A significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations ...between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms.
Sixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r = 0.83, p = 0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented.
These data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Core competencies for public health in Canada require proficiency in evidence informed decision making (EIDM). However, decision makers often lack access to information, many workers lack knowledge ...and skills to conduct systematic literature reviews, and public health settings typically lack infrastructure to support EIDM activities. This research was conducted to explore and describe critical factors and dynamics in the early implementation of one public health unit's strategic initiative to develop capacity to make EIDM standard practice.
This qualitative case study was conducted in one public health unit in Ontario, Canada between 2008 and 2010. In-depth information was gathered from two sets of semi-structured interviews and focus groups (n = 27) with 70 members of the health unit, and through a review of 137 documents. Thematic analysis was used to code the key informant and document data.
The critical factors and dynamics for building EIDM capacity at an organizational level included: clear vision and strong leadership, workforce and skills development, ability to access research (library services), fiscal investments, acquisition and development of technological resources, a knowledge management strategy, effective communication, a receptive organizational culture, and a focus on change management.
With leadership, planning, commitment and substantial investments, a public health department has made significant progress, within the first two years of a 10-year initiative, towards achieving its goal of becoming an evidence informed decision making organization.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives To evaluate the efficacy and side effects of oral mammalian target of rapamycin (mTOR) inhibitors in children and adolescents with tuberous sclerosis complex (TSC) and intractable epilepsy ...or subependymal giant cell astrocytoma (SEGA). Study design Single-center series of 13 children and adolescents with TSC who received sirolimus or everolimus (mTOR inhibitors). The anticonvulsant response was evaluated in 7 patients with TSC and refractory seizures. Six patients with SEGAs were treated with either sirolimus or everolimus for nonsurgical management. SEGA volumes were assessed longitudinally using 1.5-T magnetic resonance imaging. Results Of the intractable seizure group (7 patients), 1 patient had >90% reduction, 4 had 50%-90% reduction, and 2 had <50% reduction. Three reported subjective improvements in learning. By 12 months of treatment, there were statistically significant reductions in the SEGA volumes in 4 patients who received mTOR inhibitors ( P < .04). The mean SEGA volume after 6 months of treatment was 2.18 cm3 , which represents 33% reduction in the mean baseline volume of 3.26 cm3 . The mTOR inhibitors were well tolerated. Adverse effects include dyslipidaemia (3 of 13), gingivitis (1 of 13), anorexia (1 of 13), and mild gastrointestinal side effects (1 of 13). Conclusion This case series suggests that mTOR inhibitors can improve seizures in those with TSC and refractory epilepsy. They are also an effective treatment for reducing the volume of SEGAs in patients with TSC not amenable to surgery with an acceptable side effect profile.
Whole-exome sequencing (WES) has revolutionized Mendelian diagnostics, however, there is no consensus on the timing of data review in undiagnosed individuals and only preliminary data on the ...cost-effectiveness of this technology. We aimed to assess the utility of WES data reanalysis for diagnosis in Mendelian disorders and to analyze the cost-effectiveness of this technology compared with a traditional diagnostic pathway.
WES was applied to a cohort of 54 patients from 37 families with a variety of Mendelian disorders to identify the genetic etiology. Reanalysis was performed after 12 months with an improved WES diagnostic pipeline. A comparison was made between costs of a modeled WES pathway and a traditional diagnostic pathway in a cohort with intellectual disability (ID).
Reanalysis of WES data at 12 months improved diagnostic success from 30 to 41% due to interim publication of disease genes, expanded phenotype data from referrer, and an improved bioinformatics pipeline. Cost analysis on the ID cohort showed average cost savings of US$586 (AU$782) for each additional diagnosis.
Early application of WES in Mendelian disorders is cost-effective and reanalysis of an undiagnosed individual at a 12-month time point increases total diagnoses by 11%.
Zimmermann-Laband syndrome (ZLS) is a developmental disorder characterized by facial dysmorphism with gingival enlargement, intellectual disability, hypoplasia or aplasia of nails and terminal ...phalanges, and hypertrichosis. We report that heterozygous missense mutations in KCNH1 account for a considerable proportion of ZLS. KCNH1 encodes the voltage-gated K(+) channel Eag1 (Kv10.1). Patch-clamp recordings showed strong negative shifts in voltage-dependent activation for all but one KCNH1 channel mutant (Gly469Arg). Coexpression of Gly469Arg with wild-type KCNH1 resulted in heterotetrameric channels with reduced conductance at positive potentials but pronounced conductance at negative potentials. These data support a gain-of-function effect for all ZLS-associated KCNH1 mutants. We also identified a recurrent de novo missense change in ATP6V1B2, encoding the B2 subunit of the multimeric vacuolar H(+) ATPase, in two individuals with ZLS. Structural analysis predicts a perturbing effect of the mutation on complex assembly. Our findings demonstrate that KCNH1 mutations cause ZLS and document genetic heterogeneity for this disorder.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
Congenital cataracts are a significant cause of lifelong visual loss. They may be isolated or associated with microcornea, microphthalmia, anterior segment dysgenesis (ASD) and glaucoma, and ...there can be syndromic associations. Genetic diagnosis is challenging due to marked genetic heterogeneity. In this study, next‐generation sequencing (NGS) of 32 cataract‐associated genes was undertaken in 46 apparently nonsyndromic congenital cataract probands, around half sporadic and half familial cases. We identified pathogenic variants in 70% of cases, and over 68% of these were novel. In almost two‐thirds (20/33) of these cases, this resulted in new information about the diagnosis and/or inheritance pattern. This included identification of: new syndromic diagnoses due to NHS or BCOR mutations; complex ocular phenotypes due to PAX6 mutations; de novo autosomal‐dominant or X‐linked mutations in sporadic cases; and mutations in two separate cataract genes in one family. Variants were found in the crystallin and gap junction genes, including the first report of severe microphthalmia and sclerocornea associated with a novel GJA8 mutation. Mutations were also found in rarely reported genes including MAF, VIM, MIP, and BFSP1. Targeted NGS in presumed nonsyndromic congenital cataract patients provided significant diagnostic information in both familial and sporadic cases.
