Interstitial lung disease and pancreatic exocrine insufficiency in CADDS: Phenotypic expansion and literature review.

Contiguous ABCD1/ DXS1357E deletion syndrome (CADDS) is a rare deletion syndrome involving two contiguous genes on Xq28, ABCD1 and BCAP31 (formerly known as DXS1357E). Only nine individuals with this diagnosis have been reported in the medical literature to date. Intragenic loss-of-function variants in BCAP31 cause the deafness, dystonia, and cerebral hypomyelination syndrome (DDCH). Isolated pathogenic intragenic variants in ABCD1 are associated with the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), a single transporter deficiency, which in its more severe cerebral form is characterised by childhood-onset neurodegeneration and high levels of very-long-chain fatty acids (VLCFA). While increased VLCFA levels also feature in CADDS, the few patients described to date all presented as neonates with a severe phenotype. Here we report a tenth individual with CADDS, a male infant with dysmorphic facial features who was diagnosed through ultra-rapid whole genome sequencing (WGS) in the setting of persistent cholestatic liver disease, sensorineural hearing loss, hypotonia and growth failure and developmental delay. Biochemical studies showed elevated VLCFA and mildly reduced plasmalogens. He died at 7 months having developed pancreatic exocrine deficiency and interstitial lung disease, two features we propose to be possible extensions to the CADDS phenotype. We also review the genetic, phenotypic, and biochemical features in previously reported individuals with CADDS.

Brain magnetic resonance imaging is a predictor of bimanual performance and executive function in children with unilateral cerebral palsy.

AIM: To examine the association between brain magnetic resonance imaging (MRI) characteristics and executive function and bimanual performance in children with unilateral cerebral palsy (CP). METHOD: Clinical MRI brain scans were classified as: (1) predominant pathological pattern (normal, white matter injury [WMI]; grey matter injury; focal vascular insults [FVI]; malformations; or miscellaneous); and (2) focal lesions (frontal, basal ganglia, and/or thalamus). Assessments included: (1) bimanual performance; (2) unimanual dexterity; and (3) executive function tasks (information processing, attention control, cognitive flexibility, and goal setting) and behavioural ratings (parent). RESULTS: From 131 recruited children, 60 were ineligible for analysis, leaving 71 children (47 males, 24 females) in the final sample (mean age 9y [SD 2y], 6y-12y 8mo). Brain MRIs were WMI (69%) and FVI (31%); and frontal (59%), thalamic (45%), basal ganglia (37%), and basal ganglia plus thalamic (21%). Bimanual performance was lower in FVI versus WMI (p<0.003), and with frontal (p=0.36), basal ganglia (p=0.032), and thalamic/basal ganglia lesions (p=0.013). Other than information processing, executive function tasks were not associated with predominant pattern. Frontal lesions predicted attention control (p=0.049) and cognitive flexibility (p=0.009) but not goal setting, information processing, or behavioural ratings. INTERPRETATION: Clinical brain MRI predicts cognitive and motor outcomes when focal lesions and predominate lesion patterns are considered. What this paper adds Early brain magnetic resonance imaging (MRI) predicts bimanual performance and cognitive outcomes. Brain MRI may identify children requiring targeted interventions. Basal ganglia with/without thalamic lesions predicted bimanual performance. Frontal lesions were associated with attention control and cognitive flexibility. Brain MRI predominant patterns predicted motor, not cognitive outcomes, other than information processing.

