Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy.

Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Nav) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Nav channel function.

Neurodevelopmental profiles of children with unilateral cerebral palsy associated with middle cerebral artery and periventricular venous infarctions.

AIM: To compare the neurodevelopment of children with unilateral cerebral palsy (CP) with middle cerebral artery (MCA) and periventricular venous infarctions (PVIs). METHOD: In this cross-sectional study, children with unilateral CP completed a neurological exam, unimanual Quality of Upper Extremity Skills Test, hand usage questionnaires, and IQ test. Neuroimaging was obtained from health records. RESULTS: Two hundred and forty-five participants with unilateral CP had neuroimaging (151 [61.9%] male, ages 2-18y, median=7y 6mo, interquartile range [IQR]=6y 7mo, with 93.6% in Gross Motor Function Classification System level I/II and 78.8% in Manual Ability Classification System level I/II). Ninety-seven (39.6%) had MCA injuries and 106 (43.3%) had periventricular white matter injuries, of which 48 (45.3%) were PVIs. Median Quality of Upper Extremity Skills Test for the MCA group was 49.2 (IQR=55.8), PVI 79.9 (IQR=23.6) (Mann-Whitney U=988.50, p<0.001). Bimanual hand usage (Children's Hand-use Experience Questionnaire) (Mann-Whitney U=425, p<0.001) and light touch (odds ratio=9.12, 95% confidence interval 1.28-400.76, Fisher's exact test p=0.017) were lower in the MCA compared to the PVI group. Full-scale IQ median centile score for the MCA group was 18.0 (IQR=35.5) and 50.0 (IQR=30.0) for the PVI group (Mann-Whitney U=382, p<0.001). INTERPRETATION: Children with unilateral CP and MCA injuries demonstrated lower hand function and usage, decreased light touch, and lower IQs compared to the PVI group. This study aids in defining rehabilitation needs informed by brain injury patterns.

De novo and rare inherited copy-number variations in the hemiplegic form of cerebral palsy.

PurposeHemiplegia is a subtype of cerebral palsy (CP) in which one side of the body is affected. Our earlier study of unselected children with CP demonstrated de novo and clinically relevant rare inherited genomic copy-number variations (CNVs) in 9.6% of participants. Here, we examined the prevalence and types of CNVs specifically in hemiplegic CP.MethodsWe genotyped 97 unrelated probands with hemiplegic CP and their parents. We compared their CNVs to those of 10,851 population controls, in order to identify rare CNVs (<0.1% frequency) that might be relevant to CP. We also sequenced exomes of "CNV-positive" trios.ResultsWe detected de novo CNVs and/or sex chromosome abnormalities in 7/97 (7.2%) of probands, impacting important developmental genes such as GRIK2, LAMA1, DMD, PTPRM, and DIP2C. In 18/97 individuals (18.6%), rare inherited CNVs were found, affecting loci associated with known genomic disorders (17p12, 22q11.21) or involving genes linked to neurodevelopmental disorders.ConclusionWe found an increased rate of de novo CNVs in the hemiplegic CP subtype (7.2%) compared to controls (1%). This result is similar to that for an unselected CP group. Combined with rare inherited CNVs, the genomic data impacts the understanding of the potential etiology of hemiplegic CP in 23/97 (23.7%) of participants.

Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly.

Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype-phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype-phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.

Development of an inventory of goals using the International Classification of Functioning, Disability and Health in a population of non-ambulatory children and adolescents with cerebral palsy treated with botulinum toxin A.

