Autism spectrum: parents' perspectives reflecting the different needs of different families.

BACKGROUND: Parents of children on the autism spectrum often face great challenges in the care of their child. Early support tailored to families' individual needs is therefore crucial for the development and quality of life of both children on the autism spectrum and their families. However, to date it is unclear whether the support available meets the parents' needs. STUDY AIM: To investigate how the system of care, support, and therapies for children on the autism spectrum is perceived by their parents. METHOD: A total of 57 parents of Swiss children on the autism spectrum participated in an online survey, and 20 of them participated in additional semi-structured interviews. RESULTS: We found that parents of children on the autism spectrum may face substantial challenges and that social support is essential. Two thirds of the participating parents reported a long and difficult diagnostic process as challenging, and 60% expressed their need for closer follow-up after diagnosis and more support. Only one third of the parents stated that they manage their everyday lives well, whereas 17.5% felt exhausted, and more than half of the parents responded that they felt challenged. One fifth indicated that they had poor family support, and half reported substantial financial challenges. At the same time, most families also emphasize how important their neurodivergent children are to the family`s life together. CONCLUSION: It is important that primary pediatricians not only initiate the diagnostic process, but also assess the different needs of the different family independent of the diagnosis and, if necessary, initiate adequate measures or guide parents to institutions in charge. Parents who do not actively express their individual needs should nevertheless be advised about support services, including financial counseling. The positive aspects mentioned by families can be emphasized and used as resources to improve their quality of life.

Digital Platform Uses for Help and Support Seeking of Parents With Children Affected by Disabilities: Scoping Review.

BACKGROUND: Receiving a diagnosis that leads to severe disability in childhood can cause a traumatic experience with long-lasting emotional stress for patients and family members. In recent decades, emerging digital technologies have transformed how patients or caregivers of persons with disabilities manage their health conditions. As a result, information (eg, on treatment and resources) has become widely available to patients and their families. Parents and other caregivers can use digital platforms such as websites or social media to derive social support, usually from other patients and caregivers who share their lived experiences, challenges, and successes on these platforms. However, gaps remain in our understanding of platforms that are most frequently used or preferred among parents and caregivers of children with disabilities. In particular, it is not clear what factors primarily drive or discourage engagement with these digital tools and what the main ethical considerations are in relation to these tools. OBJECTIVE: We aimed to (1) identify prominent digital platforms used by parents or caregivers of children with disabilities; (2) explore the theoretical contexts and reasons for digital platform use, as well as the experiences made with using these platforms reported in the included studies; and (3) identify any privacy and ethical concerns emerging in the available literature in relation to the use of these platforms. METHODS: We conducted a scoping review of 5 academic databases of English-language articles published within the last 10 years for diseases with childhood onset disability and self-help or parent/caregiver-led digital platforms. RESULTS: We identified 17 papers in which digital platforms used by parents of affected children predominantly included social media elements but also search engines, health-related apps, and medical websites. Information retrieval and social support were the main reasons for their utilization. Nearly all studies were exploratory and applied either quantitative, qualitative, or mixed methods. The main ethical concerns for digital platform users included hampered access due to language barriers, privacy issues, and perceived suboptimal advice (eg, due to missing empathy of medical professionals). Older and non-college-educated individuals and ethnic minorities appeared less likely to access information online. CONCLUSIONS: This review showed that limited scientifically sound knowledge exists on digital platform use and needs in the context of disabling conditions in children, as the evidence consists mostly of exploratory studies. We could highlight that affected families seek information and support from digital platforms, as health care systems seem to be insufficient for satisfying knowledge and support needs through traditional channels.

The Coping with and Caring for Infants with Special Needs intervention was associated with improved motor development in preterm infants.

AIM: We compared the impact of standard infant physiotherapy and the family-centred programme, Coping with and Caring for Infants with Special Needs (COPCA), in infants born before 32 weeks without significant brain lesions. METHODS: This randomised controlled trial was carried out in patients' homes and outpatient settings in Switzerland between January 2016 and October 2019. We used data from the national SwissNeoNet register and an assessment battery that included infant and family outcomes and video analyses of therapy sessions. The Infant Motor Profile was the primary outcome instrument. RESULTS: The COPCA group comprised six boys and two girls with a median gestational age of 27 weeks (range 25-30), and the standard care group comprised seven boys and one girl with a median gestational age of 29.5 weeks (range 26-31). COPCA participants improved significantly more between baseline and 18 months in the IMP variation (9.0 percentage points, 95% confidence interval: 0.3-17.5) and performance (12.0 percentage points, 95% confidence interval: 4.1-20.6) domains than standard care participants. COPCA coaching was positively associated with IMP scores at 18 months, but some standard care actions were negatively associated. CONCLUSION: COPCA was associated with better motor outcome in infants born before 32 weeks than standard infant physiotherapy.

