1. Fukumura S, Hiraide T, Yamamoto A, Tsuchida K, Aoto K, Nakashima M, Saitsu H. A novel de novo TMEM63A variant in a patient with severe hypomyelination and global developmental delay. Brain & development. 2022; 44(2): 178-83.

BACKGROUND: Heterozygous variants in TMEM63A have been recently identified as the cause of infantile-onset transient hypomyelination. To date, four TMEM63A variants have been reported in five patients. These patients exhibited favorable clinical course, developmental progress, and completion of myelination. CASE REPORT: The patient was a 5-year-old girl with severe global developmental delay, absent speech, no turning over, no gazing, hypotonia, and daily episodes of autonomic seizures. Brain MRI showed hypomyelination of deep and subcortical white matter that appeared hyperintense in T2-weighted imaging from 2 months of age and that showed no change at 4 years of age. Exome sequencing of the patient and her parents revealed a novel de novo missense variant, NM_014698.3:c.1658G>T, p.(Gly553Val), in the TMEM63A gene, which was confirmed by Sanger sequencing. The variant has not been registered in public databases, and it substitutes a highly conserved glycine residue located in a pore-lining transmembrane helix. No other candidate variants were identified. CONCLUSIONS: Although TMEM63A variants are generally thought to cause transient hypomyelination with favorable developmental progress, identification of a de novo TMEM63A variant in our patient suggests that the TMEM63A-related clinical spectrum is broad and includes severe developmental delay with seizures.

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2. Gangfuß A, Czech A, Hentschel A, Münchberg U, Horvath R, Töpf A, O’Heir E, Lochmüller H, Stehling F, Kiewert C, Sickmann A, Kuechler A, Kaiser FJ, Kölbel H, Christiansen J, Schara-Schmidt U, Roos A. Homozygous WASHC4 variant in two sisters causes a syndromic phenotype defined by dysmorphisms, intellectual disability, profound developmental disorder, and skeletal muscle involvement. The Journal of pathology. 2022; 256(1): 93-107.

Recessive variants in WASHC4 are linked to intellectual disability complicated by poor language skills, short stature, and dysmorphic features. The protein encoded by WASHC4 is part of the Wiskott-Aldrich syndrome protein and SCAR homolog family, co-localizes with actin in cells, and promotes Arp2/3-dependent actin polymerization in vitro. Functional studies in a zebrafish model suggested that WASHC4 knockdown may also affect skeletal muscles by perturbing protein clearance. However, skeletal muscle involvement has not been reported so far in patients, and precise biochemical studies allowing a deeper understanding of the molecular etiology of the disease are still lacking. Here, we report two siblings with a homozygous WASHC4 variant expanding the clinical spectrum of the disease and provide a phenotypical comparison with cases reported in the literature. Proteomic profiling of fibroblasts of the WASHC4-deficient patient revealed dysregulation of proteins relevant for the maintenance of the neuromuscular axis. Immunostaining on a muscle biopsy derived from the same patient confirmed dysregulation of proteins relevant for proper muscle function, thus highlighting an affliction of muscle cells upon loss of functional WASHC4. The results of histological and coherent anti-Stokes Raman scattering microscopic studies support the concept of a functional role of the WASHC4 protein in humans by altering protein processing and clearance. The proteomic analysis confirmed key molecular players in vitro and highlighted, for the first time, the involvement of skeletal muscle in patients. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

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3. Ghanouni P, Quirke S, Blok J, Casey A. Independent living in adults with autism spectrum disorder: Stakeholders’ perspectives and experiences. Research in developmental disabilities. 2021; 119: 104085.

