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Leucine aminoacyl tRNA‐synthetase 1 (LARS1)‐deficiency (infantile liver failure syndrome type 1 (ILFS1)) has a multisystemic phenotype including fever‐associated acute liver failure (ALF), chronic neurologic abnormalities, and encephalopathic episodes. In order to better characterize encephalopathic episodes and MRI changes, 35 cranial MRIs from 13 individuals with LARS1 deficiency were systematically assessed and neurological phenotype was analyzed. All individuals had developmental delay and 10/13 had seizures. Encephalopathic episodes in 8/13 were typically associated with infections, presented with seizures and reduced consciousness, mostly accompanied by hepatic dysfunction, and recovery in 17/19 episodes. Encephalopathy without hepatic dysfunction occurred in one individual after liver transplantation. On MRI, 5/7 individuals with MRI during acute encephalopathy had deep gray matter and brainstem changes. Supratentorial cortex involvement (6/13) and cerebellar watershed injury (4/13) occurred with seizures and/or encephalopathy. Abnormal brainstem contour on sagittal images (8/13), atrophy (8/13), and myelination delay (8/13) were not clearly associated with encephalopathy. The pattern of deep gray matter and brainstem changes are apparently characteristic of encephalopathy in LARS1‐deficiency, differing from patterns of hepatic encephalopathy or metabolic stroke in organic acidurias and mitochondrial diseases. While the pathomechanism remains unclear, fever and energy deficit during infections might be causative; thus, sufficient glucose and protein intake along with pro‐active fever management is suggested. As severe episodes were observed during influenza infections, we strongly recommend seasonal vaccination. [ABSTRACT FROM AUTHOR]

Background: NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy, and the latter is associated with excessive neuronal firing. NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/β/γ. Previous studies on cultured cells show that the short NRXN1β primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of NRXN1α deletions in human neurons. We recently derived induced pluripotent stem cells (iPSCs) from five controls and three ASD patients carrying NRXN1α+/- and showed increased calcium transients in patient neurons.Methods: In this study we investigated the electrophysiological properties of iPSC-derived cortical neurons in control and ASD patients carrying NRXN1α+/- using patch clamping. Whole genome RNA sequencing was carried out to further understand the potential underlying molecular mechanism.Results: NRXN1α+/- cortical neurons were shown to display larger sodium currents, higher AP amplitude and accelerated depolarization time. RNASeq analyses revealed transcriptomic changes with significant upregulation glutamatergic synapse and ion channels/transporter activity including voltage-gated potassium channels (GRIN1, GRIN3B, SLC17A6, CACNG3, CACNA1A, SHANK1), which are likely to couple with the increased excitability in NRXN1α+/- cortical neurons.Conclusions: Together with recent evidence of increased calcium transients, our results showed that human NRXN1α+/- isoform deletions altered neuronal excitability and non-synaptic function, and NRXN1α+/- patient iPSCs may be used as an ASD model for therapeutic development with calcium transients and excitability as readouts. [ABSTRACT FROM AUTHOR]

Dystonia is a hyperkinetic movement disorder characterised by sustained or intermittent muscle contractions causing abnormal movements, postures or both. Dystonia is a challenging condition to diagnose and treat. Dystonia is often under-recognised in children, particularly in cerebral palsy, and frequently coexists with spasticity. This guide aims to simplify the approach to diagnosis, investigation and treatment of childhood-onset dystonia. The principle of treatment is similar regardless of the underlying aetiology: identification of potential triggers and consideration of both pharmacological and surgical options. [ABSTRACT FROM AUTHOR]

BackgroundCognitive behavioral therapy (CBT) for bulimia nervosa (BN) is most effective when patients demonstrate adequate skill utilization (ie, the frequency with which a patient practices or uses therapeutic skills) and skill acquisition (ie, the ability to successfully perform a skill learned in treatment). However, rates of utilization and acquisition of key treatment skills (eg, regular eating, urge management skills, and mood management skills) by the end of the treatment are frequently low; as a result, outcomes from CBT for BN are affected. Just-in-time adaptive interventions (JITAIs) may improve skill acquisition and utilization by delivering real-time interventions during algorithm-identified opportunities for skill practice. ObjectiveIn this manuscript, we describe a newly developed JITAI system called CBT+ that is designed to facilitate the acquisition and utilization of CBT for BN treatment skills when used as a treatment augmentation. We also present feasibility, acceptability, and preliminary outcomes data from a small proof-of-concept pilot trial (n=5 patients and n=3 clinicians) designed to identify opportunities for iterative development of CBT+ ahead of a larger ongoing randomized controlled trial. MethodsA total of 5 individuals with BN received 16 sessions of outpatient CBT for BN while using the CBT+ app. Data were collected from patients and clinicians to evaluate the feasibility (eg, app use and user adherence), acceptability (eg, qualitative patient and clinician feedback, including usefulness ratings of CBT+ on a 6-point Likert scale ranging from 1=extremely useless to 6=extremely useful), and preliminary outcomes (eg, improvements in skill utilization and acquisition and BN symptoms) of the CBT+ system. ResultsPatients reported that CBT+ was a relatively low burden (eg, quick and easy-to-use self-monitoring interface), and adherence to in-app self-monitoring was high (mean entries per day 3.13, SD 1.03). JITAIs were perceived as useful by both patients (median rating 5/6) and clinicians (median rating 5/6) for encouraging the use of CBT skills. Large improvements in CBT skills and clinically significant reductions in BN symptoms were observed post treatment. Although preliminary findings indicated that the CBT+ system was acceptable to most patients and clinicians, the overall study dropout was relatively high (ie, 2/5, 40% patients), which could indicate some moderate concerns regarding feasibility. ConclusionsCBT+, the first-ever JITAI system designed to facilitate the acquisition and utilization of CBT for BN treatment skills when used as a treatment augmentation, was shown to be feasible and acceptable. The results indicate that the CBT+ system should be subjected to more rigorous evaluations with larger samples and should be considered for wider implementation if found effective. Areas for iterative improvement of the CBT+ system ahead of a randomized controlled trial are also discussed.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)