默多克儿童研究学院

BACKGROUNDChildhood apraxia of speech (CAS) affects a child's ability to produce sounds and syllables precisely and consistently, and to produce words and sentences with accuracy and correct speech rhythm. It is a rare condition, affecting only 0.1% of the general population. Consensus has been reached that three core features have diagnostic validity: (1) inconsistent error production on both consonants and vowels across repeated productions of syllables or words; (2) lengthened and impaired coarticulatory transitions between sounds and syllables; and (3) inappropriate prosody (ASHA 2007). A deficit in motor programming or planning is thought to underlie the condition. This means that children know what they would like to say but there is a breakdown in the ability to programme or plan the fine and rapid movements required to accurately produce speech. Children with CAS may also have impairments in one or more of the following areas: non-speech oral motor function, dysarthria, language, phonological production impairment, phonemic awareness or metalinguistic skills and literacy, or combinations of these. High-quality evidence from randomised controlled trials (RCTs) is lacking on interventions for CAS.OBJECTIVESTo assess the efficacy of interventions targeting speech and language in children and adolescents with CAS as delivered by speech and language pathologists/therapists.SEARCH METHODSWe searched CENTRAL, MEDLINE, Embase, eight other databases and seven trial registers up to April 2017. We searched the reference lists of included reports and requested information on unpublished trials from authors of published studies and other experts as well as information groups in the areas of speech and language therapy/pathology and linguistics.SELECTION CRITERIARCTs and quasi-RCTs of children aged 3 to 16 years with CAS diagnosed by a speech and language pathologist/therapist, grouped by treatment types.DATA COLLECTION AND ANALYSISTwo review authors (FL, AM) independently assessed titles and abstracts identified from the searches and obtained full-text reports of all potentially relevant articles and assessed these for eligibility. The same two authors extracted data and conducted the 'Risk of bias' and GRADE assessments. One review author (EM) tabulated findings from excluded observational studies (Table 1).MAIN RESULTSThis review includes only one RCT, funded by the Australian Research Council; the University of Sydney International Development Fund; Douglas and Lola Douglas Scholarship on Child and Adolescent Health; Nadia Verrall Memorial Scholarship; and a James Kentley Memorial Fellowship. This study recruited 26 children aged 4 to 12 years, with mild to moderate CAS of unknown cause, and compared two interventions: the Nuffield Dyspraxia Programme-3 (NDP-3); and the Rapid Syllable Transitions Treatment (ReST). Children were allocated randomly to one of the two treatments. Treatments were delivered intensively in one-hour sessions, four days a week for three weeks, in a university clinic in Australia. Speech pathology students delivered the treatments in the English language. Outcomes were assessed before therapy, immediately after therapy, at one month and four months post-therapy. Our review looked at one-month post-therapy outcomes only.We judged all core outcome domains to be low risk of bias. We downgraded the quality of the evidence by one level to moderate due to imprecision, given that only one RCT was identified. Both the NDP-3 and ReST therapies demonstrated improvement at one month post-treatment. A number of cases in each cohort had recommenced usual treatment by their speech and language pathologist between one month and four months post-treatment (NDP-3: 9/13 participants; ReST: 9/13 participants). Hence, maintenance of treatment effects to four months post-treatment could not be analysed without significant potential bias, and thus this time point was not included for further analysis in this review.There is limited evidence that, when delivered intensively, both the NDP-3 and ReST may effect improvement in word accuracy in 4- to 12-year-old children with CAS, measured by the accuracy of production on treated and non-treated words, speech production consistency and the accuracy of connected speech. The study did not measure functional communication.AUTHORS' CONCLUSIONSThere is limited evidence that, when delivered intensively, both the NDP-3 and ReST may effect improvement in word accuracy in 4- to 12-year-old children with CAS, measured by the accuracy of production on treated and non-treated words, speech production consistency and the accuracy of connected speech. The study did not measure functional communication. No formal analyses were conducted to compare NDP-3 and ReST by the original study authors, hence one treatment cannot be reliably advocated over the other. We are also unable to say whether either treatment is better than no treatment or treatment as usual. No evidence currently exists to support the effectiveness of other treatments for children aged 4 to 12 years with idiopathic CAS without other comorbid neurodevelopmental disorders. Further RCTs replicating this study would strengthen the evidence base. Similarly, further RCTs are needed of other interventions, in other age ranges and populations with CAS and with co-occurring disorders.

