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Background A recurrent de novo variant (c.892C>T) in NACC1 causes a neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (NECFM). An unusual and consistently reported feature is episodic extreme irritability and inconsolability. We now characterize these episodes, their impact on the family, and ascertain treatments that may be effective. Parents of 14 affected individuals provided narratives describing the irritability episodes, including triggers, behavioral and physiological changes, and treatments. Simultaneously, parents of 15 children completed the Non-communicating Children’s Pain Checklist-Revised (NCCPC-R), a measure to assess pain in non-verbal children. Results The episodes of extreme irritability include a prodromal, peak, and resolving phase, with normal periods in between. The children were rated to have extreme pain-related behaviors on the NCCPC-R scale, although it is unknown whether the physiologic changes described by parents are caused by pain. Attempted treatments included various classes of medications, with psychotropic and sedative medications being most effective (7/15). Nearly all families (13/14) describe how the episodes have a profound impact on their lives. Conclusions NECFM caused by the recurrent variant c.892C>T is associated with a universal feature of incapacitating episodic irritability of unclear etiology. Further understanding of the pathophysiology can lead to more effective therapeutic strategies.

BackgroundLimited documentation exists about how frequently radiologically visible rebleeding occurs with abusive subdural hemorrhages (SDH). Likewise, little is known about rebleeding predispositions and associated symptoms.ObjectiveTo describe the frequency of subdural rebleeding after abusive head trauma (AHT), its predispositions and clinical presentation.Materials and methodsWe evaluated children with SDHs from AHT who were reimaged within a year of their initial hospitalization, retrospectively reviewing clinical details and imaging. We used the available CT and MR images. We then performed simple descriptive and comparative statistics.ResultsFifty-four of 85 reimaged children (63.5%) with AHT-SDH rebled. No child had new trauma, radiologic evidence of new parenchymal injury or acute neurologic symptoms from rebleeding. From the initial presentation, macrocephaly was associated with subsequent rebleeding. Greater subdural depth, macrocephaly, ventriculomegaly and brain atrophy at follow-up were associated with rebleeding. No other radiologic findings at initial presentation or follow-up predicted rebleeding risk, although pre-existing brain atrophy at initial admission and initial chronic SDHs barely missed significance. Impact injuries, retinal hemorrhages and clinical indices of initial injury severity were not associated with rebleeding. All rebleeding occurred within chronic SDHs; no new bridging vein rupture was identified. The mean time until rebleeding was recognized was 12 weeks; no child had rebleeding after 49 weeks.ConclusionSubdural rebleeding is common and occurs in children who have brain atrophy, ventriculomegaly, macrocephaly and deep SDHs at rebleed. It usually occurs in the early months post-injury. All children with rebleeds were neurologically asymptomatic and lacked histories or clinical or radiologic findings of new trauma. Bleeds did not occur outside of chronic SDHs. We estimate the maximum predicted frequency of non-traumatic SDH rebleeding accompanied by acute neurological symptoms in children with a prior abusive SDH is 3.5%.

Background Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the MECP2 gene. Sleep problems are reported by the majority of caregivers of individuals with RTT. Methods The present study aimed to replicate and extend previous work about the feasibility of measuring sleep with an actigraph device in a sample of girls with clinically diagnosed RTT ( N  = 13, mean age = 9 years, 5 months). Participants wore an actigraph device day and night for seven consecutive days. Materials also included a parent-completed sleep diary to measure bedtime, duration of nighttime sleep, and daytime sleep, and the Child Sleep Habit’s Questionnaire (CSHQ). Results The means for the sample as measured by actigraphy were 492.3 min (SD = 47.3) of total night sleep (TNS), 76.0% (SD = 6.7) sleep efficiency, 86.0 min (SD = 34.2) of wake after sleep onset, and 46.1 min (50.8) of sleep when parents reported a nap occurring. Parents reported 589.7 min (SD = 53.6) of TNS, 15.9 min (SD = 12.0) of WASO, and 93.6 min (SD = 66.8) of daytime sleep according to sleep diaries, with all parents reporting at least one nap during the week. Relations were found between sleep characteristics and seizure status and CSHQ total scores. No age-related changes were observed for any sleep characteristic, regardless of collection method. Five of nine participants above the cutoff score on the CSHQ indicate the need for further evaluation for a sleep disorder. Conclusions Overall, actigraphy was feasible in this community-based sample of girls with RTT. The results replicated some aspects of previous studies of sleep in RTT (e.g., no age-related changes in total nighttime sleep or efficiency). Some participants met the American Academy of Sleep Medicine guidelines for recommended total sleep time, with others showing too much or too little sleep. Each of the three methods for describing sleep presented its own advantages and challenges. Future work should be prospectively designed, validate the use of actigraphy in this population, and include a typically developing comparison sample to improve the precision of our understanding of sleep in RTT.

