1. Ayvazo S, Shmuel Y, Bin-Nun I. Supporting the Conversational Behavior of Adolescents with Autism Spectrum Disorders with Self-Monitoring and a Video-Based Supplement. J Autism Dev Disord;2024 (Sep 13)

Individuals with autism spectrum disorders (ASD) might demonstrate impairments in initiating and sustaining a conversation and experience conversational challenges such as question-asking and turn-taking. Conversational skills are pivotal for the social functioning of adolescents with ASD. The current investigation aimed to extend the available information on interventions addressing the conversational needs of adolescents with ASD. The research questions were: (a) What is the effect of self-monitoring, supplemented by a video-based model on the conversational skills of adolescent students with ASD? and (b) What is the acceptability of the intervention among the participating adolescents with ASD?. Appropriate conversational behavior of three students with ASD (aged 16-18 years) was assessed using a withdrawal design, during 10-min conversation sessions. Appropriate conversational behavior was defined as a sequence of a turn-taking response (i.e., waiting quietly until the speaker finished talking), followed by a verbal utterance which included (a) making a statement or responding on topic, and/or (b) asking a contextually appropriate « wh »- question. The independent variable consisted of a primary self-monitoring procedure and a daily video-based supplement. Treatment fidelity and treatment acceptability were also assessed. The conversational behavior of all participants consistently improved under the self-monitoring intervention with the video-based supplement. Self-monitoring with a video-based supplement can effectively support the conversational behavior in adolescents with ASD. This information can guide the evaluation and planning of appropriate interventions designed to improve limited conversational behaviors of adolescents with ASD.

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2. Elgenidy A, Gad EF, Shabaan I, Abdelrhem H, Wassef PG, Elmozugi T, Abdelfattah M, Mousa H, Nasr M, Salah-Eldin M, Altaweel A, Hussein A, Bazzazeh M, Elganainy MA, Ali AM, Ezzat M, Elhoufey A, Alatram AA, Hammour A, Saad K. Correction: Examining the association between autism spectrum disorder and atopic eczema: meta-analysis of current evidence. Pediatr Res;2024 (Sep 13)

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3. Finezilber Y, Massey C, Radley JA, Murphy E. Arginine:glycine amidinotransferase (AGAT) deficiency: an easy-to-miss treatable adult-onset myopathy. Pract Neurol;2024 (Sep 13);24(5):413-416.

Arginine:glycine amidinotransferase (AGAT) deficiency is an ultrarare disorder of creatine metabolism, presenting with developmental delay, characteristic biochemical findings and muscle weakness. Most known cases have been identified and treated in early childhood. We describe a 27-year-old woman with learning difficulties and significant myopathy who was diagnosed through genetic investigation in adulthood. Treatment with creatine (10-15 g/day) led to a significant and rapid improvement of muscle strength. A literature review of the few reported adult cases confirms that progressive myopathy is a prominent feature that responds well to creatine supplementation. AGAT deficiency, a partially treatable condition, should be considered in the differential diagnosis of a genetic myopathy, particularly in people with developmental delay and progressive myopathy.

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4. Garcia-Campos C, Pareés I, Kurtis MM. Dystonic Tremor as the Clinical Manifestation of Fragile X-Associated Tremor/Ataxia Syndrome. Mov Disord Clin Pract;2024 (Sep 13)

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5. Geng K, Wang Y, Fu W, Chen S, Yang Y. Episodic memory impairment and its influencing factors in individuals with autism spectrum disorder: systematic review and meta-analysis. Eur Arch Psychiatry Clin Neurosci;2024 (Sep 13)

Individuals with autism spectrum disorders (ASD) are considered to experience difficulties with episodic memory (EM), while studies on EM in ASD have shown inconsistent results. A meta-analysis of 65 episodic memory studies with a combined sample size of 1652 individuals with ASD and 1626 typically developing individuals was conducted to analyze factors that may affect EM in ASD. The results showed that ASD had a significant medium to large effect size decrease in EM ability. Age period, task type, and reporting method significantly reduced the observed heterogeneity while EM type did not reduce the observed heterogeneity. The results of the meta-regression revealed that it was verbal IQ rather than full-scale IQ that was significantly correlated with EM in individuals with ASD. These findings suggest that individuals with ASD have reduced EM abilities and the potential factors is still needed to be explored.