BACKGROUND: In the management of hypertonicity in children with cerebral palsy (CP), goals should be clearly identified in order to evaluate the effectiveness of botulinum toxin A (BoNT-A) treatment, specifically in non-ambulatory children and adolescents, Gross Motor Function Classification System (GMFCS), level IV or V. A retrospective chart review (Mesterman et al., 2013) identified the need for the development of a set of specific and meaningful goals linked to the International Classification of Functioning, Disability and Health (ICF) for future goal setting and evaluation in this population. Our objective is to create an inventory of goals based on the ICF framework that captures the needs and values of families with children with CP. METHODS: This cross-sectional observational study recruited parents of twenty children and youths with CP in GMFCS levels IV or V (mean age 11.2 years, SD 4.3, 13 males) who were assessed for BoNT-A treatment at the Spasticity Management Clinic at McMaster Children's Hospital (Hamilton, ON). A previous inventory of goals was developed by a group of experts at a national botulinum toxin conference held in January 2014 (Montreal, Canada). The inventory of goals was further refined by asking the parents to select goals from the inventory list that they would like their child to accomplish after receiving BoNT-A treatment, and asking healthcare professionals for clarity and phrasing of goals in the inventory list. RESULTS: All parents identified body structure and function goals, with more than 75% of parents selecting reduction in muscle tone and increased range of movements in the upper and lower extremities. More than 50% of parents identified activity goals related to ease of caregiving. Two activity goals and three participation goals were missing from the inventory. Participation goals were identified by less than 5% of parents. CONCLUSION: The inventory may be a helpful tool to facilitate a discussion about goal setting between healthcare professionals and families in the context of BoNT-A treatment. A future study is needed to conduct qualitative interviews to better understand the information that families may require about setting goals during BoNT-A treatment and to evaluate the usefulness of the inventory.

The Quality Function Measure: reliability and discriminant validity of a new measure of quality of gross motor movement in ambulatory children with cerebral palsy.

AIM: Optimizing movement quality is a common rehabilitation goal for children with cerebral palsy (CP). The new Quality Function Measure (QFM)--a revision of the Gross Motor Performance Measure (GMPM)--evaluates five attributes: Alignment, Co-ordination, Dissociated movement, Stability, and Weight-shift, for the Gross Motor Function Measure (GMFM) Stand and Walk/Run/Jump items. This study evaluated the reliability and discriminant validity of the QFM. METHOD: Thirty-three children with CP (17 females, 16 males; mean age 8y 11mo, SD 3y 1mo; Gross Motor Function Classification System [GMFCS] levels I [n=17], II [n=7], III [n=9]) participated in reliability testing. Each did a GMFM Stand/Walk assessment, repeated 2 weeks later. Both GMFM assessments were videotaped. A physiotherapist assessor pair independently scored the QFM from an assigned child's GMFM video. GMFM data from 112 children. That is, (GMFCS I [n=38], II [n=27], III [n=47]) were used for discriminant validity evaluation. RESULTS: QFM mean scores varied from 45.0% (SD 27.2; Stability) to 56.2% (SD 27.5; Alignment). Reliability was excellent across all attributes: intraclass correlation coefficients (ICCs) ≥0.97 (95% confidence intervals [CI] 0.95-0.99), interrater ICCs ≥0.89 (95% CI 0.80-0.98), and test-retest ICCs ≥0.90 (95% CI 0.79-0.99). QFM discriminated qualitative attributes of motor function among GMFCS levels (maximum p<0.05). INTERPRETATION: The QFM is reliable and valid, making it possible to assess how well young people with CP move and what areas of function to target to enhance quality of motor control.

The Pediatric Autism Research Cohort (PARC) Study: protocol for a patient-oriented prospective study examining trajectories of functioning in children with autism.

