TD), little evidence of relationships between age and amplitudes in the N2 latency window was found in autism in the 80 dB condition. Although caution should be exercised in interpretation due to the cross-sectional nature of this study, these findings suggest that developmental changes in auditory responses may differ across diagnostic groups in a manner that depends on perceived loudness and/or stimulus intensity.

The Autism Phenome Project: Toward Identifying Clinically Meaningful Subgroups of Autism.

One of the most universally accepted facts about autism is that it is heterogenous. Individuals diagnosed with autism spectrum disorder have a wide range of behavioral presentations and a variety of co-occurring medical and mental health conditions. The identification of more homogenous subgroups is likely to lead to a better understanding of etiologies as well as more targeted interventions and treatments. In 2006, we initiated the UC Davis MIND Institute Autism Phenome Project (APP) with the overarching goal of identifying clinically meaningful subtypes of autism. This ongoing longitudinal multidisciplinary study now includes over 400 children and involves comprehensive medical, behavioral, and neuroimaging assessments from early childhood through adolescence (2-19 years of age). We have employed several strategies to identify sub-populations within autistic individuals: subgrouping by neural, biological, behavioral or clinical characteristics as well as by developmental trajectories. In this Mini Review, we summarize findings to date from the APP cohort and describe progress made toward identifying meaningful subgroups of autism.