Pitfalls of using IQ short forms in neurodevelopmental disorders: a study in patients with congenital heart disease.

BACKGROUND: Short forms of IQ (S-IQ) assessments are time efficient and highly predictive of the full IQ (F-IQ) in healthy individuals. To investigate the validity of S-IQs for patients with neurodevelopmental impairments, this study tested a well-established S-IQ version in patients with congenital heart disease (CHD). METHODS: The Wechsler Intelligence Scale for Children, Fourth Edition was applied in 107 children with complex CHD aged 9-11 years. F-IQ and a well-established S-IQ version were calculated for each patient. The agreement between S-IQ and F-IQ was investigated across the whole spectrum of IQ scores. Finally, we tested a method to adjust IQs to resolve potential bias and validated this method in an independent sample of 55 CHD patients. RESULTS: S-IQ and F-IQ correlated strongly. Nevertheless, the size of the bias correlated with the true IQ, indicating larger error at the tails of the distribution. Estimating a corrected IQ by adjusting the S-IQ with correction parameters substantially improved agreement. CONCLUSION: We here report that substantial bias may underestimate low IQ scores and overestimate high ones. This bias should be considered when at-risk populations are assessed with S-IQs. Importantly, the bias can be minimized by using a correction formula.

Hippocampal volume reduction is associated with intellectual functions in adolescents with congenital heart disease.

BACKGROUND: Adolescents undergoing early cardiopulmonary bypass surgery for congenital heart disease (CHD) may demonstrate a variety of neurocognitive impairments. These impairments can affect overall intellectual functions, but also specific memory deficits, language, and executive functions. As the hippocampus is a critical structure involved in these functions, we sought to determine whether hippocampal volume was reduced in adolescents with CHD and whether altered volumes were related to functional outcome. METHODS: At a mean age of 13.8 y, 48 adolescent survivors of childhood cardiopulmonary bypass surgery for CHD and 32 healthy controls underwent neurocognitive testing and cerebral magnetic resonance imaging. Images were quantitatively analyzed using an automated regional segmentation tool (FSL-FIRST). RESULTS: Adolescents with CHD had 10% lower total hippocampal volumes compared with controls. After controlling for total brain volume, total hippocampal volume correlated with total IQ, with working memory, and verbal comprehension in CHD patients, but not in controls. CONCLUSIONS: In adolescent survivors of cardiopulmonary bypass surgery for CHD, specific brain regions such as the hippocampus may show long-term persistent alteration and correlate with intellectual deficits, particularly with verbal and memory functions.

Delayed cortical gray matter development in neonates with severe congenital heart disease.

BACKGROUND: This study aimed to assess cortical gray matter growth and maturation in neonates with congenital heart disease (CHD). METHODS: Thirty-one (near) term neonates with severe CHD (8 univentricular heart malformation (UVH), 21 d-transposition of great arteries (d-TGA) and 2 aortic coarctation) underwent cerebral MRI before (postnatal-day 7) and after (postnatal-day 24) surgery. Eighteen controls with similar gestational age had one MRI (postnatal-day 23). Cortical gray matter volume (CGM), inner cortical surface (iCS), and median cortical thickness were extracted as measures of volumetric growth, and gyrification index (GI) as measure of maturation. RESULTS: Over a median of 18 d, CGM increased by 21%, iCS by 17%, thickness and GI both by 9%. Decreased postoperative CGM and iCS were seen for CHD compared to controls (P values < 0.01), however with similar thickness and GI. UVH showed lower postoperative iCS, thickness (P values < 0.05) and GI (P value < 0.01) than d-TGA and controls. Infants requiring preoperative balloon-atrioseptostomy (BAS, 61%) had reduced postoperative CGM, iCS, and GI (P values < 0.05). CONCLUSION: Infants with severe CHD show reduced cortical volumes compared to controls with gyrification being delayed in UVH, but not in d-TGA. Infants requiring BAS show higher risk of impaired cortical volume and gyrification.

Comparison of automated brain volumetry methods with stereology in children aged 2 to 3 years.