INTRODUCTION: The developmentally variable nature of autism poses challenges in providing timely services tailored to a child's needs. Despite a recent focus on longitudinal research, priority-setting initiatives with stakeholders highlighted the importance of studying a child's day-to-day functioning and social determinants of health to inform clinical care. To address this, we are conducting a pragmatic multi-site, patient-oriented longitudinal investigation: the Pediatric Autism Research Cohort (PARC) Study. In young children (<7 years of age) newly diagnosed with autism, we will: (1) examine variability in trajectories of adaptive functioning from the point of diagnosis into transition to school; and (2) identify factors associated with trajectories of adaptive functioning. METHODS AND ANALYSIS: We aim to recruit 1300 children under 7 years of age with a recent (within 12 months) diagnosis of autism from seven sites: six in Canada; one in Israel. Participants will be followed prospectively from diagnosis to age 8 years, with assessments at 6-month intervals. Parents/caregivers will complete questionnaires administered via a customized online research portal. Following each assessment timepoint, families will receive a research summary report describing their child's progress on adaptive functioning and related domains. Analysis of the longitudinal data will map trajectories and examine child, family and service characteristics associated with chronogeneity (interindividual and intraindividual heterogeneity over time) and possible trajectory turning points around sensitive periods like the transition to school. ETHICS AND DISSEMINATION: Ethics approvals have been received by all sites. All parents/respondents will provide informed consent when enrolling in the study. Using an integrated knowledge translation approach, where stakeholders are directly engaged in the research process, the PARC Study will identify factors associated with trajectories of functioning in children with autism. Resulting evidence will be shared with government policy makers to inform provincial and national programs. Findings will be disseminated at conferences and published in peer-reviewed journals.

Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy.

We performed whole-genome sequencing (WGS) in 327 children with cerebral palsy (CP) and their biological parents. We classified 37 of 327 (11.3%) children as having pathogenic/likely pathogenic (P/LP) variants and 58 of 327 (17.7%) as having variants of uncertain significance. Multiple classes of P/LP variants included single-nucleotide variants (SNVs)/indels (6.7%), copy number variations (3.4%) and mitochondrial mutations (1.5%). The COL4A1 gene had the most P/LP SNVs. We also analyzed two pediatric control cohorts (n = 203 trios and n = 89 sib-pair families) to provide a baseline for de novo mutation rates and genetic burden analyses, the latter of which demonstrated associations between de novo deleterious variants and genes related to the nervous system. An enrichment analysis revealed previously undescribed plausible candidate CP genes (SMOC1, KDM5B, BCL11A and CYP51A1). A multifactorial CP risk profile and substantial presence of P/LP variants combine to support WGS in the diagnostic work-up across all CP and related phenotypes.

Primary Care Provider and Child Characteristics Associated with Age of Diagnosis of Autism Spectrum Disorder: A Population-Based Cohort Study.

In a cohort of kindergarten children in Ontario, Canada with Autism Spectrum Disorder (ASD) (n = 1522), we tested the association of age at ASD diagnosis and characteristics of (1) the child's primary care provider and, (2) the child using health administrative databases. We tested the association of primary care practice model and time from developmental delay identification to age at ASD diagnosis. Older age of diagnosis was associated with provider foreign training (vs. domestic) (adjusted Hazard Ratio [aHR] 1.17, 95% CI 1.03, 1.33) but not sex, care model, and years of practice. After developmental delay identification, children with paediatricians had longer time to diagnosis than children with providers in care models (aHR 0.68, 95% CI 0.54, 0.86). Findings can be used to inform primary care provider ASD training.

Exploring demographic, medical, and developmental determinants of adaptive behaviour in children with hemiplegic cerebral palsy.

Hemiplegic cerebral palsy (CP), the most common subtype, is characterized by high levels of mobility. Despite this, children with hemiplegic CP can face challenges functioning in and adapting to situations of everyday life. The purpose of this cross-sectional study (Hemi-NET database) was to identify factors associated with adaptive behaviour in 59 children with hemiplegic CP (ages 4-18; GMFCS I-IV). Using multivariate regression analyses, the relationship between demographic, medical, and developmental factors and adaptive behaviour (measured by the Adaptive Skills Composite score of the BASC-2) was explored. Results indicate that 34% of children had impaired adaptive skills. An autism diagnosis and lower communication functioning were significantly associated with poorer adaptive skills (R2 = 0.42, F(4, 43) = 7.87, p < 0.001), while factors such as IQ scores and GMFCS level were not. The results contribute to the growing literature that suggests that clinicians and researchers need to look beyond motor functioning when working with individuals with CP.

Investigating the Associations Between Child Autistic Symptoms, Socioeconomic Context, and Family Life: A Pilot Study.