La resonancia magnética cerebral es un predictor del rendimiento bimanual y la función ejecutiva en niños con parálisis cerebral unilateral OBJETIVO: Examinar la asociación entre las características de la resonancia magnética cerebral (RMN) y la función ejecutiva y el rendimiento bimanual en niños con parálisis cerebral unilateral (PC). MÉTODO: Los escáneres cerebrales de resonancia magnética clínica se clasificaron como: (1) patrón patológico predominante (normal, lesión de la sustancia blanca [WMI]; lesión de la materia gris; lesiones vasculares focales [FVI]; malformaciones; o varios); y (2) lesiones focales (ganglios frontales, basales y / o tálamo). Las evaluaciones incluyeron: (1) desempeño bimanual; (2) destreza unimanual; y (3) tareas de funciones ejecutivas (procesamiento de información, control de atención, flexibilidad cognitiva y fijación de objetivos) y calificaciones de comportamiento (padres). RESULTADOS: De 131 niños reclutados, 60 no fueron elegibles para el análisis, dejando 71 niños (47 varones, 24 mujeres) en la muestra final (edad media 9 años [DE 2 años], 6 años - 12 años 8 meses). Las RMN cerebrales fueron WMI (69%) y FVI (31%); y frontal (59%), talámico (45%), ganglios basales (37%) y ganglios basales más talámico (21%). El rendimiento bimanual fue menor en FVI versus WMI (p <0,003), y con lesiones frontales (p = 0,36), ganglios basales (p = 0,032) y talámicas / ganglios basales (p = 0,013). Aparte del procesamiento de la información, las tareas de la función ejecutiva no se asociaron con el patrón predominante. Las lesiones frontales predijeron el control de la atención (p = 0,049) y la flexibilidad cognitiva (p = 0,009) pero no el establecimiento de objetivos, el procesamiento de la información o las clasificaciones de comportamiento. INTERPRETACIÓN: La resonancia magnética cerebral clínica predice los resultados cognitivos y motores cuando se consideran las lesiones focales y los patrones de lesiones predominantes.

Imagem por ressonância magnética do cérebro como preditora do desempenho bimanual e função executiva de crianças com paralisia cerebral unilateral OBJETIVO: Examinar a associação entre as características do exame de imagem por ressonância magnética (IRM) e a função executiva e desempenho bimanual em crianças com paralisia cerebral (PC) unilateral. MÉTODO: Escaneamentos clínicos de IRM cerebrais foram classificados como: 1) padrão patológico predominante (normal, lesão da substância branca [LSB]; lesão da substância cinzenta; insultos vasculares focais [IVF]; malformações; ou outro); e (2) lesões focais (frontal, gânglios basais, e/ou tálamo). As avaliações incluíram: (1) desempenho bimanual; (2) destreza unimanual; e (3) tarefas de função executiva (processamento de informações, controle da atenção, flexibilidade cognitiva, e estabelecimento de metas) e pontuações comportamentais (pais). RESULTADOS: De 131 crianças recrutadas, 60 eram inelegíveis para análise, restando 71 crianças (47 do sexo masculino, 24 do sexo feminino) na amostra final (média de idade 9a [DP 2a], 6a-12a 8m). IRMs cerebrais eram do tipo LSB (69%) e IVFs (31%); e frontais (59%), talâmicas (45%), de gânglios da base (37%), e de gânglios da base mais talâmicas (21%). O desempenho bimanual foi menor em IVF versus LSB (p<0,003), e com lesões frontais (p=0,36), gânglios da base (p=0,032), e talâmicas/gânglios da base (p=0,013). Com exceção do processamento de informações, as tarefas da função executiva não foram associadas com o padrão predominante. Lesões frontais foram preditivas do controle da atenção (p=0,049) e flexibilidade cognitiva (p=,.009) mas não do estabelecimento de metas, processamento de informações, e pontuações comportamentais. INTERPRETAÇÃO: A IRM cerebral clínica prediz resultados cognitivos e motores quando lesões focais e padrões predominantes de lesão são considerados.

Bronchiolitis at a specialist paediatric centre: The electronic medical record helps to evaluate low-value care.