INTRODUCTION: The accurate and precise measurement of brain volumes in young children is important for early identification of children with reduced brain volumes and an increased risk for neurodevelopmental impairment. Brain volumes can be measured from cerebral MRI (cMRI), but most neuroimaging tools used for cerebral segmentation and volumetry were developed for use in adults and have not been validated in infants or young children. Here, we investigate the feasibility and accuracy of three automated software methods (i.e., SPM, FSL, and FreeSurfer) for brain volumetry in young children and compare the measures with corresponding volumes obtained using the Cavalieri method of modern design stereology. METHODS: Cerebral MRI data were collected from 21 children with a complex congenital heart disease (CHD) before Fontan procedure, at a median age of 27 months (range 20.9-42.4 months). Data were segmented with SPM, FSL, and FreeSurfer, and total intracranial volume (ICV) and total brain volume (TBV) were compared with corresponding measures obtained using the Cavalieri method. RESULTS: Agreement between the estimated brain volumes (ICV and TBV) relative to the gold standard stereological volumes was strongest for FreeSurfer (p < 0.001) and moderate for SPM segment (ICV p = 0.05; TBV p = 0.006). No significant association was evident between ICV and TBV obtained using SPM NewSegment and FSL FAST and the corresponding stereological volumes. CONCLUSIONS: FreeSurfer provides an accurate method for measuring brain volumes in young children, even in the presence of structural brain abnormalities.

Severe Congenital Heart Defects Are Associated with Global Reduction of Neonatal Brain Volumes.

OBJECTIVES: To determine neonatal global and regional brain volumes in infants with congenital heart disease (CHD) in comparison with healthy controls and to determine brain growth. STUDY DESIGN: Prospective cohort study in infants undergoing open-heart surgery for complex CHD. Global and regional volumetric measurements on preoperative cerebral magnetic resonance imaging were manually segmented in children without overt brain lesions. RESULTS: Preoperative brain volumetry of 19 patients demonstrates reduction in total and regional brain volumes, without any specific regional predilection compared with 19 healthy control infants (total brain volume reduction: 21%, regional brain volume reduction 8%-28%, all P < .001). CONCLUSIONS: Infants with CHD undergoing bypass surgery have smaller brain volumes prior to surgery without a specific regional predilection. This suggests a fetal origin of reduced brain growth.

Brain volumes predict neurodevelopment in adolescents after surgery for congenital heart disease.

Patients with complex congenital heart disease are at risk for neurodevelopmental impairments. Evidence suggests that brain maturation can be delayed and pre- and postoperative brain injury may occur, and there is limited information on the long-term effect of congenital heart disease on brain development and function in adolescent patients. At a mean age of 13.8 years, 39 adolescent survivors of childhood cardiopulmonary bypass surgery with no structural brain lesions evident through conventional cerebral magnetic resonance imaging and 32 healthy control subjects underwent extensive neurodevelopmental assessment and cerebral magnetic resonance imaging. Cerebral scans were analysed quantitatively using surface-based and voxel-based morphometry. Compared with control subjects, patients had lower total brain (P = 0.003), white matter (P = 0.004) and cortical grey matter (P = 0.005) volumes, whereas cerebrospinal fluid volumes were not different. Regional brain volume reduction ranged from 5.3% (cortical grey matter) to 11% (corpus callosum). Adolescents with cyanotic heart disease showed more brain volume loss than those with acyanotic heart disease, particularly in the white matter, thalami, hippocampi and corpus callosum (all P-values < 0.05). Brain volume reduction correlated significantly with cognitive, motor and executive functions (grey matter: P < 0.05, white matter: P < 0.01). Our findings suggest that there are long-lasting cerebral changes in adolescent survivors of cardiopulmonary bypass surgery for congenital heart disease and that these changes are associated with functional outcome.

Clinical course and interstage monitoring after the Norwood and hybrid procedures for hypoplastic left heart syndrome.