Independent living is a basic human right that enables individuals with disabilities to determine where they live, who they live with and what kind of support that they receive. Limited research exists regarding the challenges that adults with autism spectrum disorder (ASD) may face when attempting to live independently. Given the importance of independent living for adults with ASD, this study aimed to examine the perspectives of stakeholders about independent living among adults with ASD. METHODS: We recruited a total of 19 stakeholders including adults with ASD and parents of adults with ASD from Canadian provinces. In-depth, semi-structured interviews were conducted to identify factors affecting independent living among adults with ASD. Interviews were transcribed and analyzed using thematic analysis to identify overarching themes. RESULTS: Three themes emerged in our findings, including: a) Psychophysical stability and daily living; b) Financial management and planning; and c) Integrated community living and independence. CONCLUSION: The findings from this study suggest that adults with ASD face several challenges related to independent living. Factors related to psychophysical stability and daily living, financial management, and integrated community living and housing were all found to influence the ability of adults with ASD to live independently. By exploring stakeholders’ perspectives of independent living for adults with ASD, this study provides some insight that can help inform the development of programs and services to facilitate independent living for adults with ASD.

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4. Jafarnezhadgero AA, Dehghani M, Abdollahpourdarvishani M, Sheikhalizadeh H, Akrami M. Effect of textured foot orthoses on walking plantar pressure variables in children with autism spectrum disorders. Journal of biomechanics. 2021; 129: 110775.

The aim of this study was to evaluate the effect of textured foot orthoses on plantar pressure variables in children with autism spectrum disorders (ASDs). Thirty boys were divided into two groups based on their health status, namely: autism spectrum disorder and healthy matched controls. Plantar pressure data were captured during stance phases of shod walking with and without textured foot orthoses. Remarkably larger peak force under the toe1 and metatarsal1 and peak pressure under the toe1 and toe2-5 regions were observed in the autism group comparing with the healthy group, while lower peak force under the toe1, metatarsal1 and metatarsal2 were seen during walking with textured foot orthoses comparing with the cases of walking without them. The results showed higher values of peak pressure under metatarsal3, metatarsal4 and metatarsal5 for the textured foot orthoses walking against the cases without them. Also, analysis depicted huge reductions from pre-to-posttest for the peak pressure under toe2-5 only cases within the autism group. The reason of observing higher peak values of forces and pressures within their forefoot can potentially be their tendency to walk on their toes comparing against the healthy control children. This causes lower pressure values within all toes and the first metatarsal regions during normal walking with textured foot orthoses than walking without them. The findings revealed that the use of textured foot orthoses reduced peak pressure under toe2-5 only in the autism group. This suggests that the use of such interventions can help boys with ASDs move more safely.

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5. Jiang Y, Fu X, Zhang Y, Wang SF, Zhu H, Wang WK, Zhang L, Wu P, Wong CCL, Li J, Ma J, Guan JS, Huang Y, Hui J. Rett syndrome linked to defects in forming the MeCP2/Rbfox/LASR complex in mouse models. Nature communications. 2021; 12(1): 5767.

Rett syndrome (RTT) is a severe neurological disorder and a leading cause of intellectual disability in young females. RTT is mainly caused by mutations found in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Despite extensive studies, the molecular mechanism underlying RTT pathogenesis is still poorly understood. Here, we report MeCP2 as a key subunit of a higher-order multiunit protein complex Rbfox/LASR. Defective MeCP2 in RTT mouse models disrupts the assembly of the MeCP2/Rbfox/LASR complex, leading to reduced binding of Rbfox proteins to target pre-mRNAs and aberrant splicing of Nrxns and Nlgn1 critical for synaptic plasticity. We further show that MeCP2 disease mutants display defective condensate properties and fail to promote phase-separated condensates with Rbfox proteins in vitro and in cultured cells. These data link an impaired function of MeCP2 with disease mutation in splicing control to its defective properties in mediating the higher-order assembly of the MeCP2/Rbfox/LASR complex.

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6. Sharma S, Hucker A, Matthews T, Grohmann D, Laws KR. Cognitive behavioural therapy for anxiety in children and young people on the autism spectrum: a systematic review and meta-analysis. BMC psychology. 2021; 9(1): 151.