Objective: The day-to-day experience of families with an Autistic child may be shaped by both, child characteristics and available resources, which often are influenced by the socioeconomic context of the family. Using a socioecological approach, this study explored the quantitative associations between child autistic symptoms, family socioeconomic status, and family life. Methods: Data came from the Pediatric Autism Research Cohort-PARC Study (pilot). Parents of children with a recent diagnosis of autism completed a set of assessments, including the Autism Family Experience Questionnaire, Autism Impact Measure, and a Sociodemographic Questionnaire. A series of multiple, iterative linear regression models were constructed to ascertain quantitative associations between child autistic symptoms, socioeconomic context, and family life. Results: A total of 50 children (mean age: 76 months; SD: 9.5 months; and 84% male) with data on the variables of interest were included in the analysis. The frequency of child autistic symptoms was associated with family life outcomes (p = 0.02 and R 2 = 24%). Once autistic symptom frequency, symptom impact, and sociodemographic variables were considered, parents of higher educational attainment reported worse family life outcomes compared to their lesser-educated counterparts. This cumulative regression model had considerable explanatory capability (p = 0.01, R 2 = 40%). Conclusion: This study demonstrates the utility of using a socioecological approach to examine the dynamic interplay between child characteristics and family circumstances. Our findings suggest that family life for parents (of an autistic child) who have obtained higher education is reported (by the parents themselves) as less satisfactory compared to that of parents without higher education, once adjusted for the autistic symptom frequency of child, symptom impact, and income. These findings can inform the design and delivery of more family-centered care pathways during the years following a diagnosis of autism.

Definition and classification of hyperkinetic movements in childhood.

Hyperkinetic movements are unwanted or excess movements that are frequently seen in children with neurologic disorders. They are an important clinical finding with significant implications for diagnosis and treatment. However, the lack of agreement on standard terminology and definitions interferes with clinical treatment and research. We describe definitions of dystonia, chorea, athetosis, myoclonus, tremor, tics, and stereotypies that arose from a consensus meeting in June 2008 of specialists from different clinical and basic science fields. Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Chorea is an ongoing random-appearing sequence of one or more discrete involuntary movements or movement fragments. Athetosis is a slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Myoclonus is a sequence of repeated, often nonrhythmic, brief shock-like jerks due to sudden involuntary contraction or relaxation of one or more muscles. Tremor is a rhythmic back-and-forth or oscillating involuntary movement about a joint axis. Tics are repeated, individually recognizable, intermittent movements or movement fragments that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement. Stereotypies are repetitive, simple movements that can be voluntarily suppressed. We provide recommended techniques for clinical examination and suggestions for differentiating between the different types of hyperkinetic movements, noting that there may be overlap between conditions. These definitions and the diagnostic recommendations are intended to be reliable and useful for clinical practice, communication between clinicians and researchers, and for the design of quantitative tests that will guide and assess the outcome of future clinical trials.

Association between neighbourhood socioeconomic status and developmental vulnerability of kindergarten children with Autism Spectrum Disorder: A population level study.

There is limited knowledge about the relationship between neighbourhood socioeconomic status (SES) and development of kindergarten children with ASD. The primary objective of this study was to determine the association between neighbourhood SES and developmental vulnerability of kindergarten children with ASD while controlling for family SES across 10 provinces and territories in Canada. This study used data from a population level database of child development in kindergarten, collected with the Early Development Instrument (EDI). The EDI covers five broad domains of developmental health: physical health and well-being, social competence, emotional maturity, language and cognitive development, and communication skills and general knowledge. Neighbourhood SES was assessed with an SES index created using 10 variables from the 2011 Canadian Census and 2010 Taxfiler data. Family SES was assessed using 4 variables from the 2016 Canadian Census. Descriptive statistics and regression-based models were used in this study. Multilevel binary logistic regression analyses were used to examine the association between neighbourhood SES and child developmental vulnerability (yes/no), at the individual level, while controlling for family SES, demographic characteristics, and neighbourhood clustering. The association between neighbourhood SES and child developmental vulnerability at the individual level, while controlling for family SES and demographic characteristics was examined with binary single level logistic regression analyses. Multivariable linear regression analyses were used to examine the association between neighbourhood SES and developmental vulnerability at the neighbourhood level (% of kindergarten children with ASD demonstrating developmental vulnerability in a neighbourhood). In Ontario, British Columbia, Manitoba, and Newfoundland and Labrador, higher neighbourhood SES was associated with lower likelihood of developmental vulnerability. In Nova Scotia, higher neighbourhood SES was associated with higher likelihood of vulnerability in the social competence and communication skills and general knowledge domains. These findings emphasize the importance of addressing neighbourhood deprivation to support the development of children with ASD. Additionally, the inconsistency highlights the importance of examining the mechanisms through which neighbourhood SES impacts development of these children on a provincial basis.