Infants with hypoplastic left heart syndrome (HLHS) are at risk for interstage morbidity and mortality, especially between the first and second surgical stages after the Norwood and hybrid procedures. This study compared the morbidity and mortality of patients treated by either the Norwood or the hybrid procedure for HLHS between the first and second stages who were undergoing interstage monitoring. Between October 2008 and December 2011, 26 infants (14 boys) with HLHS (n = 16) and other univentricular heart malformations with aortic arch anomaly (n = 10) were scheduled for interstage monitoring after Norwood I (n = 12) and hybrid (n = 14) procedures. Three infants (11.5 %) died after first-stage palliation (one hybrid patient and two Norwood patients), and three infants (11.5 %) died after second-stage palliation (two hybrid patients and one Norwood patient) (p = 0.83), all after early second-stage surgery (<90 days). The Norwood I and hybrid procedures did not differ in terms of overall mortality (23 %) (three hybrid and three Norwood patients; p = 1.00). Seven infants (26.9 %) could not be discharged from the hospital due to hemodynamic instability and were referred for early second-stage surgery (<90 days). After the first stage, the invasive reevaluation rate before discharge was high (53.8 %), with cardiac catheterizations for 8 of 14 patients after the hybrid procedure and for 6 of 12 patients after the Norwood procedure (p = 0.69). A total of 11 reinterventions were performed (eight by catheter and three by surgery). Of the eight catheter reinterventions, five were performed for hybrid patients (p = 0.22). For 14 infants, 89 days (range 10-177 days) of interstage monitoring were scheduled. One infant (3.9 %) died during the interstage monitoring. The findings showed a breach of the physiologic criteria for interstage monitoring in seven infants (50 %) after 10 days (range 4-68 days) (five hybrid and two Norwood patients), leading to rehospitalization and catheterization for six patients (four hybrid and two Norwood patients), requiring interventions for two patients (patent arterial duct stent dilation, and atrial septal defect stenting, all for hybrid patients). Overall, three of the seven patients with red flag events of interstage monitoring were candidates for early second-stage surgery. In conclusion, morbidity among infants treated for HLHS remains high, either before or after hospital discharge, emphasizing the need of interstage monitoring programs. Despite retrograde aortic flow in infants with HLHS after the hybrid procedure, the mortality rate was comparable between the two groups. Mortality occurs after early second-stage surgery (<90 days).

The effect of the COVID-19 pandemic on pediatric emergency department utilization in three regions in Switzerland.

PURPOSE: The COVID-19 pandemic was associated with a decrease in emergency department (ED) visits. However, contradictory, and sparse data regarding children could not yet answer the question, how pediatric ED utilization evolved throughout the pandemic. Our objectives were to investigate the impact of the pandemic in three language regions of Switzerland by analyzing trends over time, describe regional differences, and address implications for future healthcare. METHODS: We conducted a retrospective, longitudinal cohort study at three Swiss tertiary pediatric EDs (March 1st, 2018-February 28th, 2022), analyzing the numbers of ED visits (including patients` age, triage categories, and urgent vs. non-urgent cases). The impact of COVID-19 related non-pharmaceutical interventions (NPIs) on pediatric ED utilization was assessed by interrupted time series (ITS) modelling. RESULTS: Based on 304'438 ED visits, we found a drop of nearly 50% at the onset of NPIs, followed by a gradual recovery. This primarily affected children 0-4 years, and both non-urgent and urgent cases. However, the decline in urgent visits appeared to be more pronounced in two centers compared to a third, where also hospitalization rates did not decrease significantly during the pandemic. A subgroup analysis showed a significant decrease in respiratory and gastrointestinal diseases, and an increase in the proportion of trauma patients during the pandemic. CONCLUSIONS: The COVID-19 pandemic had substantial effects on number and reasons for pediatric ED visits, particularly among children 0-4 years. Despite equal regulatory conditions, the utilization dynamics varied markedly between the three regions, highlighting the multifactorial modification of pediatric ED utilization during the pandemic. Furthermore, future policy decisions should take regional differences into account.

Neurodevelopmental outcome, psychological adjustment, and quality of life in adolescents with congenital heart disease.

