1. Abrahamson V, Zhang W, Wilson P, Farr W, Male I. {{Realist Evaluation of Autism ServiCe Delivery (RE-ASCeD): which diagnostic pathways work best, for whom and in what context? Protocol for a rapid realist review}}. {BMJ Open}. 2020; 10(7): e037846.
INTRODUCTION: The National Health Service (NHS) Long-Term Plan (2019) acknowledges that children and young people with suspected autism wait too long for diagnostic assessment and sets out to reduce waiting times. However, diagnostic pathways vary with limited evidence on what model works best, for whom and in what circumstances. The National Autism Plan for Children (2003) recommended that assessment should be completed within 13 weeks but referral to diagnosis can take as long as 799 days.This Rapid Realist Review (RRR) is the first work package in a national programme of research: a Realist Evaluation of Autism ServiCe Delivery (RE-ASCeD). We explore how particular approaches may deliver high-quality and timely autism diagnostic services for children with possible autism; high quality is defined as compliant with National Institute for Heath and Care Excellence (2011) guidelines, and timely as a pathway lasting no more than one calendar year, based on previous work. METHODS AND ANALYSIS: RRR is a well-established approach to synthesising evidence within a compressed timeframe to identify models of service delivery leading to desired outcomes. RRR works backwards from intended outcomes, identified by NICE guidelines and the NHS England Long-Term Plan. The focus is a clearly defined intervention (the diagnostic pathway), associated with specific outcomes (high quality and timely), within a particular set of parameters (Autism and Child & Adolescent Mental Health services in the UK). Our Expert Stakeholder Group consists of policymakers, content experts and knowledge users with a wide range of experience to supplement, tailor and expedite the process. The RRR is consistent with Realist And Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) and includes identifying the research question, searching for information, quality appraisal, data extraction, synthesising the evidence, validation of findings with experts and dissemination. ETHICS AND DISSEMINATION: Ethical approval not required. Findings will inform the wider RE-ASCeD evaluation and be reported to NHS England. TRIAL REGISTRATION NUMBER: NCT04422483. This protocol relates to Pre-results.
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2. Carbone PS, Campbell K, Wilkes J, Stoddard GJ, Huynh K, Young PC, Gabrielsen TP. {{Primary Care Autism Screening and Later Autism Diagnosis}}. {Pediatrics}. 2020.
OBJECTIVES: To describe the proportion of children screened by the Modified Checklist for Autism in Toddlers (M-CHAT), identify characteristics associated with screen completion, and examine associations between autism spectrum disorder (ASD) screening and later ASD diagnosis. METHODS: We examined data from children attending 18- and 24-month visits between 2013 and 2016 from 20 clinics within a health care system for evidence of screening with the M-CHAT and subsequent coding of ASD diagnosis at age >4.75 years. We interviewed providers for information about usual methods of M-CHAT scoring and ASD referral. RESULTS: Of 36 233 toddlers, 73% were screened and 1.4% were later diagnosed with ASD. Hispanic children were less likely to be screened (adjusted prevalence ratio [APR]: 0.95, 95% confidence interval [CI]: 0.92-0.98), and family physicians were less likely to screen (APR: 0.12, 95% CI: 0.09-0.15). Compared with unscreened children, screen-positive children were more likely to be diagnosed with ASD (APR: 10.3, 95% CI: 7.6-14.1) and were diagnosed younger (38.5 vs 48.5 months, P < .001). The M-CHAT's sensitivity for ASD diagnosis was 33.1%, and the positive predictive value was 17.8%. Providers routinely omitted the M-CHAT follow-up interview and had uneven referral patterns. CONCLUSIONS: A majority of children were screened for ASD, but disparities exist among those screened. Benefits for screen-positive children are improved detection and younger age of diagnosis. Performance of the M-CHAT can be improved in real-world health care settings by administering screens with fidelity and facilitating timely ASD evaluations for screen-positive children. Providers should continue to monitor for signs of ASD in screen-negative children. Lien vers le texte intégral (Open Access ou abonnement)
3. Delehanty A, Lee J, Hooker JL, Cortese J, Woods J. {{Exploring message framing to engage parents in early screening for autism spectrum disorder}}. {Patient education and counseling}. 2020.