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6. Gv S, Paul PM, Gudimindla H, Rachapudi V. Fractional whale driving training-based optimization enabled transfer learning for detecting autism spectrum disorder. Comput Biol Chem;2024 (Aug 30);113:108200.

Autism Spectrum Disorder (ASD) is a neurological illness that degrades communication and interaction among others. Autism can be detected at any stage. Early detection of ASD is important in preventing the communication, interaction and behavioral outcomes of individuals. Hence, this research introduced the Fractional Whale-driving Driving Training-based Based Optimization with Convolutional Neural Network-based Transfer learning (FWDTBO-CNN_TL) for identifying ASD. Here, the FWDTBO is modelled by the incorporation of Fractional calculus (FC), Whale optimization algorithm (WOA) and Driving Training-based Optimization (DTBO) that trains the hyperparameters of CNN-TL. Moreover, the Convolutional Neural Networks (CNN) utilize the hyperparameters from trained models, like Alex Net and Shuffle Net in such a way that the CNN-TL is designed. To improve the detection efficiency, the nub region was extracted and carried out with the functional connectivity-based Whale Driving Training Optimization (WDTBO) algorithm. Moreover, the TL is tuned by the FWDTBO algorithm. The result reveals that the ASD detection technique, FWDTBO-CNN-TL acquired 90.7 % accuracy, 95.4 % sensitivity, 93.7 % specificity and 93 % f-measure with the ABIDE-II dataset.

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7. Hsu CC, Lee NC, Chien YH, Liu CF, Chang YL. Perinatal lethal form Gaucher disease with compound heterozygosity of single nucleotide variants and copy number variations presenting as nonimmune hydrops fetalis and cerebellar hypoplasia: A case report. Taiwan J Obstet Gynecol;2024 (Sep);63(5):771-776.

OBJECTIVE: To present the ultrasound imaging and genetic diagnosis of a fetus with prenatal lethal form of Gaucher disease. CASE REPORT: A 37-year-old primiparous woman was pregnant at her 23 weeks of gestation and the prenatal fetal ultrasound revealed hydrops fetalis, cerebellum hypoplasia, and fetal immobility. The pregnancy was terminated due to major fetal anomaly, and whole exome sequencing (WES) analysis of fetal tissue and parental blood unveiled a pathogenic variant in exon 10 of the GBA gene (NM_001005741.3: c.1265T > G: p.L422R) originating from the mother. Additionally, a novel CNV (chr1: 155204785-155205635 deletion, 0.85 kb) spanning exon 10-12 in the GBA gene was identified from the father. This compound heterozygosity confirmed the diagnosis of prenatal lethal form of Gaucher disease and was informative for genetic counseling. CONCLUSION: WES is a powerful tool to detect pathogenic variants among fetuses with nonimmune hydrops fetalis and complex abnormality from prenatal ultrasound. Compound heterozygosity consisted of single nucleotide variants (SNV) and copy number variations (CNVs) may lead rare inherited metabolic disorders including prenatal lethal form of Gaucher disease.

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8. Karaosmanoglu B, Imren G, Ozisin MS, Reçber T, Simsek Kiper PO, Haliloglu G, Alikaşifoğlu M, Nemutlu E, Taskiran EZ, Utine GE. Ex vivo disease modelling of Rett syndrome: the transcriptomic and metabolomic implications of direct neuronal conversion. Mol Biol Rep;2024 (Sep 13);51(1):979.

BACKGROUND: Rett syndrome (RTT) is a rare neurodevelopmental disorder that primarily affects females and is characterized by a period of normal development followed by severe cognitive, motor, and communication impairment. The syndrome is predominantly caused by mutations in the MECP2. This study aimed to use comprehensive multi-omic analysis to identify the molecular and metabolic alterations associated with Rett syndrome. METHODS AND RESULTS: Transcriptomic and metabolomic profiling was performed using neuron-like cells derived from the fibroblasts of 3 Rett syndrome patients with different MECP2 mutations (R168X, P152R, and R133C) and 1 healthy control. Differential gene expression, alternative splicing events, and metabolite changes were analyzed to identify the key pathways and processes affected in patients with Rett syndrome. Transcriptomic analysis showed there was significant down-regulation of genes associated with the extracellular matrix (ECM) and cytoskeletal components, which was particularly notable in patient P3 (R133C mutation), who had non-random X chromosome inactivation. Additionally, significant changes in microtubule-related gene expression and alternative splicing events were observed, especially in patient P2 (P152R mutation). Metabolomic profiling showed that there were alterations in metabolic pathways, particularly up-regulation of ketone body synthesis and degradation pathways, in addition to an increase in free fatty acid levels. Integrated analysis highlighted the interplay between structural gene down-regulation and metabolic shifts, underscoring the adaptive responses to cellular stress in Rett neurons. CONCLUSION: The present findings provide valuable insights into the molecular and metabolic landscape of Rett syndrome, emphasizing the importance of combining omic data to enlighten the molecular pathophysiology of this syndrome.