AIM: The aim of this study was to examine neurodevelopment, psychological adjustment, and health-related quality of life (HRQoL) in adolescents after bypass surgery for congenital heart disease (CHD) during early childhood. METHOD: Fifty-nine adolescents (34 females, 25 males) with CHD were examined at a median age of 13 years 8 months (range 11 y 5 mo-16 y 11 mo). Outcome was assessed with the Wechsler Intelligence Scale for Children, (fourth edition); the Beery Test of Visual-Motor Integration; the Rey-Osterrieth Complex Figure Test; the Zurich Neuromotor Assessment; the Strengths and Difficulties Questionnaire; and the KIDSCREEN questionnaires. Results were compared with those of 40 age- and sex-matched healthy comparison individuals. RESULTS: Outcome with regard to full-scale IQ, perceptual reasoning, and the working memory scale was poorer in patients with CHD than in the comparison group (all p ≤ 0.001). Visual perception, visuomotor integration (p ≤ 0.001), and executive functions (Rey figure copy: p=0.05) were also affected. Patients with CHD also had lower scores on all motor domains (p < 0.02) except static balance. Psychological adjustment was affected only in the 'peer relationship' domain (p=0.05). Quality of life was similar to that of typically developing peers. INTERPRETATION: Adolescents with CHD may manifest persistent cognitive and motor impairments, while psychological adjustment and self-reported HRQoL are mostly typical. Thus, long-term neurodevelopmental evaluations are necessary to provide early educational and therapeutic support.

[Developmental disorders in preschool children: an interdisciplinary approach]. / Entwicklungsstörungen im Vorschulalter - interdisziplinär beurteilt.

Many children show developmental abnormalities in the first years of life. Thus, the primary care physician should know the procedures of developmental surveillance and screening and be informed about the further steps in the evaluation of children with developmental disorders. This article presents current developmental screening methods in primary care, defines the terminology of developmental disorders in young children, demonstrates the essential diagnostic procedures in developmentally impaired children and describes the interdisciplinary collaboration between physicians, psychologists, therapists and special needs educators.

Mental health challenges and digital platform opportunities in patients and families affected by pediatric neuromuscular diseases - experiences from Switzerland.

Receiving the diagnosis of a severe disease may present a traumatic event for patients and their families. To cope with the related challenges, digital interventions can be combined with traditional psychological support to help meet respective needs. We aimed to 1) discuss the most common consequences and challenges for resilience in Neuro Muscular Disease patients and family members and 2) elicit practical needs, concerns, and opportunities for digital platform use. We draw from findings of a transdisciplinary workshop and conference with participants ranging from the fields of clinical practice to patient representatives. Reported consequences of the severe diseases were related to psychosocial challenges, living in the nexus between physical development and disease progression, social exclusion, care-related challenges, structural and financial challenges, and non-inclusive urban design. Practical needs and concerns regarding digital platform use included social and professional support through these platforms, credibility and trust in online information, and concerns about privacy and informed consent. Furthermore, the need for safe, reliable, and expert-guided information on digital platforms and psychosocial and relationship-based digital interventions was expressed. There is a need to focus on a family-centered approach in digital health and social care and a further need in researching the suitability of digital platforms to promote resilience in the affected population. Our results can also inform city councils regarding investments in inclusive urban design allowing for disability affected groups to enjoy a better quality of life.

Neurodevelopmental and functional outcome in hypoplastic left heart syndrome after Hybrid procedure as stage I.

Background: Patients with hypoplastic left heart syndrome (HLHS) undergoing staged palliation until Fontan procedure are at risk for impaired neurodevelopmental (ND) outcome. The Hybrid procedure with bilateral pulmonary artery banding, ductal stenting, and balloon atrioseptostomy may offer a less invasive stage I procedure compared to the Norwood stage I procedure avoiding early neonatal cardiopulmonary bypass (CPB) surgery. Despite altered fetal cerebral hemodynamics, the type of stage I procedure may be a covariate influencing ND outcome and functional outcome may also be altered due to postponing neonatal CPB surgery. Within this review, we analyzed ND outcome as well as functional outcome after Hybrid procedure as stage I procedure. Methods: The review analyzed original publications (OPs) published before March 15, 2022, identified by Cochrane, EMBASE, OVID, Scopus, and Web of science. An OP was included if short-to-long-term neurodevelopment outcome, brain development, somatic, and cardiac outcome in patients for HLHS and variants treated by Hybrid procedure were analyzed. In addition to database searches, we reviewed all references of the analyzed OP to obtain a comprehensive list of available studies. The author, year of publication, demographic characteristics of study population, study design (prospective or retrospective), study assessment, and main findings were summarized. Results: Twenty-one OPs were included with data of patients with ND outcome and functional cardiac outcome. Overall, there is an impaired mid-term ND outcome in patients with Hybrid procedure as stage I for HLHS. Only slight differences between stage I procedures (Hybrid vs. Norwood) in two comparing studies have been determined affecting right ventricular remodeling, short- and mid-term ND outcome, reduced brain growth until two years of age, sufficient quality of life, and altered hemodynamics influencing brain volumes and cerebral perfusion pattern. Conclusions: Despite some minor differences regarding the mid-term follow-up in patients with HLHS comparing Hybrid vs. Norwood procedure, its impact on ND outcome seems rather low. This may be explained by the large number of covariates as well as the small study populations and the different selection criteria for patients undergoing Hybrid or Norwood procedure as stage I.