OBJECTIVE: With the average age of diagnosis of autism hovering between 4 and 5 years of age, many children do not receive critical early intervention. Health information messages may be useful for increasing parents’ understanding of the importance of early autism screening. METHODS: Messages promoting autism screening were presented to 282 parents in a 2 (message frame: gain, loss) x 3 (evidence type: narrative, statistical, and hybrid), online, between-participants factorial design. Participants’ involvement, affective responses, perceived threat to behavioral freedom, attitudes, and intentions to discuss screening with a healthcare provider were analyzed. RESULTS: Loss-framed messages that included a hybrid of first-person narrative and statistical evidence were related to favorable ratings for most outcomes. Levels of perceived threat to behavioral freedom partially mediated involvement and attitudes, in a negative direction, for loss-framed narrative messages. CONCLUSION: Results of this preliminary study supported the inclusion of both evidence types in messages developed to encourage parents to engage in early screening for autism, and partially supported focusing these messages on the potential costs of not screening. PRACTICE IMPLICATIONS: Effective use of messaging with parents could help to increase knowledge and facilitate shared decision-making with health care providers to engage in early screening for autism.
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4. Du RY, Lam PPY, Yiu CKY, McGrath CP. {{Evaluation of visual pedagogy in improving plaque control and gingival inflammation among preschool children with Autism Spectrum Disorder: An interventional study}}. {Int J Paediatr Dent}. 2020.
BACKGROUND: Visual pedagogy (VP) is a behavioural intervention used to facilitate learning among autistic children. Limited studies have evaluated VP when applied to dentistry. AIM: Evaluate the effectiveness of VP in improving oral hygiene and gingival health status of autistic children. DESIGN: The interventional study was conducted among 122 autistic preschool children and their parents in Hong Kong. Toothbrushing visual pedagogy (TBVP) were provided to parents for supervising their children with toothbrushing at home. The children’s sociodemographic background, developmental profile, clinical parameters were obtained via parental questionnaire, standardised assessment form and clinical examination respectively. The change in plaque and gingival indices over time, and potential confounding factors were evaluated with Friedman’s Two-Way Analysis and logistic regressions respectively. RESULTS: Significantly lower level of plaque and gingival inflammation were found at 3 months and 6 months than baseline. The oral health status of children with poorer baseline oral hygiene status and gingival health were more likely to improve with TPVP. Other developmental and socioeconomic backgrounds had insignificant associations on the improvement of these clinical parameters. CONCLUSION: The findings suggest TBVP is effective in promoting oral hygiene maintenance and improving the periodontal conditions among individuals diagnosed with ASD.
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5. Geir B, Lyudmila P, Maryam D, Nagwa AM, Yuliya S, Mona A, Salvatore C. {{Gastrointestinal Alterations in Autism Spectrum Disorder: What Do We Know?}}. {Neurosci Biobehav Rev}. 2020.
There is an emerging body of evidence associating children having autism spectrum disorder (ASD) with gastrointestinal (GI) symptoms, such as abdominal pain, chronic diarrhea, constipation, vomiting, gastroesophageal reflux, intestinal infections, and increased intestinal permeability. Moreover, in many studies, large differences in the composition of intestinal microbiota and metabolic products between ASD patients and controls were reported. Deepening the role and the biology of the gut microbiome may be fundamental to elucidate the onset of GI symptoms in ASD individuals and their etiopathogenetic causes. The gut-brain axis may affect brain development and behaviors through the neuroendocrine, neuroimmune, and autonomic nervous systems.
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6. Gui A, Jones EJH, Wong CCY, Meaburn E, Xia B, Pasco G, Lloyd-Fox S, Charman T, Bolton P, Johnson MH. {{Leveraging epigenetics to examine differences in developmental trajectories of social attention: A proof-of-principle study of DNA methylation in infants with older siblings with autism}}. {Infant Behav Dev}. 2020; 60: 101409.