Neighbourhood-level prevalence of teacher-reported Autism Spectrum Disorder among kindergarten children in Canada: A population level study.

•Number of children with ASD per neighbourhood varies from none to as high as 21.•Developmental vulnerabilities were not associated with levels of clustering.•Highest level of clustering of children with ASD was found in Nova Scotia.

Effects of Botulinum Toxin Treatment in Nonambulatory Children and Adolescents With Cerebral Palsy: Understanding Parents' Perspectives.

Children and adolescents with cerebral palsy often receive botulinum toxin A (BoNT-A) to manage hypertonia. This qualitative study aimed to describe and categorize BoNT-A effects that parents observed using the WHO's International Classification of Functioning, Disability and Health (ICF) framework. An interpretive description methodology was used; semi-structured interviews were conducted with 15 parents of nonambulatory young people with cerebral palsy (mean age 10.2 years, SD 3.9, 7 males) who received BoNT-A. Parents reported BoNT-A effects on each ICF category. Through interpretive description, an overall theme emerged: "finding the right path to do what is best." Five subthemes included (1) Parents' hopes, (2) Parents' goals for their child, (3) Parents' learning what works, (4) Parents' reflections, and (5) Parents' destination. This study provides insights into parents' journeys of how they learned about BoNT-A effects in their child, which helped them to identify goals for future treatment.

A Long-term, epidemiological survey of outcome and adjustment of children with developmental disabilities.

The medical, educational, and psychosocial outcomes of 3224 subjects (age range, 7-33 years; mean age, 20.06 years; SD, 5.74) diagnosed and treated in the Institute for Child Development in Tel Aviv between the years 1975 and 1994 were assessed by a telephone interview. Results indicate that only 9% of the subjects are seriously disabled, and 8% are mentally retarded. Over the years, subjects were referred to the Child Development Center at an increasingly younger age, probably reflecting greater professional and parental awareness of the importance of early intervention. The nature of interventions changed, so that physiotherapy, occupational therapy, and psychological guidance were more often provided. While more children were referred to special education at kindergarten, the percentage of those graduating from regular schools has increased. Most completed 12 years of schooling and successfully acquired full or partial matriculation certificates. As adults, most function independently; fulfill civic obligations, such as their army service; are fully employed; and express satisfaction with their life. These results suggest that children with developmental disabilities who receive early intervention are likely to be functionally independent and to be satisfied with their lives, although they continue to need medical services and require some government support. Further studies are essential to examine the correlation of specific risk factors and early interventions with outcome.

Neuroplastic Sensorimotor Resting State Network Reorganization in Children With Hemiplegic Cerebral Palsy Treated With Constraint-Induced Movement Therapy.

Using resting state functional magnetic resonance imaging (MRI), we aim to understand the neurologic basis of improved function in children with hemiplegic cerebral palsy treated with constraint-induced movement therapy. Eleven children including 4 untreated comparison subjects diagnosed with hemiplegic cerebral palsy were recruited from 3 clinical centers. MRI and clinical data were gathered at baseline and 1 month for both groups, and 6 months later for the case group only. After constraint therapy, the sensorimotor resting state network became more bilateral, with balanced contributions from each hemisphere, which was sustained 6 months later. Sensorimotor resting state network reorganization after therapy was correlated with a change in the Quality of Upper Extremity Skills Test score at 1 month (r = 0.79, P = .06), and Canadian Occupational Performance Measure scores at 6 months (r = 0.82, P = .05). This clinically correlated resting state network reorganization provides further evidence of the neuroplastic mechanisms underlying constraint-induced movement therapy.