Congenital cataracts cause severe visual impairment and are highly genetically heterogeneous. They may be familial or sporadic and there may be a subtle or evolving syndromic diagnosis, even in apparently non‐syndromic cases. This study demonstrates the value of next‐generation sequencing in this condition, with pathogenic mutations identified in approximately 70% of both familial and sporadic cases. This approach led to new genetic, clinical diagnostic or management information in a majority of the cases.
Macfarlane and colleagues, writing about Toronto, provide a reminder that the built environment as a health issue has, in some places, a history of several decades, in the form of the Healthy Cities ...movement, providing a foundation for the current initiatives.20 Montreal has a history of engaging neighbourhoods and non-governmental organizations (NGOs) in issues concerning the built environment, as related in the paper by Dubé and colleagues on the participation of citizens in the development of public policies for active transportation.21 The paper by Gagnon and Bellefleur examines two aspects of the development of healthy public policies: predicting effects and assessing political viability.22 The first of these is taken up by Ulmer et al., who describe the application of an evidence-based software tool in a health impact evaluation of the redevelopment of a brownfield site in Toronto.23 The paper by Moloughney et al. describes another evidence-based tool and how it is being adopted for routine use in the assessment of development proposals, mainly in greenfield sites, in the Region of Peel.24 Miro and colleagues reflect upon the experience in British Columbia in increasing the capacity to participate in planning processes for land use and transportation, building relationships among stakeholders and influencing plans and policies.25 Last, illustrating the issue of political acceptability, the results of a residential preferences survey conducted in the Greater Toronto Area and Metro Vancouver by Frank and colleagues demonstrate a demand for walkable communities that is not being fully met by present patterns of development.26 The projects described here show how it is possible to build upon empirical evidence to develop initiatives that test practical approaches and to share the findings with others.
Pathways to policy Politis, Christopher E.; Mowat, David L.; Keen, Deb
Canadian journal of public health,
01/2017, Letnik:
108, Številka:
2
Journal Article
Recenzirano
Odprti dostop
OBJECTIVES:
The Canadian Partnership Against Cancer funded 12 large-scale knowledge to action cancer and chronic disease prevention projects between 2009 and 2016 through the Coalitions Linking ...Action and Science for Prevention (CLASP) initiative. Two projects, Healthy Canada by Design (HCBD) and Children’s Mobility, Health and Happiness (CMHH), developed policies to address physical activity and the built environment through a multisectoral approach. A qualitative analysis involving a review of 183 knowledge products and 8 key informant interviews was conducted to understand what policy changes occurred, and the underlying critical success factors, through these projects.
SETTING:
Both projects worked at the local level to change physical activity and built environment policy in 203 sites, including municipalities and schools. Both projects brought multisectoral expertise (e.g., public health, land use planning, transportation engineering, education, etc.) together to inform the development of local healthy public policy in the areas of land use, transportation and school travel planning.
INTERVENTION:
Through the qualitative analysis of the knowledge products and key informant interviews, 163 policies were attributed to HCBD and CMHH work.
OUTCOMES:
Fourteen “pathways to policy” were identified as critical success factors facilitating and accelerating the development and implementation of physical activity and built environment policy. Of the 14 pathways to policy, 8 had a focus on multisectoral collaboration.
IMPLICATIONS:
The lessons learned from the CLASP experience could support enhanced multisectoral collaborations to accelerate the development and implementation of physical activity and built environment policy in new jurisdictions across Canada and internationally.
Current carrier screening methods do not identify a proportion of carriers that may have children affected by spinal muscular atrophy (SMA). Additional genetic data is essential to inform accurate ...risk assessment and genetic counselling of SMA carriers. This study aims to quantify the various genotypes among parents of children with SMA.
A retrospective cohort study was undertaken at Sydney Children's Hospital Network, the major SMA referral centre for New South Wales, Australia. Participants included children with genetically confirmed SMA born between 2005 and 2021. Data was collected on parent genotype inclusive of copy number of
exons 7 and 8. The number of
exon 7 copies were recorded for the affected children. Descriptive statistics were used to determine the proportion of carriers of 2+0 genotype classified as silent carriers. Chi-square test was used to correlate the association between parents with a heterozygous
exon 7 deletion and two copies of exon 8 and ≥3
copy number in the proband.
SMA carrier testing was performed in 118/154 (76.6%) parents, incorporating 59 probands with homozygous
deletions and one proband with compound heterozygote pathogenic variants. Among parents with a child with SMA, 7.6% had two copies of
exon 7. When only probands with a homozygous
exon 7 deletion were included, 6.9% of parents had two copies of
exon 7. An association was observed between heterozygous deletion of
exon 7 with two copies of exon 8 in a parent and ≥3
copy number in the affected proband (
= 0.07).
This study confirmed a small but substantial proportion of silent carriers not identified by conventional screening within an Australian context. Accordingly, the effectiveness of carrier screening for SMA is linked with genetic counselling to enable health literacy regarding high and low risk results and is complemented by new-born screening and maintaining clinical awareness for SMA. Gene conversion events may underpin the associations between parent carrier status and proband
copy number.
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