Preliminary evidence suggests that changes in DNA methylation, a widely studied epigenetic mechanism, contribute to the etiology of Autism Spectrum Disorder (ASD). However, data is primarily derived from post-mortem brain samples or peripheral tissue from adults. Deep-phenotyped longitudinal infant cohorts are essential to understand how epigenetic modifications relate to early developmental trajectories and emergence of ASD symptoms. We present a proof-of-principle study designed to evaluate the potential of prospective epigenetic studies of infant siblings of children with ASD. Illumina genome-wide 450 K DNA methylation data from buccal swabs was generated for 63 male infants at multiple time-points from 8 months to 2 years of age (total N = 107 samples). 11 of those infants received a diagnosis of ASD at 3 years. We conducted a series of analyses to characterize DNA methylation signatures associated with categorical outcome and neurocognitive measures from parent-report questionnaire, eye-tracking and electro-encephalography. Effects observed across the entire genome (epigenome-wide association analyses) suggest that collecting DNA methylation samples within infant-sibling designs allows for the detection of meaningful signals with smaller sample sizes than previously estimated. Mapping networks of co-methylated probes associated with neural correlates of social attention implicated enrichment of pathways involved in brain development. Longitudinal modelling found covariation between phenotypic traits and DNA methylation levels in the proximity of genes previously associated with cognitive development, although larger samples and more complete datasets are needed to obtain generalizable results. In conclusion, assessment of DNA methylation profiles at multiple time-points in infant-sibling designs is a promising avenue to comprehend developmental origins and mechanisms of ASD.
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7. Hampton LH, Kaiser AP, Fuller EA. {{Multi-component communication intervention for children with autism: A randomized controlled trial}}. {Autism}. 2020: 1362361320934558.
This study reports the results of a randomized trial for preverbal preschoolers with autism that demonstrates the effects of multiple intervention strategies including caregiver training. About 50% of children with autism are not talking by age 3 and up to 30% of children with autism will remain minimally verbal past age 5. Interventions delivered by clinicians and caregivers have the greatest effects on spoken language and may reduce the rate of those who remain minimally verbal. Sixty-eight children ages 3-5 with autism and their caregivers participated in this randomized trial comparing the communication intervention to a comparison group. A brief, multi-component, communication intervention (including a speech-generating device) for children with autism that addresses core deficits may be effective in improving joint attention skills immediately following intervention and social communication skills 4 months following intervention. Future research is needed to understand for whom and under what conditions this intervention is most effective.
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8. Johnson CM, Cui N, Xing H, Wu Y, Jiang C. {{The antitussive cloperastine improves breathing abnormalities in a Rett Syndrome mouse model by blocking presynaptic GIRK channels and enhancing GABA release}}. {Neuropharmacology}. 2020: 108214.
Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder caused mainly by mutations in the MECP2 gene. One of the major RTT features is breathing dysfunction characterized by periodic hypo- and hyperventilation. The breathing disorders are associated with increased brainstem neuronal excitability, which can be alleviated with antagonistic agents. Since neuronal hypoexcitability occurs in the forebrain of RTT models, it is necessary to find pharmacological agents with a relative preference to brainstem neurons. Here we show evidence for the improvement of breathing disorders of Mecp2-null mice with the brainstem-acting drug cloperastine (CPS) and its likely neuronal targets. CPS is an over-the-counter cough medicine that has an inhibitory effect on brainstem neuronal networks. In Mecp2-null mice, CPS (30 mg/kg, i.p.) decreased the occurrence of apneas/h and breath frequency variation. GIRK currents expressed in HEK cells were inhibited by CPS with IC(50) 1 μM. Whole-cell patch clamp recordings in locus coeruleus (LC) and dorsal tegmental nucleus (DTN) neurons revealed an overall inhibitory effect of CPS (10 μM) on neuronal firing activity. Such an effect was reversed by the GABA(A) receptor antagonist bicuculline (20 μM). Voltage clamp studies showed that CPS increased GABAergic sIPSCs in LC cells, which was blocked by the GABA(B) receptor antagonist phaclofen. Functional GABAergic connections of DTN neurons with LC cells were shown. These results suggest that CPS improves breathing dysfunction in Mecp2-null mice by blocking GIRK channels in synaptic terminals and enhancing GABA release.
