Deciphering the natural history of SCA7 in children.

BACKGROUND AND PURPOSE: Childhood-onset autosomal dominant cerebellar ataxia type 7 (SCA7) is a severe disease which leads to premature loss of ambulation and death. Early diagnosis of SCA7 is of major importance for genetic counselling and still relies on specific genetic testing, driven by clinical expertise. However, the precise phenotype and natural history of paediatric SCA7 has not yet been fully described. Our aims were to describe the natural history of SCA7 in a large multicentric series of children of all ages, and to find correlates to variables defining this natural history. METHODS: We collected and analysed clinical data from 28 children with proven SCA7. All had clinical manifestations of SCA7 and either a definite number of CAG repeats in ATXN7 or a long expansion > 100 CAG. RESULTS: We identified four clinical presentation patterns related to age at onset. Children of all age groups had cerebellar atrophy and retinal dystrophy. Our data, combined with those in the literature, suggest that definite ranges of CAG repeats determine paediatric SCA7 subtypes. The number of CAG repeats inversely correlated to all variables of the natural history. Age at gait ataxia onset correlated accurately to age at loss of walking ability and to age at death. CONCLUSION: SCA7 in children has four presentation patterns that are roughly correlated to the number of CAG repeats. Our depiction of the natural history of SCA7 in children may help in monitoring the effect of future therapeutic trials.

Pediatric stroke related to Lyme neuroborreliosis: Data from the Swiss NeuroPaediatric Stroke Registry and literature review.

BACKGROUND: Cerebrovascular complications of Lyme neuroborreliosis (LNB) are poorly documented in the paediatric population. METHODS: We performed a retrospective analysis from prospectively registered cases of acute ischemic stroke (AIS) from the Swiss NeuroPaediatric Stroke Registry (SNPSR) from 2000 to 2015. Only cases with serologically confirmed LNB were included. In addition, a literature review on paediatric stroke cases secondary to Lyme neuroborreliosis in the same time frame was performed. RESULTS: 4 children out of 229 children with arterial ischemic childhood stroke and serologically confirmed LNB were identified in the SNPSR giving a global incidence of 1.7%. Median age was 9.9 years. A prior history of tick bites or erythema migrans (EM) was reported in two cases. Clinical presenting signs were suggestive of acute cerebellar/brainstem dysfunction. On imaging, three children demonstrated a stroke in the distribution of the posterior inferior cerebellar artery. The remaining fourth child had a "stroke-like" picture with scattered white matter lesions and a multifocal vasculitis with prominent basilar artery involvement. Lymphocytic pleocytosis as well as intrathecal synthesis of Borrelia burgdorferi antibodies were typical biological features. Acute intravenous third generation cephalosporins proved to be effective with rapid improvement in all patients. No child had recurrent stroke. Data from the literature concerning eight patients gave similar results, with prominent posterior circulation stroke, multifocal vasculitis and abnormal CSF as distinctive features. CONCLUSIONS: Lyme Neuroborreliosis accounts for a small proportion of paediatric stroke even in an endemic country. The strong predilection towards posterior cerebral circulation with clinical occurrence of brainstem signs associated with meningeal symptoms and CSF lymphocytosis are suggestive features that should rapidly point to the diagnosis. This can be confirmed by appropriate serological testing in the serum and CSF. Clinicians must be aware of this rare neurological complication of Lyme disease that demands specific antibiotic treatment.

Congenital Neuronal Ceroid Lipofuscinosis with a Novel CTSD Gene Mutation: A Rare Cause of Neonatal-Onset Neurodegenerative Disorder.

