Nicolas Krawiecki

Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1).

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.

Subacute necrotizing encephalopathy Oxidative phosphorylation defects and the ATPase 6 point mutation

Subacute necrotizing encephalopathy (SNE) or Leighs disease is associated with various defects in oxidative phosphorylation (OXPHOS). However, the relationships between these OXPHOS defects and nuclear DNA or mitochondrial DNA (mtDNA) mutations is still unclear. We evaluated three SNE pedigrees (two singleton cases and a pedigree) biochemically for OXPHOS abnormalities and genetically for four mtDNA point mutations. There was a complex I defect in ail three pedigrees that was associated with a complex III defect in two individuals. An mtDNA mutation in the ATPase, subunit 6 gene (np 8993) was present in one SNE pedigree. This mutation was maternally inherited, heteroplasmic, produced marked clinical and biochemical heterogeneity between pedigree members, and varied along the maternai lineage at levels ranging from 0% to >95% of the total mtDNAs. These mtDNA mutations were not present in the other two pedigrees. These observations emphasize the importance of screening for OXPHOS defects and mtDNA mutations in SNE cases.

Aggregation of Actin and Cofilin in Identical Twins with Juvenile-Onset Dystonia

The neuropathology of the primary dystonias is not well understood. We examined brains from identical twins with DYT1‐negative, dopa‐unresponsive dystonia. The twins exhibited mild developmental delays until age 12 years when they began developing rapidly progressive generalized dystonia. Genetic, metabolic, and imaging studies ruled out known causes of dystonia. Cognition was subnormal but stable until the last few years. Death occurred at ages 21 and 22 years. The brains were macroscopically unremarkable. Microscopic examination showed unusual glial fibrillary acidic protein–immunoreactive astrocytes in multiple regions and iron accumulation in pallidal and nigral neurons. However, the most striking findings were 1) eosinophilic, rod‐like cytoplasmic inclusions in neocortical and thalamic neurons that were actin depolymerizing factor/cofilin‐immunoreactive but only rarely actin‐positive; and 2) abundant eosinophilic spherical structures in the striatum that were strongly actin‐ and actin depolymerizing factor/cofilin‐positive. Electron microscopy suggested that these structures represent degenerating neurons and processes; the accumulating filaments had the same dimensions as actin microfilaments. To our knowledge, aggregation of actin has not been reported previously as the predominant feature in any neurodegenerative disease. Thus, our findings may shed light on a novel neuropathological change associated with dystonia that may represent a new degenerative mechanism involving actin, a ubiquitous constituent of the cytoskeletal system.

Moral Distress in Pediatric Healthcare Providers

Pediatric providers across professions and clinical settings experience moral distress. Higher moral distress correlates with intent to leave for all professionals. Physicians as professional group had the highest moral distress. Intensive care nurses had the highest moral distress for nurses. While all providers describe distressing scenarios as disturbing, physicians report situations as occurring more frequently. The most distressing situations include requests for aggressive treatments not in childs best interest, poor team communication and lack of provider continuity. Understanding moral distress as experienced by all pediatric providers is needed to create interventions with a goal of reducing provider turnover.

Neuropsychological, Academic, and Adaptive Functioning in Children Who Survive in-Hospital Cardiac Arrest and Resuscitation

Children suffering cardiac arrest (CA) are not uncommon in certain pediatric populations. Due to the increasing survival rates of child CA patients, there is a growing interest in, and concern for, their long-term intellectual, academic, emotional, and adaptive functioning. This article describes the possible neurologic sequelae of CA in children and presents standardized assessment results on 25 children, 2 to 15 years of age, who survived a CA while in the hospital. A majority of these children exhibited low-average to deficient levels of performance on neuropsychologic, achievement, and adaptive behavior measures. Duration of cardiac arrest and a medical risk score were significantly correlated with decreased functioning in child CA patients. Children who suffer a cardiac arrest are at high risk for academic struggles, and many may need special education services.