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9. Lushin V, Marcus S, Gaston D, Beidas R, Lamson A, Goy I, Godina I, Rees J, Rivera R, Mandell D. {{The role of staffing and classroom characteristics on preschool teachers’ use of one-to-one intervention with children with autism}}. {Autism}. 2020: 1362361320932726.
For preschool children with autism, individual (one-to-one) behavioral interventions are among the best-tested treatments. However, they are rarely used in special education preschools. We observed formally and informally delivered one-to-one behavioral interventions use by classroom staff (n = 51) in 12 classrooms across three special education preschools for children with autism, aged 3-6 years, in a major US city. We estimated the associations between one-to-one intervention use and classroom characteristics including staff-student ratio, professional role composition, and frequency of challenging child behaviors. As a whole, the factors we examined were considerably important for both formally and informally delivered one-to-one interventions. The number of individually assigned personal care aides in the classroom was negatively associated with the use of formally delivered one-to-one intervention. Classroom challenging behavior was positively associated with use of formally delivered one-to-one interventions. Interventionist’s professional roles and the number of children in the class were most important for the use of informally delivered interventions. Staff training, clarifying professional roles, setting performance expectations for personal care aides and other classroom team members, and reducing class size may represent promising implementation targets. Findings suggest caution around task-shifting policies that transfer clinical functions from more highly trained to less highly trained staff.
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10. Marcantoni A, Calorio C, Hidisoglu E, Chiantia G, Carbone E. {{Cav1.2 channelopathies causing autism: new hallmarks on Timothy syndrome}}. {Pflugers Archiv : European journal of physiology}. 2020; 472(7): 775-89.
Cav1.2 L-type calcium channels play key roles in long-term synaptic plasticity, sensory transduction, muscle contraction, and hormone release. De novo mutations in the gene encoding Cav1.2 (CACNA1C) causes two forms of Timothy syndrome (TS1, TS2), characterized by a multisystem disorder inclusive of cardiac arrhythmias, long QT, autism, and adrenal gland dysfunction. In both TS1 and TS2, the missense mutation G406R is on the alternatively spliced exon 8 and 8A coding for the IS6-helix of Cav1.2 and is responsible for the penetrant form of autism in most TS individuals. The mutation causes specific gain-of-function changes to Cav1.2 channel gating: a « leftward shift » of voltage-dependent activation, reduced voltage-dependent inactivation, and a « leftward shift » of steady-state inactivation. How this occurs and how Cav1.2 gating changes alter neuronal firing and synaptic plasticity is still largely unexplained. Trying to better understanding the molecular basis of Cav1.2 gating dysfunctions leading to autism, here, we will present and discuss the properties of recently reported typical and atypical TS phenotypes and the effective gating changes exhibited by missense mutations associated with long QTs without extracardiac symptoms, unrelated to TS. We will also discuss new emerging views achieved from using iPSCs-derived neurons and the newly available autistic TS2-neo mouse model, both appearing promising for understanding neuronal mistuning in autistic TS patients. We will also analyze and describe recent proposals of molecular pathways that might explain mistuned Ca(2+)-mediated and Ca(2+)-independent excitation-transcription signals to the nucleus. Briefly, we will also discuss possible pharmacological approaches to treat autism associated with L-type channelopathies.
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11. McNally Keehn R, Ciccarelli M, Szczepaniak D, Tomlin A, Lock T, Swigonski N. {{A Statewide Tiered System for Screening and Diagnosis of Autism Spectrum Disorder}}. {Pediatrics}. 2020.