Favourable Short- to Mid-Term Outcome after PDA-Stenting in Duct-Dependent Pulmonary Circulation.

BACKGROUND: Stenting of patent ductus arteriosus (PDA) is a minimally invasive catheter-based temporary palliative procedure that is an alternative to a surgical shunt in neonates with duct-dependent pulmonary perfusion. METHODS: An observational, single-centre, cross-sectional study of patients with duct-dependent pulmonary perfusion undergoing PDA-stenting as a stage I procedure and an analysis of short- to mid-term follow-up until a subsequent surgical procedure (stage II), with a focus on the interstage course. RESULTS: Twenty-six patients were treated with PDA-stenting at a median (IQR) age of 7 (4-10) days; 10/26 patients (38.5%) (6/10 single pulmonary perfusion) were intended for later univentricular palliation, 16/26 patients (61.5%) (13/16 single pulmonary perfusion) for biventricular repair. PDA diameter was 2.7 (1.8-3.2) mm, stent diameter 3.5 (3.5-4.0) mm. Immediate procedural success was 88.5%. The procedure was aborted, switching to immediate surgery after stent embolisation, malposition or pulmonary coarctation in three patients (each n = 1). During mid-term follow-up, one patient needed an additional surgical shunt due to severe cyanosis, while five patients underwent successful catheter re-intervention 27 (17-30) days after PDA-stenting due to pulmonary hypo- (n = 4) or hyperperfusion (n = 1). Interstage mortality was 8.6% (2/23), both in-hospital and non-procedure-related. LPA grew significantly (p = 0.06) between PDA-stenting and last follow-up prior to subsequent surgical procedure (p = 0.06). RPA Z-scores remained similar (p = 0.22). The subsequent surgical procedure was performed at a median age of 106 (76.5-125) days. CONCLUSIONS: PDA-stenting is a feasible, safe treatment option, with the need for interdisciplinary decision-making beforehand and surgical backup afterwards. It allows adequate body and pulmonary vessel growth for subsequent surgical procedures. Factors determining the individual patient's course should be identified in larger prospective studies.

ORCHID (Outcome Registry for CHIldren with severe congenital heart Disease) a Swiss, nationwide, prospective, population-based, neurodevelopmental paediatric patient registry: framework, regulations and implementation.

INTRODUCTION: Congenital heart disease (CHD) is the most frequent birth defect. As survival has significantly improved, attention has turned to neurodevelopmental outcomes of children undergoing heart surgery in early infancy. Since multiple risk factors contribute to neurodevelopmental alterations, a nationwide registry collecting data on medical characteristics, interventions, clinical course and neurodevelopment until school-age is needed to improve the quality of management, identify risk- and protective factors affecting neurodevelopment, and facilitate multicentre trials. METHODS AND ANALYSIS: The Swiss Outcome Registry for CHIldren with severe congenital heart Disease (ORCHID) is a nationwide, prospective, population-based patient registry developed (1) to collect baseline characteristics and clinical data of CHD patients operated with bypass-surgery or hybrid procedures in the first 6 weeks of life in Switzerland, (2) to monitor long-term neurodevelopment, and (3) to relate clinical characteristics and neurodevelopment to identify risk and protective factors in these children. This registry started data collection relating to pregnancy, birth, preoperative course, catheter-based and surgical treatment, postoperative course and reinterventions in 2019. The primary outcome includes standardised neurodevelopmental assessments at 9 to 12 months, 18 to 24 months and 5.5 to 6 years. We expect to include 80 to 100 children per year. Correlation and regression analyses will be used to investigate risk- and protective factors influencing neurodevelopment. ETHICS AND DISSEMINATION OF RESULTS: Swiss ORCHID received support by the Accentus Charitable Foundation, the Anna Mueller Grocholoski Stiftung, the Swiss Society of Paediatric Cardiology, the Verein Kinderherzforschung, and the Corelina - Stiftung für das Kinderherz, and was approved by the cantonal ethics committees. Findings will be presented at national and international scientific meetings, and published in peer-reviewed journals. Results will also be shared with patient organizations, primary health care providers, and public health stakeholders to ensure a widespread dissemination of the results.

Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy.

X-linked infantile spinal muscular atrophy (XL-SMA) is an X-linked disorder presenting with the clinical features hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and infantile death. To identify the XL-SMA disease gene, we performed large-scale mutation analysis in genes located between markers DXS8080 and DXS7132 (Xp11.3-Xq11.1). This resulted in detection of three rare novel variants in exon 15 of UBE1 that segregate with disease: two missense mutations (c.1617 G-->T, p.Met539Ile; c.1639 A-->G, p.Ser547Gly) present each in one XL-SMA family, and one synonymous C-->T substitution (c.1731 C-->T, p.Asn577Asn) identified in another three unrelated families. Absence of the missense mutations was demonstrated for 3550 and absence of the synonymous mutation was shown in 7914 control X chromosomes; therefore, these results yielded statistical significant evidence for the association of the synonymous substitution and the two missense mutations with XL-SMA (p = 2.416 x 10(-10), p = 0.001815). We also demonstrated that the synonymous C-->T substitution leads to significant reduction of UBE1 expression and alters the methylation pattern of exon 15, implying a plausible role of this DNA element in developmental UBE1 expression in humans. Our observations indicate first that XL-SMA is part of a growing list of neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway and second that synonymous C-->T transitions might have the potential to affect gene expression.

Structural brain lesions in adolescents with congenital heart disease.

OBJECTIVES: To assess long-term neurodevelopmental outcome of adolescents with congenital heart disease after open-heart surgery and to evaluate whether deficits are associated with cerebral injury detectable on magnetic resonance imaging (MRI). STUDY DESIGN: We conducted a cohort study with longitudinal follow-up of 53 adolescents (mean age, 13.7 years; range, 11.4 to 16.9 years) who had undergone open-heart surgery with full-flow cardiopulmonary bypass during childhood and compared them with 41 age-matched controls. Assessment included conventional MRI and neurodevelopmental testing. RESULTS: MRI abnormalities were detected in 11 of the 53 patients (21%), comprising predominately white matter abnormalities and volume loss. Neurodevelopmental outcome was impaired in several domains, including neuromotor, intellectual, and executive functions, as well as visuomotor perception and integration. Adolescents with cerebral abnormalities had greater impairment in most neurodevelopmental domains compared with those without cerebral abnormalities. CONCLUSIONS: Cerebral abnormalities can be detected in a significant proportion of adolescents with corrected congenital heart disease. These abnormalities are found predominately in the white matter and are apparently of hypoxic-ischemic origin, most likely acquired during the neonatal period.

Microstructural alterations of the corticospinal tract are associated with poor motor function in patients with severe congenital heart disease.

Congenital heart disease (CHD) patients are at risk for neurodevelopmental impairments, including altered motor function. However, little is known about the neuroanatomical correlates of persistent motor deficits in CHD. Thus, we examined the link between corticospinal tract (CST) microstructure and motor function in adolescent and adult CHD patients compared to healthy controls. This study investigated 89 CHD patients (N(adolescents) = 47, N(adults) = 42, mean age = 19.9 years) and 97 age-matched healthy controls (N(adolescents) = 44, N(adults) = 53, mean age = 20.6 years). Diffusion tensor imaging was conducted and fractional anisotropy (FA) of the left and right CST was extracted for each participant. Fine (pegboard) and pure motor (repeated finger, hand and foot movements) performance was evaluated with a standardized test battery. FA and motor performance were correlated and the effect of CHD complexity was tested using multivariate linear regression. Clinically relevant motor impairments (>2SD below normative mean) were evident in 24% of patients and 9% of controls. On average, motor performance was lower in CHD patients compared to controls, particularly in those with more complex CHD (fine motor: p = 0.023; pure motor: p < 0.001). FA CST was lower in patients compared to controls, particularly in those with more complex CHD (left: p < 0.001, right: p = 0.003). There was a significant interaction between CHD complexity and FA CST (left: p = 0.025, right: p = 0.025), indicating that FA correlates significantly with pure motor in patients with severe CHD, while there is only a weak association in moderate CHD and no association in patients with simple CHD and controls. Microstructure of the CST is altered in CHD patients, and is associated with pure motor impairments in patients with severe CHD. This indicates that persistent motor impairments may arise from atypical development of the primary motor pathway in the presence of a complex CHD. Early interventions promoting brain maturation in infancy may prevent persisting impairments across the lifetime.