We investigated the pathogenicity of a homozygous intronic variant in CDK5RAP3, a key UFMylation adapter, in three individuals from two unrelated families with a lethal neurodevelopmental disorder. CDK5RAP3 variants have not been linked to human disorders to date; however, murine Cdk5rap3 knockout is embryonic lethal and variants in five other UFMylation components cause severe neurodevelopmental conditions. A segregating homozygous variant, chr17(GRCh38):g.47974691G > A, CDK5RAP3 NM_176096.3:c.334 + 243G > A, was identified by trio whole-genome and proband RNA sequencing in Family A and by trio whole-exome sequencing data reanalysis in Family B. Variant pathogenicity investigations included RT-PCR, Western blot, co-immunoprecipitation and (phospho)proteomics to assess transcript, protein and UFMylation complex effects. Antisense oligonucleotide-mediated rescue of CDK5RAP3 expression combined with proteomics and phosphoproteomics defined the mechanistic impact of CDK5RAP3 deficiency and rescue in amniocytes from an affected individual. All three affected individuals showed foetal growth restriction, foetal akinesia, pontocerebellar hypoplasia, arthrogryposis and hepatic pathology. CDK5RAP3 c.334 + 243G > A activates a cryptic donor splice-site causing pseudoexon/intron inclusion triggering nonsense-mediated decay and deficiency of full-length CDK5RAP3 (NP_788276.1), while potentially allowing retained expression of C-terminal alternative isoforms. Co-immunoprecipitation revealed only full-length CDK5RAP3 binds UFL1, whereas C-terminal isoforms cannot. Primary amniocytes showed CDK5RAP3 deficiency was associated with impaired UFMylation of known substrates, RPL26 and UFBP1. Proteomic and phosphoproteomic analyses revealed dysregulation of extracellular matrix organisation, cell adhesion, mitotic/genome stability pathways, cytoskeletal networks and neuronal guidance, which were reversed by restoration of canonical CDK5RAP3 expression via splice-correcting antisense oligonucleotides. Phosphoproteomic data implicate CDK5RAP3 as an upstream regulator of UFL1 S462 phosphorylation, known to be regulated by Ataxia-telangiectasia mutated (ATM) signalling. Our findings provide strong evidence linking deficiency of full-length CDK5RAP3 to severe neurodevelopmental, liver and muscle dysfunction. This study further highlights the therapeutic potential of ASO-based deep-intronic splicing defect correction.

Facial features undergo continuous transformations across the lifespan. This study quantified and visualized the effects of aging on facial morphology in individuals of European ancestry. Three-dimensional facial photographs of 4,038 individuals (1,455 males and 2,583 females), aged 5 to 85 years and of European descent, were analyzed. Morphological changes in the face were modeled using kernel linear regression, with a focus on age-related changes. Age- and sex-specific expected facial shapes were generated for individuals aged 10 to 60 years in 5-year intervals. Changes in the face were analyzed in the sagittal, vertical, and horizontal directions, with linear distances and angular variations in the upper, middle, and lower regions of the face evaluated. Our results show that facial shape changes decelerate progressively after the age of 25 for both males and females. Facial aging is characterized by the loss of fullness in the forehead, sunken temples, formation of eye bags, deepening nasolabial folds, cheek hollowness and thinning, lengthening, and retrusion of the lips. Notable changes begin in the 30s, with the most pronounced alterations occurring in the 40s and 50s, intensifying in the 50s and 60s. Although the overall aging trajectory is similar in males and females, the magnitude and rate of change demonstrate sexual dimorphism. This study provides comprehensive insights into age-related facial morphological changes in healthy individuals of European ancestry using 3D photogrammetric analysis. These findings have important implications for clinical disciplines such as dentistry, plastic and maxillofacial surgery, and forensic medicine.

Speech and language impairments are central features of CDK13-related disorder. While pathogenic CDK13 variants have been associated with childhood apraxia of speech (CAS), a systematic characterisation of communication has not been conducted. Here we examined speech, language, non-verbal communication skills, social behaviour and health and development in 41 individuals with CDK13-related disorder from 10 countries (male = 22, median-age 7 years 1 month, range 1–25 years; 33 novel). Most participants used augmentative and alternative communication (AAC) in early childhood (24/41). CAS was common (14/22). Performance varied widely across intellectual ability, social behaviour and expressive language skills, with participants ranging from within average through to the severely impaired range. Receptive language was significantly stronger than expressive language ability. Social motivation was a relative strength. In terms of a broader health phenotype, a quarter had one or more of: renal, urogenital, musculoskeletal, and cardiac malformations, vision impairment, ear infections and/or sleep disturbance. All had gross and fine motor impairments (41/41). Other conditions included mild-moderate intellectual disability (16/22) and autism (7/41). No genotype-phenotype correlations were found. Recognition of CAS, a rare speech disorder, is required to ensure appropriately targeted therapy. The high prevalence of speech and language impairment underscores the importance of tailored speech therapy, particularly early access to AAC supports.

Autism spectrum disorder (autism) describes a heterogeneous neurodevelopmental phenotype arising from the interplay of environmental and genetic factors in early life. In a general population birth cohort, we employed a scoping approach to identify prospective associations between prenatal and birth factors and a subsequent autism diagnosis. Factors associated with increased likelihood of autism included those related to i) maternal health (maternal pre-pregnancy body mass index, pre-existing maternal mental health conditions, maternal use of selective serotonin reuptake inhibitors) ii) environmental exposures (maternal passive tobacco smoke exposure, and exposure to vinyl floors) iii) demographic factors (socioeconomic disadvantage). Factors associated with a decreased likelihood of autism included maternal dietary nutrition and supplementation (higher folic acid, magnesium, and iron, as well as adherence to the Australian Dietary Guidelines). Our findings extend the evidence that autism may have a multifactorial origin in early life. Further studies should explore the composite effects of these prenatal and birth factors on autism outcomes via shared biological pathways, such as inflammation, and oxidative stress, in concert with genetic predisposition.