Neuronal ceroid lipofuscinoses represent a heterogeneous group of early onset neurodegenerative disorders that are characterized by progressive cognitive and motor function decline, visual loss, and epilepsy. The age of onset has been historically used for the phenotypic classification of this group of disorders, but their molecular genetic delineation has now enabled a better characterization, demonstrating significant genetic heterogeneity even among individuals with a similar phenotype. The rare Congenital Neuronal Ceroid Lipofuscinosis (CLN10) caused by mutations in the CTSD gene encoding for cathepsin D is associated with a dramatic presentation with onset before or around birth. We report on a female born to consanguineous parents who presented at birth with severe neonatal encephalopathy with massive cerebral and cerebellar shrinking on magnetic resonance imaging. Whole exome sequencing with targeted bioinformatic analysis of a panel of genes associated with prenatal/perinatal onset of neurodegenerative disease was performed and revealed the presence of a novel homozygous in-frame deletion in CTSD. Additional functional studies further confirmed the pathogenic character of this variant and established the diagnosis of CLN10 in the patient.

Perspectives in neonatal and childhood arterial ischemic stroke.

INTRODUCTION: Over the last decade considerable advances have been made in the identification, understanding and management of pediatric arterial ischemic stroke. Such increasing knowledge has also brought new perspectives and interrogations in the current acute and rehabilitative care of these patients. Areas covered: In developed countries, focal cerebral arteriopathy is one of the most common causes of arterial ischemic stroke in childhood and imaging features are well characterized. However, there are ongoing debates regarding its underlying mechanisms, natural evolution and proper management. The implementation of thrombolytic therapy in acute pediatric stroke has been shown to be efficient in anecdotal cases but is still limited by a number of caveats, even in large tertiary centers. Finally, neonatal stroke represents a unique circumstance of possible early intervention before the onset of any neurological disability but this appears meaningful only in a selective group of neonates. Expert commentary: While perinatal stroke, a leading cause of cerebral palsy, appears to be multifactorial, a large number of childhood ischemic stroke are probably essentially triggered by infectious factors leading to vessel wall damage. Current research is aiming at better identifying risk factors in both conditions, and to define optimal acute and preventive therapeutic strategies in order to reduce significant long-term morbidity.

[Current management of post-varicella stroke in children: a literature review]. / Prise en charge diagnostique et thérapeutique actuelle des accidents vasculaires cérébraux post-varicelleux chez l'enfant : revue de la littérature.

Among infectious factors, varicella-zoster virus (VZV) is a leading cause of central nervous system vasculopathy and stroke in childhood. Not only have viral markers been detected in the cerebrospinal fluid of affected patients, but also direct evidence of viral particles in the wall of cerebral arteries has been demonstrated in rare pathological specimens. This certainly reflects a localized infectious process likely associated with variable indirect inflammatory responses. Yet the usefulness in this setting of a lumbar puncture as well as of subsequent targeted antiviral and/or anti-inflammatory therapies is uncertain. Indeed, in the majority of cases, the so-called post-varicella angiopathy has a monophasic evolution with spontaneous resolution or stabilization, explaining diverging diagnostic and treatment approaches. In this paper, we have addressed this problematic area by reviewing 26 published cases from the year 2000 and three unpublished cases. Post-varicella stroke is typically associated with angiopathy most often involving the initial portion of the middle cerebral artery, causing a basal ganglia stroke. It tends to occur in young immunocompetent children. Thrombophilia work-up is in general negative. Lumbar puncture was performed in 17 out of 29 cases. Viral markers were examined in 14 cases, but were positive in only eight cases. Antiviral therapy was administrated in 11 children. In this small retrospective study, the treated children's vasculopathy did not progress more favorably nor was there a better outcome compared with untreated subjects.

[Evolution of competence in reading, spelling and comprehension levels in low socioeconomic environments and impact of cognitive and behavioral factors on outcome in two years]. / Evolution des compétences en lecture, compréhension et orthographe en environnement socioéconomique défavorisé et impact des facteurs cognitifs et comportementaux sur le devenir à deux ans.

