Joel Victor Fluss

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.

The Influence of Socioeconomic Status on Children’s Brain Structure

Children’s cognitive abilities and school achievements are deeply affected by parental socioeconomic status (SES). Numerous studies have reported lower cognitive performance in relation to unfavorable environments, but little is known about the effects of SES on the child’s neural structures. Here, we systematically explore the association between SES and brain anatomy through MRI in a group of 23 healthy 10-year-old children with a wide range of parental SES. We confirm behaviorally that language is one of the cognitive domains most affected by SES. Furthermore, we observe widespread modifications in children’s brain structure. A lower SES is associated with smaller volumes of gray matter in bilateral hippocampi, middle temporal gyri, left fusiform and right inferior occipito-temporal gyri, according to both volume- and surface-based morphometry. Moreover, we identify local gyrification effects in anterior frontal regions, supportive of a potential developmental lag in lower SES children. In contrast, we found no significant association between SES and white matter architecture. These findings point to the potential neural mediators of the link between unfavourable environmental conditions and cognitive skills.

Cortical networks for vision and language in dyslexic and normal children of variable socio-economic status

In dyslexia, anomalous activations have been described in both left temporo-parietal language cortices and in left ventral visual occipito-temporal cortex. However, the reproducibility, task-dependency, and presence of these brain anomalies in childhood rather than adulthood remain debated. We probed the large-scale organization of ventral visual and spoken language areas in dyslexic children using minimal target-detection tasks that were performed equally well by all groups. In 23 normal and 23 dyslexic 10-year-old children from two different socio-economic status (SES) backgrounds, we compared fMRI activity to visually presented houses, faces, and written strings, and to spoken sentences in the native or in a foreign language. Our results confirm a disorganization of both ventral visual and spoken language areas in dyslexic children. Visually, dyslexic children showed a normal lateral-to-medial mosaic of preferences, as well as normal responses to houses and checkerboards, but a reduced activation to words in the visual word form area (VWFA) and to faces in the right fusiform face area (FFA). Auditorily, dyslexic children exhibited reduced responses to speech in posterior temporal cortex, left insula and supplementary motor area, as well as reduced responses to maternal language in subparts of the planum temporale, left basal language area and VWFA. By correlating these two findings, we identify spoken-language predictors of VWFA activation to written words, which differ for dyslexic and normal readers. Similarities in fMRI deficits in both SES groups emphasize the existence of a core set of brain activation anomalies in dyslexia, regardless of culture, language and SES, without however resolving whether these anomalies are a cause or a consequence of impaired reading.

Acute ischemic stroke in children versus young adults.

The aim of this study was to compare children and young adults with acute ischemic stroke (AIS) in 2 large registries.

Incidence and Outcomes of Symptomatic Neonatal Arterial Ischemic Stroke

BACKGROUND AND OBJECTIVES: Neonatal arterial ischemic stroke (NAIS) is associated with considerable lifetime burdens such as cerebral palsy, epilepsy, and cognitive impairment. Prospective epidemiologic studies that include outcome assessments are scarce. This study aimed to provide information on the epidemiology, clinical manifestations, infarct characteristics, associated clinical variables, treatment strategies, and outcomes of NAIS in a prospective, population-based cohort of Swiss children. METHODS: This prospective study evaluated the epidemiology, clinical manifestations, vascular territories, associated clinical variables, and treatment of all full-term neonates diagnosed with NAIS and born in Switzerland between 2000 and 2010. Follow-up was performed 2 years (mean 23.3 months, SD 4.3 months) after birth. RESULTS: One hundred neonates (67 boys) had a diagnosis of NAIS. The NAIS incidence in Switzerland during this time was 13 (95% confidence interval [CI], 11–17) per 100 000 live births. Seizures were the most common symptom (95%). Eighty-one percent had unilateral (80% left-sided) and 19% had bilateral lesions. Risk factors included maternal risk conditions (32%), birth complications (68%), and neonatal comorbidities (54%). Antithrombotic and antiplatelet therapy use was low (17%). No serious side effects were reported. Two years after birth, 39% were diagnosed with cerebral palsy and 31% had delayed mental performance. CONCLUSIONS: NAIS in Switzerland shows a similar incidence as other population-based studies. About one-third of patients developed cerebral palsy or showed delayed mental performance 2 years after birth, and children with normal mental performance may still develop deficits later in life.