Rett syndrome (RTT) is associated with myriad debilitating health issues and significant motor and communicative impairments. Because of the former there is concern about the possibility of recurrent and chronic pain but because of the latter it remains difficult to determine what pain ‘looks like’ in RTT. This study investigated pain experience and expression using multiple complementary subjective and objective approaches among a clinical RTT sample. Following informed consent, 18 participants (all female) with RTT (mean age = 12.8 years, SD = 6.32) were characterized in terms of pain experience and interference, typical pain expression, and elicited pain behavior during a passive range of motion-like examination procedure. Parents completed the Dalhousie Pain Interview (DPI; pain type, frequency, duration, intensity), the Brief Pain Inventory (BPI; pain interference), and the Non-Communicating Children’s Pain Checklist – Revised (NCCPC-R; typical pain expression). A Pain Examination Procedure (PEP) was conducted and scored using the Pain and Discomfort Scale (PADS). The majority of the sample (89 %) were reported to experience pain in the previous week which presented as gastrointestinal ( n  = 8), musculoskeletal ( n  = 5), and seizure related pain ( n  = 5) that was intense (scored 0–10; M  = 5.67, SD  = 3.09) and long in duration ( M  = 25.22 h, SD  = 53.52). Numerous pain-expressive behaviors were inventoried (e.g., vocal, facial, mood/interaction changes) when parents reported their child’s typical pain behaviors and based on independent direct observation during a reliably coded pain exam. This study provides subjective and objective evidence that individuals with RTT experience recurring and chronic pain for which pain expression appears intact.

The original article included a statement which is not fully accurate. This correction clarifies the original statement.

Objective. We investigated the preliminary efficacy of cathodal transcranial direct current stimulation (tDCS) combined with bimanual training in children and young adults with unilateral cerebral palsy based on the principle of exaggerated interhemispheric inhibition (IHI). Methods. Eight participants with corticospinal tract (CST) connectivity from the lesioned hemisphere participated in an open-label study of 10 sessions of cathodal tDCS to the nonlesioned hemisphere (20 minutes) concurrently with bimanual, goal-directed training (120 minutes). We measured the frequency of adverse events and intervention efficacy with performance (bimanual—Assisting Hand Assessment (AHA)—and unimanual—Box and Blocks), self-report (Canadian Occupational Performance Measure (COPM), ABILHAND), and neurophysiologic (motor-evoked potential amplitude, cortical silent period (CSP) duration, and motor mapping) assessments. Results. All participants completed the study with no serious adverse events. Three of 8 participants showed gains on the AHA, and 4 of 8 participants showed gains in Box and Blocks (more affected hand). Nonlesioned CSP duration decreased in 6 of 6 participants with analyzable data. Cortical representation of the first dorsal interosseous expanded in the nonlesioned hemisphere in 4 of 6 participants and decreased in the lesioned hemisphere in 3 of 4 participants with analyzable data. Conclusions. While goal achievement was observed, objective measures of hand function showed inconsistent gains. Neurophysiologic data suggests nonlinear responses to cathodal stimulation of the nonlesioned hemisphere. Future studies examining the contributions of activity-dependent competition and cortical excitability imbalances are indicated.

Background Rett syndrome (RTT) is a rare neurodevelopmental disorder associated with pathogenic MECP2 variants. Because the MECP2 gene is subject to X‐chromosome inactivation (XCI), factors including MECP2 genotypic variation, tissue differences in XCI, and skewing of XCI all likely contribute to the clinical severity of individuals with RTT. Methods We analyzed the XCI patterns from blood samples of 320 individuals and their mothers. It includes individuals with RTT (n = 287) and other syndromes sharing overlapping phenotypes with RTT (such as CDKL5 Deficiency Disorder [CDD, n = 16]). XCI status in each proband/mother duo and the parental origin of the preferentially inactivated X chromosome were analyzed. Results The average XCI ratio in probands was slightly increased compared to their unaffected mothers (73% vs. 69%, p = .0006). Among the duos with informative XCI data, the majority of individuals with classic RTT had their paternal allele preferentially inactivated (n = 180/220, 82%). In sharp contrast, individuals with CDD had their maternal allele preferentially inactivated (n = 10/12, 83%). Our data indicate a weak positive correlation between XCI skewing ratio and clinical severity scale (CSS) scores in classic RTT patients with maternal allele preferentially inactivated XCI (rs = 0.35, n = 40), but not in those with paternal allele preferentially inactivated XCI (rs = −0.06, n = 180). The most frequent MECP2 pathogenic variants were enriched in individuals with highly/moderately skewed XCI patterns, suggesting an association with higher levels of XCI skewing. Conclusion These results extend our understanding of the pathogenesis of RTT and other syndromes with overlapping clinical features by providing insight into the both XCI and the preferential XCI of parental alleles. X chromosome inactivation (XCI) analysis of 320 proband‐mother duos showed that majority of individuals with classic Rett syndrome had their paternal allele preferentially inactivated, while, in sharp contrast, majority of individuals with CDKL5 Deficiency Disorder had their maternal allele preferentially inactivated. Our data also indicated that in individuals with classic Rett syndrome, there is a weak positive correlation between XCI skewing ratio and clinical severity of individuals with maternal allele preferentially inactivated, but not in those with paternal allele preferentially inactivated.