Although autism spectrum disorder (ASD) can be reliably detected in the second year of life, the average age of diagnosis is 4 to 5 years. Limitations in access to timely ASD diagnostic evaluations delay enrollment in interventions known to improve developmental outcomes. As such, developing and testing streamlined methods for ASD diagnosis is a public health and research priority. In this report, we describe the Early Autism Evaluation (EAE) Hub system, a statewide initiative for ASD screening and diagnosis in the primary care setting. Development of the EAE Hub system involved geographically targeted provision of developmental screening technical assistance to primary care, community outreach, and training primary care clinicians in ASD evaluation. At the EAE Hubs, a standard clinical pathway was implemented for evaluation of children, ages 18 to 48 months, at risk for ASD. From 2012 to 2018, 2076 children were evaluated (mean age: 30 months; median evaluation wait time: 62 days), and 33% of children received a diagnosis of ASD. Our findings suggest that developing a tiered system of developmental screening and early ASD evaluation is feasible in a geographic region facing health care access problems. Through targeted delivery of education, outreach, and intensive practice-based training, large numbers of young children at risk for ASD can be identified, referred, and evaluated in the local primary care setting. The EAE Hub model has potential for dissemination to other states facing similar neurodevelopmental health care system burdens. Implementation lessons learned and key system successes, challenges, and future directions are reviewed.
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12. Nunes AS, Vakorin VA, Kozhemiako N, Peatfield N, Ribary U, Doesburg SM. {{Atypical age-related changes in cortical thickness in autism spectrum disorder}}. {Sci Rep}. 2020; 10(1): 11067.
Recent longitudinal neuroimaging and neurophysiological studies have shown that tracking relative age-related changes in neural signals, rather than a static snapshot of a neural measure, could offer higher sensitivity for discriminating typically developing (TD) individuals from those with autism spectrum disorder (ASD). It is not clear, however, which aspects of age-related changes (trajectories) would be optimal for identifying atypical brain development in ASD. Using a large cross-sectional data set (Autism Brain Imaging Data Exchange [ABIDE] repository; releases I and II), we aimed to explore age-related changes in cortical thickness (CT) in TD and ASD populations (age range 6-30 years old). Cortical thickness was estimated from T1-weighted MRI images at three scales of spatial coarseness (three parcellations with different numbers of regions of interest). For each parcellation, three polynomial models of age-related changes in CT were tested. Specifically, to characterize alterations in CT trajectories, we compared the linear slope, curvature, and aberrancy of CT trajectories across experimental groups, which was estimated using linear, quadratic, and cubic polynomial models, respectively. Also, we explored associations between age-related changes with ASD symptomatology quantified as the Autism Diagnostic Observation Schedule (ADOS) scores. While no overall group differences in cortical thickness were observed across the entire age range, ASD and TD populations were different in terms of age-related changes, which were located primarily in frontal and tempo-parietal areas. These atypical age-related changes were also associated with ADOS scores in the ASD group and used to predict ASD from TD development. These results indicate that the curvature is the most reliable feature for localizing brain areas developmentally atypical in ASD with a more pronounced effect with symptomatology and is the most sensitive in predicting ASD development.
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13. Pinto OY, Raz R. {{Employment Outcomes After a Birth of a Child with a Developmental Disability: A National Nested Case-Control Study}}. {J Autism Dev Disord}. 2020.
Using records from the National Insurance Institute of Israel, we recognized all children with autism spectrum disorders (ASD, N = 8072) or hearing loss (HL, N = 2231) born in Israel between 2005 and 2010. Typical developed children were taken from a random 20% sample of children born during the same years (N = 227,492). Analyses were adjusted for year of birth, population group, parental ages, parental education, child birth order and peripherality. Working women, who gave birth to children with either ASD or HL, were at increased risk of not maintaining their working status over the 5 years after birth. There is a decreased ratio between household wage after and before birth, in families with children with either ASD or HL.
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14. Rivard M, Mello C, Mercier C, Lefebvre C, Millau M, Morin M, Morin D, Abouzeid N, Chatenoud C. {{Development of a questionnaire to assess the quality of service trajectories in autism spectrum disorder from families’ perspective}}. {J Appl Res Intellect Disabil}. 2020.