AIM: Low-value care (LVC) is common. We aimed, using infants presenting to a major tertiary paediatric hospital with bronchiolitis between April 2016 and July 2018, to: (i) assess rates of chest X-ray (CXR) and medication use; (ii) identify associated factors; and (iii) measure the harm of not performing these practices. METHODS: We extracted data from the electronic medical record for all children aged 1-12 months given a diagnosis of bronchiolitis in the emergency department. Factors potentially associated with LVC practices were extracted, including patient demographics, ordering physician characteristics, order indication, medications prescribed and admission ward. To assess for harm, a radiologist, blinded to CXR indication, reviewed all CXRs ordered over the winter of 2017 for infants with bronchiolitis. RESULTS: A CXR was ordered for 439 (11.2%) infants, most commonly to rule out consolidation and collapse (65%). CXRs were more likely to be ordered for admitted infants (40.9% admitted to the general medical ward), and 62% were ordered by emergency department staff. Salbutamol was prescribed for 9.3% (n = 199). Amongst those who had a CXR, 28% were prescribed an antibiotic compared to 2.1% for those who did not. In an audit of 98 CXRs ordered over the winter of 2017, there were no CXR findings that meaningfully affected patient outcomes. CONCLUSION: Using electronic medical record data, we found that CXR and medication use in bronchiolitis were higher than expected given our hospital guideline advice. Future research needs to understand why and develop interventions to reduce LVC.

Cognition and bimanual performance in children with unilateral cerebral palsy: protocol for a multicentre, cross-sectional study.

BACKGROUND: Motor outcomes of children with unilateral cerebral palsy are clearly documented and well understood, yet few studies describe the cognitive functioning in this population, and the associations between the two is poorly understood. Using two hands together in daily life involves complex motor and cognitive processes. Impairment in either domain may contribute to difficulties with bimanual performance. Research is yet to derive whether, and how, cognition affects a child's ability to use their two hands to perform bimanual tasks. METHODS/DESIGN: This study will use a prospective, cross-sectional multi-centre observational design. Children (aged 6-12 years) with unilateral cerebral palsy will be recruited from one of five Australian treatment centres. We will examine associations between cognition, bimanual performance and brain neuropathology (lesion type and severity) in a sample of 131 children. The primary outcomes are: Motor - the Assisting Hand Assessment; Cognitive - Executive Function; and Brain - lesion location on structural MRI. Secondary data collected will include: Motor - Box and Blocks, ABILHAND- Kids, Sword Test; Cognitive - standard neuropsychological measures of intelligence. We will use generalized linear modelling and structural equation modelling techniques to investigate relationships between bimanual performance, executive function and brain lesion location. DISCUSSION: This large multi-centre study will examine how cognition affects bimanual performance in children with unilateral cerebral palsy. First, it is anticipated that distinct relationships between bimanual performance and cognition (executive function) will be identified. Second, it is anticipated that interrelationships between bimanual performance and cognition will be associated with common underlying neuropathology. Findings have the potential to improve the specificity of existing upper limb interventions by providing more targeted treatments and influence the development of novel methods to improve both cognitive and motor outcomes in children with unilateral cerebral palsy. TRIAL REGISTRATION: ACTRN12614000631606 ; Date of retrospective registration 29/05/2014.

Relationship between characteristics on magnetic resonance imaging and motor outcomes in children with cerebral palsy and white matter injury.

In a population cohort of children with white matter injury (WMI) and cerebral palsy (CP), we aimed to describe the magnetic resonance imaging (MRI) characteristics, identify key structure-function relationships, and classify the severity of WMI in a clinically relevant way. Stratified on MRI laterality/symmetry, variables indicating the extent and location of cerebral abnormalities for 272 children with CP and WMI on chronic-phase MRI were related to gross motor function and motor topography using univariable and multivariable approaches. We found that symmetrical involvement, severe WM loss in the hemispheres and corpus callosum, and cerebellar involvement were the strongest predictors of poor gross motor function, but the final model explained only a small proportion of the variability. Bilateral, extensive WM loss was more likely to result in quadriplegia, whereas volume loss in the posterior-mid WM more frequently resulted in diplegia. The extent and location of MRI abnormalities differed according to laterality/symmetry; asymmetry was associated with less extensive hemispheric involvement than symmetrical WMI, and unilateral lesions were more focal and located more anteriorly. In summary, laterality/symmetry of WMI, possibly reflecting different pathogenic mechanisms, together with extent of WM loss and cerebellar abnormality predicted gross motor function in CP, but to a limited extent.