BACKGROUND: The prevalence of poor reading skills is particularly high among children from low socioeconomic backgrounds, but no longitudinal studies have been conducted so far in France to determine whether poor reading in a socioeconomically challenged population is persistent and warrants preventive action. DESIGN: One hundred and fifty-four children were divided into three groups according to their reading skills: poor, intermediate and typical readers. They were followed over a period of 2 years. Reading levels, spelling and comprehension were assessed by standardized measurement scales in order to determine reading outcome and predictive variables. RESULTS: The reading skills in each group progressed at similar rates, but the differences between the three groups remained relatively constant over the 2 years. The gap between good and poor readers actually increased for the poorest readers. Spelling scores followed a similar pattern and remained weak. Comprehension scores followed a different pattern. Most of the initially poor readers with low comprehension scores almost caught up and reached the level of the typical readers. The best predictive variables of reading and spelling outcome were phonological awareness, rapid naming and attention deficit. The strongest predictive variables for comprehension were IQ, lexical level and attention. CONCLUSIONS: Our results confirm the relative stability of reading measurement across time in poor readers from low socioeconomic backgrounds. Their behavior are similar to the classic dyslexic population. The predictive variables are different depending on whether reading or spelling or comprehension is considered. These results provide a clear agenda for preventive literacy action in children with low socioeconomic levels (SES): phonological decoding and oral language skills in early grades, and screening and treatment of attention disorders.

De novo duplication of MECP2 in a girl with mental retardation and no obvious dysmorphic features.

Loss-of-function mutations of MECP2 are responsible for Rett syndrome (RTT), an X-linked neurodevelopmental disorder affecting mainly girls. The availability of MECP2 testing has led to the identification of such mutations in girls with atypical RTT features and the recognition of milder forms. Furthermore, duplication of the entire gene has recently been described in boys with mental retardation and recurrent infections. We describe a girl with a heterozygous de novo MECP2 duplication. The patient, at the age of 19, has mental retardation with no autistic features. She is friendly but gets frequently anxious. She has neither dysmorphic features nor malformations. Her motor development was delayed with walking at 20 months. Speech is fluid with good pronunciation but is simple and repetitive. Diagnosis was made after single-strand conformation analysis (SSCA) and multiplex ligation-dependent probe amplification (MLPA) analysis of MECP2. Array comparative genomic hybridization (aCGH) analysis showed a duplication of 29 kb including MECP2 and part of IRAK1. Fluorescent in situ hybridization (FISH) has revealed that the duplicated region is inserted near the telomere of the short arm of chromosome 10. X-chromosome inactivation in leukocyte DNA was not skewed. We conclude that it is likely that this MECP2 duplication is responsible for the mental retardation in this patient. This case broadens the phenotypic spectrum of MECP2 abnormalities with consequent implication in diagnosis and genetic counselling of girls with non-syndromic mental retardation.

[Deficits in reading acquisition in primary school: cognitive, social and behavioral factors studied in a sample of 1062 children]. / Troubles d'acquisition de la lecture en cours élémentaire : facteurs cognitifs, sociaux et comportementaux dans un échantillon de 1062 enfants.