Role of thrombophilic risk factors in children with non-stroke cerebral palsy.

BACKGROUND: Thrombophilic risk factors play an important role in the pathogenesis of perinatal stroke and resultant cerebral palsy (CP). The association between thrombophilia and CP caused by etiologies other than stroke is undetermined. METHODS: We assessed three genetic thrombophilic markers (mutation of Factor V Leiden [FV G1691A], 677T polymorphism of thermolabile methylenetetrahydrofolate reductase [MTHFR] and G20210A mutation of the prothrombin gene) in 49 pediatric patients with non-stroke CP and compared the findings with 118 apparently healthy controls. CP in the study group was due to periventricular leukomalacia (n=27), intraventricular hemorrhage (n=9), hypoxic ischemic encephalopathy (n=4), prematurity with no apparent complication (n=8) and intrauterine growth retardation (n=1). Twenty-five children had spastic diplegia, 20 had spastic quadriplegia and 4 had spastic hemiplegia. CP was graded as being severe in 26 children (53%). RESULTS: No significant difference in the prevalence of thrombophilic risk factors was found between the study and control groups. Twelve study children (24.5%) had at least one of the three thrombophilic mutations compared with 27 controls (23%). There was no significant difference in the prevalence of each thrombophilic risk factor in the various etiologic groups and in the subgroups of mild/severe CP and the control group. CONCLUSION: These findings support the notion that thrombophilia neither contributes to the occurrence nor affects the clinical outcome and severity of non-stroke CP.

Resting State and Diffusion Neuroimaging Predictors of Clinical Improvements Following Constraint-Induced Movement Therapy in Children With Hemiplegic Cerebral Palsy.

The aim was to identify neuroimaging predictors of clinical improvements following constraint-induced movement therapy. Resting state functional magnetic resonance and diffusion tensor imaging data was acquired in 7 children with hemiplegic cerebral palsy. Clinical and magnetic resonance imaging (MRI) data were acquired at baseline and 1 month later following a 3-week constraint therapy regimen. A more negative baseline laterality index characterizing an atypical unilateral sensorimotor resting state network significantly correlated with an improvement in the Canadian Occupational Performance Measure score (r = -0.81, P = .03). A more unilateral network with decreased activity in the affected hemisphere was associated with greater improvements in clinical scores. Higher mean diffusivity in the posterior limb of the internal capsule of the affect tract correlated significantly with improvements in the Jebsen-Taylor score (r = -0.83, P = .02). Children with more compromised networks and tracts improved the most following constraint therapy.

Antenatal diagnosis of central nervous system anomalies: can we predict prognosis?

Our technical ability to diagnose fetal anomalies of the central nervous system by ultrasonography and by fetal magnetic resonance imaging far exceeds our current knowledge of their possible neurodevelopmental implications later in life. This limitation often makes obstetric and clinical decisions very difficult. We retrospectively reviewed the ultrasonographic records of 6220 women who had been followed up at two large medical centers between 1994 and 1999. One hundred and sixty (2.6%) women had abnormal fetal central nervous system findings. The neurodevelopmental outcome of these children was assessed by a telephone interview with the parents. Small cerebellar size was the most frequent anomaly, followed by isolated mild ventriculomegaly and isolated choroid plexus pathology. Suboptimal neurodevelopmental outcome was found in 24% of children with isolated ventriculomegaly and in 9% with choroid plexus pathology. In the group of children with a "small cerebellum," suboptimal neurodevelopment was found in 19%. The measurement of transcerebellar diameter in respect to its developmental implication is, to our knowledge, described here for the first time. We believe that cerebellar measurements and their possible neurocognitive implications should be an integral part of future studies.