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9. Kaye AD, Green AM, Claude JT, 2nd, Daniel CP, Cooley JF, Sala KR, Potharaju P, Rieger R, Patil S, Ahmadzadeh S, Shekoohi S. Efficacy and Safety of Alpha-2 Agonists in Autism Spectrum Disorder: A Systematic Review. Adv Ther;2024 (Sep 13)

BACKGROUND: This analysis is a systematic literature review assessing efficacy and adverse effects of three alpha-2 agonists for the symptomatic management of autism spectrum disorder (ASD). METHODS: The present investigation involved an extensive systematic search for eligible studies in PubMed, Embase, Cochrane Library, and Google Scholar. Nine studies, collectively incorporating 226 patients, were assessed. RESULTS: The results demonstrated promising indications for use of alpha-2 agonists in the symptomatic management of autism spectrum disorders, including improvement of hyperactivity, impulsivity, attention deficit symptoms, irritability, and stereotypies in many of the participants studied. CONCLUSION: The present investigation encourages physicians to consider treatment outcomes of clonidine, guanfacine, and lofexidine to determine the most effective management of ASD-related symptoms and to minimize adverse effects. However, our review cannot provide definitive treatment protocols related to various study limitations.

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10. Oestreicher S, Bowler DM, Derwent CT, Gaigg SB, Roessner V, Vetter N, Volk T, Beyer N, Ring M. Structural Learning in Autistic and Non-Autistic Children: A Replication and Extension. J Autism Dev Disord;2024 (Sep 13)

The hippocampus is involved in many cognitive domains which are difficult for autistic individuals. Our previous study using a Structural Learning task that has been shown to depend on hippocampal functioning found that structural learning is diminished in autistic adults (Ring et al., 2017). The aim of the present study was to examine whether those results can be replicated in and extended to a sample of autistic and non-autistic children. We tested 43 autistic children and 38 non-autistic children with a subsample of 25 autistic and 28 non-autistic children who were well-matched on IQ. The children took part in a Simple Discrimination task which a simpler form of compound learning, and a Structural Learning task. We expected both groups to perform similarly in Simple Discrimination but reduced performance by the autism group on the Structural Learning task, which is what we found in both the well-matched and the non-matched sample. However, contrary to our prediction and the findings from autistic adults in our previous study, autistic children demonstrated a capacity for Structural Learning and showed an overall better performance in the tasks than was seen in earlier studies. We discuss developmental differences in autism as well as the role of executive functions that may have contributed to better than predicted task performance in this study.

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11. Percy AK, Neul JL, Benke TA, Berry-Kravis EM, Glaze DG, Marsh ED, An D, Bishop KM, Youakim JM. Trofinetide for the treatment of Rett syndrome: Results from the open-label extension LILAC study. Med;2024 (Sep 13);5(9):1178-1189.e1173.

BACKGROUND: Trofinetide was approved for the treatment of Rett syndrome based on the results of the phase 3, randomized, placebo-controlled, 12-week LAVENDER study. Rett syndrome is a chronic disorder requiring long-term treatment. We report the efficacy and safety results of LILAC, a 40-week, open-label extension study of LAVENDER. METHODS: Females with Rett syndrome aged 5-21 years received open-label treatment with trofinetide for 40 weeks. The primary endpoint was long-term safety of trofinetide; secondary endpoints included the change from baseline at week 40 in the Rett Syndrome Behaviour Questionnaire score and the Clinical Global Impression-Improvement score at week 40. FINDINGS: Overall, 154 participants were enrolled and treated with trofinetide in LILAC. The most common adverse events in LILAC were diarrhea (74.7%), vomiting (28.6%), and COVID-19 (11.0%). Diarrhea was the most common adverse event leading to treatment withdrawal (21.4%). The Rett Syndrome Behaviour Questionnaire mean score (standard error) improvement from the LAVENDER baseline to week 40 in LILAC was -7.3 (1.62) and -7.0 (1.61) for participants treated with trofinetide and placebo in LAVENDER, respectively. Mean Clinical Global Impression-Improvement scores (standard error) at week 40 rated from the LILAC baseline were 3.1 (0.11) and 3.2 (0.14) for participants treated with trofinetide and placebo in LAVENDER, respectively. CONCLUSIONS: Treatment with trofinetide for ≤40 weeks continued to improve symptoms of Rett syndrome. Trofinetide had a similar safety profile in LILAC as in LAVENDER. FUNDING: The study was supported by Acadia Pharmaceuticals Inc. (San Diego, CA, USA). This trial was registered at ClinicalTrials.gov (NCT04279314).