BACKGROUND: Anxiety is common in youth on the autism spectrum and cognitive behavioural therapy (CBT) has been adapted to address associated symptoms. The aim of the current systematic review and meta-analysis was to examine the efficacy of CBT for reducing anxiety in autistic youth. METHOD: Searches of PubMed and Scopus databases were undertaken from January 1990 until December 2020. Studies were included if they consisted of randomised controlled trials (RCTs) using CBT to reduce anxiety in autistic youth. Separate random effects meta-analyses assessed anxiety ratings according to informant (clinician; parent; child), both at end-of-trial and at follow-up. RESULTS: A total of 19 RCTs met our inclusion criteria (833 participants: CBT N = 487; controls N = 346). Random effects meta-analyses revealed a large effect size for clinician rated symptoms (g = 0.88, 95% CI 0.55, 1.12, k = 11), while those for both parent (g = 0.40, 95% CI 0.24, 0.56; k = 18) and child-reported anxiety (g = 0.25, 95% CI 0.06, 0.43; k = 13) were smaller, but significant. These benefits were not however maintained at follow-up. Moderator analyses showed that CBT was more efficacious for younger children (for clinician and parent ratings) and when delivered as individual therapy (for clinician ratings). Using the Cochrane Risk of Bias 2 tool, we found concerns about reporting bias across most trials. CONCLUSIONS: The efficacy of CBT for anxiety in autistic youth was supported in the immediate intervention period. However, substantial inconsistency emerged in the magnitude of benefit depending upon who was rating symptoms (clinician, parent or child). Follow-up analyses failed to reveal sustained benefits, though few studies have included this data. It will be important for future trials to address robustness of treatment gains overtime and to further explore inconsistency in efficacy by informant. We also recommend pre-registration of methods by trialists to address concerns with reporting bias.

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7. Williams TI, Loucas T, Sin J, Jeremic M, Aslett G, Knight M, Fincham-Majumdar S, Liu F. A randomised controlled feasibility trial of music-assisted language telehealth intervention for minimally verbal autistic children-the MAP study protocol. Pilot and feasibility studies. 2021; 7(1): 182.

BACKGROUND: About 30% of children with autism spectrum disorder (ASD) do not develop functional speech and remain non-verbal or minimally verbal even after years of speech, language and educational interventions. A wide range of interventions have been developed for improving communication in ASD, but none have proved effective in eliciting functional language in ASD children. Research has found that people with ASD are more likely to have perfect pitch and prefer music to language. Further, it seems that language delay tends to co-occur with better musical skills. Brain imaging research has found that music alongside words increases the attention that people with ASD pay to spoken words. METHODS: In this protocol, we describe our music-assisted programmes (MAP) that will use music to attract the attention of people with ASD to speech. MAP may open the brain pathways to language and therefore help improve communication skills for people with ASD more than standard communication protocols. In particular, we aim to develop and test whether individualised, easily used MAP would increase spoken language in 24-60-month-old, nonverbal or minimally verbal children with ASD. We will develop a structured training method, delivered through naturalistic, interactive activities (e.g. songs) to teach language to ASD children. We will test this by comparing two groups: one undertaking music-assisted programmes, and the other receiving speech and language therapy in the way that is recommended in NHS clinics. Participants will be allocated to groups randomly. The feasibility of MAP will be assessed through estimations of recruitment and retention rates, the sensitivity and reliability of the outcome measures, the intensity and frequency of the trial, the usability of the MAP app (beta version), and the burden of the assessments for the children and parents. DISCUSSION: This feasibility randomised controlled trial will establish the acceptability and estimate the power of the MAP intervention to improve early word learning in children with ASD. In the longer term, this research will help us develop an app for parents or carers of children with ASD to design their own songs and implement their own individualised MAP. TRIAL REGISTRATION: ISRCTN, ISRCTN12536062 . Registered on 26 June 2019.

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