BACKGROUND: ETAP-1 was created to evaluate the quality of services trajectory from families’ perspective. The items of ETAP-1 were developed from previous studies on integrated care, existing quality assessments, and consultations with families and experts in evaluation and in autism spectrum disorder (ASD). METHOD: The questionnaire was completed by 200 parents of children aged 5 and under who were recently diagnosed with ASD or intellectual disability. Of these, 183 received diagnostic evaluation through a clinic specialized in ASD; the other 17 underwent diagnostic evaluation in hospital settings. RESULTS: Factor analysis supported the a priori dimensions of quality and distinctions between experiences before and during diagnostic evaluation. The instrument had high internal consistency, convergent and discriminant validity with other measures and was sensitive to differences in service delivery models. DISCUSSION: ETAP-1 is useful in organizing information on families’ experiences throughout their services trajectories and according to a dynamic perspective.
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15. Safa A, Noroozi R, Taheri M, Ghafouri-Fard S. {{Association Analysis of ANRIL Polymorphisms and Haplotypes with Autism Spectrum Disorders}}. {Journal of molecular neuroscience : MN}. 2020.
Autism spectrum disorder (ASD) has been shown to have a complex inheritance. Several single-nucleotide polymorphisms (SNPs) have been shown to be associated with risk of this neurodevelopmental disorder. In the current study, we genotyped four SNPs in a genomic hotspot for human disorders. The selected SNPs were located in adjacency of the antisense noncoding RNA in the INK4 locus (ANRIL) and have been shown to be associated with a number of human disorders. Genotyping was performed in 420 ASD cases and 420 normally developed children. After correction of P values for multiple comparisons, there was no significant difference in frequencies of rs1333045, rs1333048, rs4977574, and rs10757278 alleles, genotypes, or haplotypes between ASD children and children with normal development. However, one estimated haplotype (T A A A haplotype corresponding to rs1333045, rs1333048, rs4977574, and rs10757278 SNPs, respectively) tended to be more prevalent among cases compared with controls (OR (95% CI) = 1.77 (1.19-2.64), adjusted P value = 0.07). Besides, the T A G G tended to be less common among ASD cases compared with controls (OR (95% CI) = 0.64 (0.47-0.87), adjusted P value = 0.07). Although we could not detect significant difference in alleles, genotypes, or haplotypes frequencies between cases and controls, the trend toward association between two haplotypes and ASD risk implies that there might be a putative causative variant in the mentioned haplotypes whose association with ASD could be determined in larger cohorts of patients.
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16. Wallis KE, Guthrie W. {{Identifying Autism Spectrum Disorder in Real-World Health Care Settings}}. {Pediatrics}. 2020.
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17. Zafarullah M, Tang HT, Durbin-Johnson B, Fourie E, Hessl D, Rivera SM, Tassone F. {{FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS)}}. {Sci Rep}. 2020; 10(1): 11099.
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 of 55-200 CGG repeats in the Fragile X mental retardation (FMR1) gene. It is currently unknown if and when an individual carrier of a premutation allele will develop FXTAS, as clinical assessment fails to identify carriers at risk before significant neurological symptoms are evident. The primary objective of this study was to investigate the alternative splicing landscape at the FMR1 locus in conjunction with brain measures in male individuals with a premutation allele enrolled in a very first longitudinal study, compared to age-matched healthy male controls, with the purpose of identifying biomarkers for early diagnosis, disease prediction and, a progression of FXTAS. Our findings indicate that increased expression of FMR1 mRNA isoforms, including Iso4/4b, Iso10/10b, as well as of the ASFMR1 mRNAs Iso131bp, are present in premutation carriers as compared to non-carrier healthy controls. More specifically, we observed a higher expression of Iso4/4b and Iso10/10b, which encode for truncated proteins, only in those premutation carriers who developed symptoms of FXTAS over time as compared to non-carrier healthy controls, suggesting a potential role in the development of the disorder. In addition, we found a significant association of these molecular changes with various measurements of brain morphology, including the middle cerebellar peduncle (MCP), superior cerebellar peduncle (SCP), pons, and midbrain, indicating their potential contribution to the pathogenesis of FXTAS. Interestingly, the high expression levels of Iso4/4b observed both at visit 1 and visit 2 and found to be associated with a decrease in mean MCP width only in those individuals who developed FXTAS over time, suggests their role as potential biomarkers for early diagnosis of FXTAS.