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12. Qu L, Colombi C, Chen W, Miller A, Miller H, Ulrich DA. The Efficacy of a Culturally-Adapted Group-based Parent Coaching Program for Autistic Children in China via Telehealth: A Randomized Controlled Trial. J Autism Dev Disord;2024 (Sep 13)

The study aimed to examine the efficacy of a culturally-adapted, group-based parent coaching program for autistic children in China delivered via telehealth. A randomized controlled trial was conducted, with 18 parents allocated to the self-directed group that received the intervention through an online learning platform, and 19 parents allocated to the web + group therapy group, which included the same program along with weekly 1.5-hour group coaching sessions via videoconferencing. The primary outcomes were parents’ mental health and children’s adaptive functioning, while the secondary outcomes focused on the child behaviors, parenting stress and parenting style, and family quality of life. Linear Mixed Models were used to evaluate treatment effects across time and to model longitudinal trajectories of outcomes in both children and parents. Both intervention groups showed significant improvements in children’s communication skills (F (1, 60.27) = 29.86, p < 0.001) and social engagement (F (1, 60.07) = 11.73, p = 0.001), as well as reductions in parenting stress (F (1, 59.07) = 8.76, p = 0.004) and anxiety levels (F (1, 57.62) = 4.84, p = 0.032). Additionally, the group-based parent coaching via videoconferencing was associated with greater improvements in children's quality of life (F (1, 59.95) = 5.90, p = 0.018) and parents' anxiety outcomes (F (1, 57.62) = 4.84, p = 0.032). This study demonstrated the efficacy of a culturally adapted telehealth intervention for both autistic children and their parents. The preliminary findings suggest positive outcomes in children's adaptive functioning and parents' mental well-being. Group-based parent coaching through videoconferencing could be a promising and practical model for in-home services, particularly for families with limited access to in-person services.

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13. Selim B, Satti A, Abdelgadir IS. COVID-19 autism spectrum disorder-like transient neurocognitive clinical presentation. BMJ Case Rep;2024 (Sep 12);17(9)

The COVID-19 pandemic has impacted the general population in different ways, including the vulnerable population of children with special needs.In this case report, we will discuss the emergence of a transient, full-blown picture of autism spectrum disorder (ASD) in a child who contracted a COVID-19 infection, and his gradual improvement over the course of a few months. This broadens our perspective on the possible neurocognitive clinical presentations of COVID-19 infection.

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14. Torralbas-Ortega J, Valls-Ibáñez V, Roca J, Campoy-Guerrero C, Sastre-Rus M, García-Expósito J. Sexual Affectivity in Autism Spectrum Disorder: Bibliometric Profile of Scientific Production. Arch Sex Behav;2024 (Sep 13)

The aim of the present study was to describe the scientific production on sexuality and affectivity of autistic people. The inclusion criteria were articles published in all languages from the year 2000 to 2023, excluding reviews, proceedings, and other works not considered original. The search was performed in the Web of Science Core Collection and RStudio was utilized to analyze the records, with the « Bibliometrix 4.1.0 » package and the VOSviewer software. A total of 314 articles were included, from the USA, Australia, and parts of Europe. The production peak was found in the year 2020, the most cited articles referred to the children’s population, and the most important journals were specialized on the subject. As for the thematic content, 29 keywords emerged that were grouped into three clusters. In the first group, children associated with vulnerability and victimization were underlined, in which multifocal interventions were needed to prevent risk; in the second, we found adolescents and the need for sex education that is adapted and comprehensive; and lastly, adults who must be able to perform an adequate transition that eases the adaptation of neurodivergent individuals.