Quantifying Pediatric Neuro-oncology Risk Factors: Development of the Neurological Predictor Scale

Pediatric neuro-oncology researchers face methodological challenges associated with quantifying the influence of tumor and treatment-related risk factors on child outcomes. The Neurological Predictor Scale was developed to serve as a cumulative index of a childs exposure to risk factors. The clinical utility of the Neurological Predictor Scale was explored in a sample of 25 children with heterogeneous brain tumors. Consistent with expectation, a series of regression analyses demonstrated that the Neurological Predictor Scale significantly predicted composite intellectual functioning (r 2 = 0.21, p < .05), short-term memory (r 2 = 0.16, p = .05), and abstract visual reasoning abilities (r 2 = 0.28, p < .05). With the exception of chemotherapy, the Neurological Predictor Scale accounted for a significant amount of the variance in child intellectual functioning above and beyond individually examined variables. The Neurological Predictor Scale can be used to quickly quantify the cumulative risk factors associated with pediatric brain tumor diagnoses.

Risk Factors Associated with Long-Term Social and Behavioral Problems Among Children with Brain Tumors

Abstract This study investigated long-term social and behavioral outcomes in 40 children with brain tumors. Demographic, medical, cognitive, and psychosocial predictors at short-term follow-up at Time 1 (one to two years postdiagnosis) were used to predict long-term social and behavioral outcomes three to four years after diagnosis (Time 2). Below-average social competence and average overall behavioral ratings were reported at Time 2. Multiple medical treatments and lower social competence scores at Time 1 were significant predictors of long-term difficulties concerning social competence, whereas lower socioeconomic status and higher total scores regarding behavior problems at Time 1 were the best predictors of long-term behavioral problems. The results of the study have implications for mental health screening and intervention during the early years after diagnosis.

Oxidative phosphorylation defect associated with primary adrenal insufficiency

An 18-month-old girl with an oxidative phosphorylation defect had neonatal onset of chronic lactic acidosis, lipid storage myopathy, bilateral cataracts, and primary adrenal insufficiency. Chronic lactic acidosis responded to treatment with dichloroacetate. Sequential muscle biopsies demonstrated resolution of the lipid storage myopathy associated with the return to normal muscle free carnitine levels. This case demonstrates a new clinical phenotype associated with a defect in oxidative phosphorylation and the need to consider mitochondrial disorders in the differential diagnosis of primary adrenal insufficiency in childhood.

Cognitive Predictors of Adaptive Functioning Vary According to Pediatric Brain Tumor Location

This archival study sought to determine if the relationship between cognitive and adaptive abilities varied according to brain tumor location. Participants were 36 children treated for brain tumors. The best cognitive predictors of adaptive functioning were hypothesized to be attention span within the cerebellar group and verbal memory within the third ventricle group. Auditory attention span significantly predicted communication skills for the cerebellar group, whereas verbal memory significantly predicted socialization skills for the third ventricle group. These findings suggest that cognitive predictors vary according to tumor location, and highlight the need for more research examining adaptive functioning and its correlates.

Social problem solving in children with acquired brain injuries.

Objectives: To assess the performance of children with acquired brain injuries (ABIs) on a measure of social problem solving and to examine the relationships between participant characteristics and performance on the Social Knowledge Interview (SKI) and between parent-reported child behavior and performance on the SKI. Design: Between-group comparisons using correlational analyses, matched pairs t-tests, and analysis of covariance (ANCOVA). Participants: Thirty-one children 6–12 years old with ABI and 31 control participants, matched on age and sex. Main outcome measure: The SKI, a measure of social problem-solving skills. Results: Using matched pairs t-tests and ANCOVA, groups were compared on several SKI measures, including the number of unique responses generated for each problem scenario, the quality of those responses, and the ability to select the best response from a set of alternatives. When equated for socioeconomic status (SES), ABI and control participants performed similarly on the SKI; however, a trend for children with ABI to generate more assertive responses was observed. Performance on the SKI was positively correlated with IQ and related to parent-reported adaptive behavior. In children with ABI, performance was also related to primary lesion location and treatment regimen. Conclusions: Children with ABI are as capable of judging the appropriateness of behavior and generating response options on an analog measure of social problem solving as were their typically developing peers. However, those individual children with ABI who are more likely to have social problems may be identified by the qualitative aspects of their responses on analog tasks. These findings have implications for the identification of children with social skills deficits following ABI and for the development ofeffective rehabilitation strategies.