Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.

PURPOSE: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. METHODS: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. RESULTS: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. CONCLUSION: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.

Cerebral palsy.

Cerebral palsy is the most common cause of childhood-onset, lifelong physical disability in most countries, affecting about 1 in 500 neonates with an estimated prevalence of 17 million people worldwide. Cerebral palsy is not a disease entity in the traditional sense but a clinical description of children who share features of a non-progressive brain injury or lesion acquired during the antenatal, perinatal or early postnatal period. The clinical manifestations of cerebral palsy vary greatly in the type of movement disorder, the degree of functional ability and limitation and the affected parts of the body. There is currently no cure, but progress is being made in both the prevention and the amelioration of the brain injury. For example, administration of magnesium sulfate during premature labour and cooling of high-risk infants can reduce the rate and severity of cerebral palsy. Although the disorder affects individuals throughout their lifetime, most cerebral palsy research efforts and management strategies currently focus on the needs of children. Clinical management of children with cerebral palsy is directed towards maximizing function and participation in activities and minimizing the effects of the factors that can make the condition worse, such as epilepsy, feeding challenges, hip dislocation and scoliosis. These management strategies include enhancing neurological function during early development; managing medical co-morbidities, weakness and hypertonia; using rehabilitation technologies to enhance motor function; and preventing secondary musculoskeletal problems. Meeting the needs of people with cerebral palsy in resource-poor settings is particularly challenging.

Therapy service use in children and adolescents with cerebral palsy: An Australian perspective.

AIM: The aim of this study was to describe the patterns of therapy service use for a sample of children and adolescents with cerebral palsy over a 1 year period and to identify factors associated with frequency of therapy and parental satisfaction with therapy frequency. METHODS: Parents of 83 children completed a survey on their child's use of occupational therapy, physiotherapy and speech and language pathology services over the previous year. Participants were randomly selected from a sample stratified by age and Gross Motor Function Classification System (GMFCS) level. RESULTS: During the year prior to survey completion, 83% of children had received occupational therapy, 88% had received physiotherapy and 60% had received speech and language pathology services. Frequency of therapy was higher for younger children (P < 0.01), those classified at GMFCS levels IV-V (P < 0.05) and those attending schools specifically for children with disabilities. CONCLUSIONS: Current structures for therapy service delivery for children with cerebral palsy are systems-based, and age-based funding systems and the organisation of services around the education system are preventing the delivery of needs-based therapy. Paediatricians that care for children and young people with cerebral palsy need to pay particular attention to those that may miss out on therapy due to age or school type, and support these families in accessing appropriate therapy.

Feasibility of trialling cord blood stem cell treatments for cerebral palsy in Australia.

AIM: Umbilical cord blood may have therapeutic benefit in children with cerebral palsy (CP), but further studies are required. On first appearance it seems that Australia is well placed for such a trial because we have excellence in CP research backed by extensive CP registers, and both public and private cord blood banks. We aimed to examine the possibilities of conducting a trial of autologous umbilical cord blood cells (UCBCs) as a treatment for children with CP in Australia. METHODS: Data linkages between CP registers and cord blood banks were used to estimate potential participant numbers for a trial of autologous UCBCs for children with CP. RESULTS: As of early 2013, one Victorian child with CP had cord blood stored in the public bank, and between 1 and 3 children had their cord blood stored at Cell Care Australia (private cord blood bank). In New South Wales, we counted two children on the CP register who had their stored cord blood available in early 2013. We estimate that there are between 10 and 24 children with CP of any type who have autologous cord blood available across Australia. CONCLUSIONS: In nations with small populations like Australia, combined with Australia's relatively low per capita cord blood storage to date, it is not currently feasible to conduct trials of autologous UCBCs for children with CP. Other options must be explored, such as allogeneic UCBCs or prospective trials for neonates at risk of CP.

Evaluation of a novel biodegradable polymer for the generation of a dermal matrix.

Dermal skin substitutes can be used to overcome the immediate problem of donor site shortage in the treatment of major skin loss conditions, such as burn injury. In this study, the biocompatibility, safety, and potential of three variants of NovoSorb (a family of novel biodegradable polyurethanes) as dermal scaffolds were determined in a series of in vitro and in vivo systems. All three polymers exhibited minimal cytotoxic effects on human skin cells, allowing keratinocytes, dermal fibroblasts, and microvascular endothelial cells to grow normally in coculture. Subcutaneous implantation of the polymers in rats demonstrated no systemic toxic effects of the materials or their degradation products. The anticipated local foreign body reaction compared favorably with commercially available medical sutures. Assessment of a three-dimensional polymer matrix followed. The success of sequential culturing of dermal fibroblasts and keratinocytes within the matrix indicated that the generation of a cultured skin substitute is achievable. The polymeric matrix also provided a scaffold for the guided formation of a cultured microvasculature. When engrafted onto a surgically created full-thickness sheep wound, the noncellular matrix integrated, healed with an epidermis supported by a basement membrane, and was capable of withstanding wound contraction. The resistance to contraction compared favorably with a commercially available collagen-based dermal matrix (Integra). These results suggest that the NovoSorb matrix could form the basis of an elegant two-stage burn treatment strategy, with an initial noncellular biodegradable temporizing matrix to stabilize the wound bed followed by the application of cultured skin substitute.

Neural tissue engineering of the CNS using hydrogels.

Current therapies have limited capacity to curtail disease progression or damage of the central nervous system (CNS) of adult mammals and successful regeneration following injury or disease does not occur. Regeneration of the CNS is limited by physical and chemical inhibitory barriers within the injured environment and the absence of positive cues that elicit and guide repair. Neural tissue engineering strategies focus on developing scaffolds that artificially generate favourable cellular microenvironments that attempt to tip the balance in favour of regeneration. Some recent advances using scaffolds to promote regeneration within the CNS, particularly in conjunction with stem cells, has generated promising results. This review focuses on hydrogel scaffolds which have been used extensively in neural tissue engineering applications and addresses the physical and chemical modifications of these materials to promote nerve regeneration.