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15. Tromans SJ, Teece L, Saunders C, McManus S, Brugha T. Characteristics and primary care experiences of people who self-report as autistic: a probability sample survey of adults registered with primary care services in England. BMJ Open;2024 (Sep 13);14(9):e081388.

OBJECTIVES: Little is known about adults who self-report as autistic. This study aimed to profile the demographic characteristics, long-term health conditions and primary care experiences of adults who self-report as autistic (including those with and without a formal diagnosis). DESIGN/SETTING: A nationally representative cross-sectional survey of adults registered with National Health Service (NHS) General Practitioner (GP) surgeries in England. PARTICIPANTS: 623 157 survey respondents aged 16 and over, including 4481 who self-report as autistic. OUTCOMES: Weighted descriptive statistics, with 95% CIs. Logistic regression modelling adjusted for age, gender, ethnicity and area-level deprivation compared those who self-report as autistic with the rest of the population. RESULTS: A total of 4481 of the 623 157 survey participants included in the analysis self-reported autism, yielding a weighted proportion estimate of 1.41% (95% CI 1.35% to 1.46%). Adults self-reporting as autistic were more likely to be younger, male or non-binary, to identify as a gender different from their sex at birth, have a non-heterosexual sexual identity, be of white or mixed or multiple ethnic groups, non-religious, without caring responsibilities, unemployed, live in more deprived areas and not smoke. All chronic conditions covered were more prevalent among adults self-reporting as autistic, including learning disability, mental health conditions, neurological conditions, dementia, blindness or partial sight and deafness or hearing loss. Adults self-reporting as autistic were also less likely to report a positive experience of making an appointment (adjusted OR (aOR) 0.90, 95% CI 0.82 to 0.98) and navigating GP practice websites (aOR 0.78, 95% CI 0.70 to 0.87) and more likely to report seeking advice from a friend or family member prior to making an appointment (aOR 1.25, 95% CI 1.14 to 1.38) and having a preferred GP (aOR 2.25, 95% CI 2.06 to 2.46). They were less likely to report that their needs were met (aOR 0.73, 95% CI 0.65 to 0.83). CONCLUSIONS: Adults self-reporting as autistic have a distinctive sociodemographic profile and heightened rates of long-term conditions. They report challenges in both accessing primary care and having their needs met when they do. These findings should inform future care initiatives designed to meet the needs of this group.

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16. Wiggins LD, Overwyk K, Powell P, Daniels J, DiGuiseppi C, Nadler C, Reyes N, Barger B, Moody E, Pazol K. Changes in Autism and Co-Occurring Conditions from Preschool to Adolescence: Considerations for Precision Monitoring and Treatment Planning. J Autism Dev Disord;2024 (Sep 13)

PURPOSE: To describe retention of an autism spectrum disorder (ASD) diagnosis from preschool to adolescence and the most common co-occurring diagnoses among children with ASD in preschool and adolescence. A second objective was to identify co-occurring diagnoses more likely to emerge between preschool and adolescence among children with ASD vs. another developmental or mental health diagnosis in preschool. METHODS: Children completed a case-control study when they were between 2 and 5 years of age. Caregivers reported their child’s diagnoses of ASD and attention deficit hyperactivity disorder (ADHD), any developmental delay (DD), epilepsy/seizure disorder, obsessive-compulsive disorder, sensory integration disorder, and speech/language disorder when the child was preschool age and, separately, during adolescence. Any anxiety and depression/mood disorder, intellectual disability (ID), and learning disability (LD) were considered only in adolescence. RESULTS: 85.5% of preschool children retained their ASD diagnosis in adolescence. DD, sensory integration disorder, and speech-language disorder co-occurred in over 20% of preschool age children with ASD. These same conditions, along with anxiety disorders, ADHD, ID, and LD, co-occurred in over 20% of adolescents with ASD. Significantly more children with ASD vs. another developmental or mental health diagnosis in preschool gained diagnoses of ADHD, DD, sensory integration disorder, and speech-language disorder by adolescence. CONCLUSION: ASD is a highly stable diagnosis and co-occurring conditions are common. The prevalence of co-occurring diagnoses may depend on age, with some persisting from preschool to adolescence and others emerging over time. Health and education providers can use these findings to inform precision monitoring and treatment planning.