Poor Reading in French Elementary School: The Interplay of Cognitive, Behavioral, and Socioeconomic Factors

Background: Reading impairment is the major learning disability in childhood. Most previous studies were done on English-speaking populations. Yet, it has been argued that the English writing system exacerbates phonological deficits because of its exceptionally high inconsistency between spelling and sound. Thus, cross-language studies are needed to explore the universal versus language-specific factors underlying reading impairment. The goal of the present research was to study biological, socioeconomic, cognitive, and behavioral factors underlying poor reading in French-speaking second grade children. Methods: A total of 1062 children from 20 different schools in the city of Paris participated in the study. After an initial test phase, children with a suspected impairment in reading acquisition were assessed individually. Subsequently, 100 poor readers and 50 controls were matched for sex, age, school, and neighborhood socioeconomic status (SES). They underwent comprehensive medical, cognitive, and behavioral assessment complemented by individual socioeconomic data. Results: The average prevalence of reading impairment was around 12% in our sample. It was highly influenced by neighborhood SES, varying from 3.3% in high SES to 24.2% in low SES areas. Among the individual SES variables, low maternal education significantly distinguished poor from typical readers. Multiple regression analyses showed that reading outcome was best predicted by phonological awareness skills and attention deficits. Conclusion: The majority of poor readers come from low SES areas. As in the English literature, the most robust predictor for reading impairment is phonological awareness. In addition, behavioral problems, such as attention deficits, seem to aggravate reading deficits for children with weak phonological awareness skills.

Cerebral sinus venous thrombosis in Swiss children

Aim  To describe the characteristics of paediatric cerebral sinus venous thrombosis (CSVT) in Switzerland.

Factors affecting cognitive outcome in early pediatric stroke

Objective: We examined cognitive performance in children after stroke to study the influence of age at stroke, seizures, lesion characteristics, neurologic impairment (NI), and functional outcome on cognitive outcome. Methods: This was a prospectively designed study conducted in 99 children who sustained an arterial ischemic stroke (AIS) between the age of 1 month and 16 years. All children underwent cognitive and neurologic follow-up examination sessions 2 years after the insult. Cognitive development was assessed with age-appropriate instruments. Results: Although mean cognitive performance was in the lower normative range, we found poorer results in subtests measuring visuoconstructive skills, short-term memory, and processing speed. Risk factors for negative cognitive outcome were young age at stroke, seizures, combined lesion location (cortical and subcortical), as well as marked NI. Conclusions: We recommend that all children with a history of AIS undergo regularly scheduled neuropsychological assessment to ensure implementation of appropriate interventions and environmental adjustments as early as possible.

A Functionally Guided Approach to the Morphometry of Occipitotemporal Regions in Developmental Dyslexia: Evidence for Differential Effects in Boys and Girls

Developmental dyslexia is a learning disability that specifically affects reading acquisition. Cortical anomalies and gray matter volume differences in various temporal regions have been reported in dyslexic subjects compared with controls. However, consistency between studies is lacking. In the present experiments, we focused our structural analyses on the ventral occipitotemporal regions, defined by their functional response to visual categories. We applied a subject-by-subject functionally guided approach on a total of 76 participants (31 dyslexic children). Cortical thickness was estimated for each participant around his/her peak of specific functional activation to visual words, faces, or places. Results from two independent datasets showed a reduction in thickness in dyslexic children compared with controls in the region responsive to words, in the left hemisphere. Additionally, a gender-by-diagnosis interaction was observed at the same location, due to differences in girls only. To avoid the potential confound of reading level, we also contrasted dyslexic and control children matched for reading performance, and we observed a similar difference, although in a smaller extent of cortex. The present study thus provides the first account of a focal cortical thickness reduction in dyslexia in the subregion of ventral occipitotemporal cortex specifically responsive to visual words, when age, gender, and reading performance are taken into account.

Long-term outcome after arterial ischemic stroke in children and young adults

Objective: To compare long-term outcome of children and young adults with arterial ischemic stroke (AIS) from 2 large registries. Methods: Prospective cohort study comparing functional and psychosocial long-term outcome (≥2 years after AIS) in patients who had AIS during childhood (1 month–16 years) or young adulthood (16.1–45 years) between January 2000 and December 2008, who consented to follow-up. Data of children were collected prospectively in the Swiss Neuropediatric Stroke Registry, young adults in the Bernese stroke database. Results: Follow-up information was available in 95/116 children and 154/187 young adults. Median follow-up of survivors was 6.9 years (interquartile range 4.7–9.4) and did not differ between the groups (p = 0.122). Long-term functional outcome was similar (p = 0.896): 53 (56%) children and 84 (55%) young adults had a favorable outcome (modified Rankin Scale 0–1). Mortality in children was 14% (13/95) and in young adults 7% (11/154) (p = 0.121) and recurrence rate did not differ (p = 0.759). Overall psychosocial impairment and quality of life did not differ, except for more behavioral problems among children (13% vs 5%, p = 0.040) and more frequent reports of an impact of AIS on everyday life among adults (27% vs 64%, p < 0.001). In a multivariate regression analysis, low Pediatric NIH Stroke Scale/NIH Stroke Scale score was the most important predictor of favorable outcome (p < 0.001). Conclusion: There were no major differences in long-term outcome after AIS in children and young adults for mortality, disability, quality of life, psychological, or social variables.