Introduction Rett syndrome (RTT), a rare neurodevelopmental disorder occurring primarily in females (1:10–15,000 female live births), is most often caused by loss‐of‐function mutations in the X‐linked methyl‐CpG‐binding protein 2 gene (MECP2). Clinical observations and preclinical findings indicate apparent abnormal sensory and nociceptive function. There have been no direct investigations of epidermal sensory innervation in patients with RTT. Methods We compared 3 mm epidermal punch biopsy specimens from adolescent female RTT patients (N = 4, aged 12–19 years) against an archived approximate age‐, sex‐, body‐site matched comparison sample of healthy adolescent females (N = 8, ages 11–17). Results Confocal imaging revealed, on average, statistically significant increased epidermal nerve fiber (ENF) peptidergic (co‐stained calcitonin gene‐related protein [CGRP]) innervation density compared with healthy female control individuals. Conclusions Given the clinical phenotype of disrupted sensory function along with diagnostic criteria specific to cold hands/feet and insensitivity to pain, our preliminary observations of ENF peptidergic fiber density differences warrants further investigation of the peripheral neurobiology in RTT. Epidermal skin punch biopsy specimens from four adolescent female patients with Rett syndrome (RTT) were compared against an archived approximate age‐, sex‐, body‐site matched comparison sample of healthy adolescent females. Confocal imaging revealed, on average, increased epidermal nerve fiber (ENF) peptidergic (co‐stained calcitonin gene‐related protein) innervation density compared with healthy female control individuals. Given the clinical phenotype of disrupted sensory function along with diagnostic criteria specific to cold hands/feet and insensitivity to pain, our preliminary observations of ENF peptidergic fiber density differences warrants further investigation of the peripheral neurobiology in RTT.

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent–offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two ( TUBA1A and CTNNB1 ) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB , and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy. Whole-exome sequencing of 250 parent–offspring trios identifies an enrichment of rare damaging de novo mutations in individuals with cerebral palsy and implicates genetically mediated dysregulation of early neuronal connectivity in the etiology of this disorder.

Objective Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) have enabled the discovery of novel therapeutic approaches that require formal clinical evaluation of efficacy. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top caregiver concerns to guide the development and selection of appropriate clinical trial outcome measures for these disorders. Methods Caregivers of participants enrolled in the US Natural History Study of RTT and RTT-related disorders ( n  = 925) were asked to identify the top 3 concerning problems impacting the affected participant. We generated a weighted list of top caregiver concerns for each of the diagnostic categories and compared results between the disorders. Further, for classic RTT, caregiver concerns were analyzed by age, clinical severity, and common RTT-causing mutations in MECP2 . Results The top caregiver concerns for classic RTT were effective communication, seizures, walking/balance issues, lack of hand use, and constipation. The frequency of the top caregiver concerns for classic RTT varied by age, clinical severity, and specific mutations, consistent with known variation in the frequency of clinical features across these domains. Caregivers of participants with increased seizure severity often ranked seizures as the first concern, whereas caregivers of participants without active seizures often ranked hand use or communication as the top concern. Comparison across disorders found commonalities in the top caregiver concerns between classic RTT, atypical RTT, MECP2 duplication syndrome, CDKL5 deficiency disorder, and FOXG1 syndrome; however, distinct differences in caregiver concerns between these disorders are consistent with the relative prevalence and impact of specific clinical features. Conclusion The top caregiver concerns for individuals with RTT and RTT-related disorders reflect the impact of the primary clinical symptoms of these disorders. This work is critical in the development of meaningful therapies, as optimal therapy should address these concerns. Further, outcome measures to be utilized in clinical trials should assess these clinical issues identified as most concerning by caregivers.