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17. Yao M, Daniels J, Grosvenor L, Morrill V, Feinberg JI, Bakulski KM, Piven J, Hazlett HC, Shen MD, Newschaffer C, Lyall K, Schmidt RJ, Hertz-Picciotto I, Croen LA, Fallin MD, Ladd-Acosta C, Volk H, Benke K. Commonly used genomic arrays may lose information due to imperfect coverage of discovered variants for autism spectrum disorder. J Neurodev Disord;2024 (Sep 12);16(1):54.

BACKGROUND: Common genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS. METHODS: We studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants. RESULTS: Prior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric. LIMITATIONS: The studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries. CONCLUSIONS: We show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits.

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18. Yu R, Hafeez R, Ibrahim M, Alonazi WB, Li B. The complex interplay between autism spectrum disorder and gut microbiota in children: A comprehensive review. Behav Brain Res;2024 (Sep 13);473:115177.

Autism spectrum disorder (ASD) is characterized by defects in social communication and interaction along with restricted interests and/or repetitive behavior. Children with ASD often also experience gastrointestinal (GI) problems in fact incidence of GI problems in ASD is estimated up to 80 percent. Intestinal microbiota, which is a collection of trillions of microorganisms both beneficial and potentially harmful bacteria living inside the gut, has been considered one of the key elements of gut disorders. The goal of this review is to explore potential link between gut microbiota and ASD in children, based on the recently available data. This review discusses recent advances in this rapidly expanding area of neurodevelopmental disorders, which focuses on what is known about the changes in composition of gut bacteria in children with ASD, exploration of possible mechanisms via which gut microbiota might influence the brain and thus lead to appearance of ASD symptoms, as well as potential treatments that involve modulation of gut flora to improve symptoms in children with ASD, i.e., probiotics, postbiotics or changes in the diet. Of course, it’s important to keep in mind inherent difficulties in proving of existence of causal relationships between gut bacteria and ASD. There are significant gaps in understanding of the mechanism of gut-brain axis and the mechanisms that underlie ASD. Standardized approaches for research in this area are needed. This review would provide an overview of this exciting emerging field of research.

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19. Zheng N, Luo S, Zhang X, Hu L, Huang M, Li M, McCaig C, Ding YQ, Lang B. Haploinsufficiency of intraflagellar transport protein 172 causes autism-like behavioral phenotypes in mice through BDNF. J Adv Res;2024 (Sep 10)

INTRODUCTION: Primary cilia are hair-like solitary organelles growing on most mammalian cells that play fundamental roles in embryonic patterning and organogenesis. Defective cilia often cause a suite of inherited diseases called ciliopathies with multifaceted manifestations. Intraflagellar transport (IFT), a bidirectional protein trafficking along the cilium, actively facilitates the formation and absorption of primary cilia. IFT172 is the largest component of the IFT-B complex, and its roles in Bardet-Biedl Syndrome (BBS) have been appreciated with unclear mechanisms. OBJECTIVES: We performed a battery of behavioral tests with Ift172 haploinsufficiency (Ift172(+/-)) and WT littermates. We use RNA sequencing to identify the genes and signaling pathways that are differentially expressed and enriched in the hippocampus of Ift172(+/-) mice. Using AAV-mediated sparse labeling, electron microscopic examination, patch clamp and local field potential recording, western blot, luciferase reporter assay, chromatin immunoprecipitation, and neuropharmacological approach, we investigated the underlying mechanisms for the aberrant phenotypes presented by Ift172(+/-) mice. RESULTS: Ift172(+/-) mice displayed excessive self-grooming, elevated anxiety, and impaired cognition. RNA sequencing revealed enrichment of differentially expressed genes in pathways relevant to axonogenesis and synaptic plasticity, which were further confirmed by less spine density and synaptic number. Ift172(+/-) mice demonstrated fewer parvalbumin-expressing neurons, decreased inhibitory synaptic transmission, augmented theta oscillation, and sharp-wave ripples in the CA1 region. Moreover, Ift172 haploinsufficiency caused less BDNF production and less activated BDNF-TrkB signaling pathway through transcription factor Gli3. Application of 7,8-Dihydroxyflavone, a potent small molecular TrkB agonist, fully restored BDNF-TrkB signaling activity and abnormal behavioral phenotypes presented by Ift172(+/-) mice. With luciferase and chip assays, we provided further evidence that Gli3 may physically interact with BDNF promoter I and regulate BDNF expression. CONCLUSIONS: Our data suggest that Ift172 per se drives neurotrophic effects and, when defective, could cause neurodevelopmental disorders reminiscent of autism-like disorders.

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