BACKGROUND: Reading impairment is the major learning disability in children. While research on illiteracy has mainly been conducted from a sociological perspective, research on dyslexia has typically been studied from a cognitive-linguistic perspective. Studies that jointly investigate sociological, behavioral and cognitive factors in predicting reading outcome are rare and limited to English-speaking populations. The goal of the present study was to screen second grade children with reading impairment in French urban elementary schools and to pin down the factors that explain the various facets of reading failure and success. METHODS: A total of 1062 children from 20 different schools in the city of Paris participated in the study. Different aspects of reading were assessed individually for children with a suspected impairment in reading acquisition. Subsequently, 131 poor readers and 50 typically developing readers were matched for sex, age, and school. For these children, medical, cognitive, behavioral and individual socioeconomic data were obtained. Group differences were examined and multiple regression analyses were conducted to examine how much variance in reading was explained by the various variables. RESULTS: The prevalence of poor reading skills in grade 2 was highly influenced by neighborhood socioeconomic status (SES) (ranging from 3.3% in high SES to 20.5% in low SES areas). Among the SES variables, employment of the father was a significant predictor of poor reading. Among the cognitive variables, phonological awareness and rapid naming were the most significant factors, much more than verbal or nonverbal intelligence. Among the behavioral variables, attention was an important factor but not externalized symptoms. Multiple regression analyses showed that reading outcome was best predicted by phonological awareness skills and attention deficits. CONCLUSION: The majority of children with reading disability come from low SES areas. As in the English literature, the most robust predictor for reading impairment is phonological awareness, even when SES is taken into account. In addition, attention deficits seemed to aggravate reading impairments for children with weak phonological awareness skills. Successful early prevention should focus on reinforcing phonological awareness, recoding and attention skills.

[Study of causal factors of reading impairment in a sample of 1062 7 to 8-year-old children]. / Etude des facteurs liés aux difficultés d'apprentissage de la lecture. A partir d'un échantillon de 1062 enfants de seconde année d'école élémentaire.

OBJECTIVE: From an original large sample of 1062 7 to 8-year-old children, reading skills were assessed and found to be highly linked with socioeconomic status (SES). The purpose of the present study was to further determine underlying medical, sociocultural, cognitive and behavioural factors explaining the diversity of reading skills and the influence of SES. METHOD: Individual testing among low-SES children identified 100 poor readers, 50 typical readers and 31 children with intermediate reading scores. All 3 groups underwent a thorough assessment, including a medical evaluation, a full cognitive battery, a structured parental interview and behavioural questionnaire. Logistic regression was used to demonstrate the variables predicting reading score outcome. RESULTS: None of the medical factors studied was statistically related to reading scores. Due to the methodology buffering the impact of SES sociocultural variables, such as parental levels of education, parental occupation, as well as familial income were weak, but statistically significant predictors. The strongest variables were phonological abilities and symptoms of attention disorders. In a final regression model, phonological awareness, level of mother's education and attention explained the differences in reading skills. CONCLUSIONS: These results, which are unique in France, are similar to existing data in the literature. They support the need to conceptualize an early screening programme to detect reading difficulties and to promote an intervention based on phonological processing and decoding in low-SES environments.

[Prevalence of reading disabilities in early elementary school: impact of socioeconomic environment on reading development in 3 different educational zones]. / Prévalence des troubles d'apprentissages du langage écrit en début de scolarité : l'impact du milieu socioéconomique dans 3 zones d'éducations distinctes.

OBJECTIVE: Socioeconomic status (SES) has a known influence on academic achievement. Most studies, however, were conducted in English-speaking countries. Because recent cross-linguistic studies suggest that reading English is much harder to learn than reading other languages, an epidemiological study was conducted in French investigating the impact of socioeconomic background on early reading development. DESIGN: One thousand and twenty second-grade children (476 girls and 544 boys) from 20 different schools participated in the study. Approximately 1/3 of the children lived and were schooled in a high SES area, 1/3 in an intermediate SES area, and one final third in a very low SES area. Assessment of reading, writing and mathematical skills was conducted initially in small groups. Children with suspected learning difficulties were further tested individually. Forty-two children of equivalent age who repeated the first grade received similar individual testing. RESULTS: Average reading scores were in accordance with chronological age, without gender differences. Children from low SES schools had academic performances significantly lower than their peers. Boys exhibited superior arithmetic skills than girls. A significant reading delay was observed in 12.7% of children. The prevalence of poor reading was highly correlated with the area of schooling, varying from 3.3% in the high SES area to 24.2% in low SES area. CONCLUSION: The high rate of children from our sample with a significant delay in reading depended on general socioeconomic environment. An understanding of the origin of such differences is mandatory for defining and coordinating preventive actions and appropriate interventions.