TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila.

Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities.

The Knowledge Translation of Early Cerebral Palsy (KiTE CP) Study: Implementing Screening Among a High-Risk Prospective Cohort of Australian Infants.

OBJECTIVE: To describe the implementation of the international guidelines for the early diagnosis of cerebral palsy (CP) and engagement in the screening process in an Australian cohort of infants with neonatal risk factors for CP. STUDY DESIGN: Prospective cohort study of infants with neonatal risk factors recruited at <6 months corrected age from 11 sites in the states of Victoria, New South Wales, and Queensland, Australia. First, we implemented a multimodal knowledge translation strategy including barrier identification, technology integration, and special interest groups. Screening was implemented as follows: infants with clinical indications for neuroimaging underwent magnetic resonance imaging and/or cranial ultrasound. The Prechtl General Movements Assessment (GMA) was recorded clinically or using an app (Baby Moves). Infants with absent or abnormal fidgety movements on GMA videos were offered further assessment using the Hammersmith Infant Neurological Examination (HINE). Infants with atypical findings on 2/3 assessments met criteria for high risk of CP. RESULTS: Of the 597 infants (56% male) recruited, 95% (n = 565) received neuroimaging, 90% (n = 537) had scorable GMA videos (2% unscorable/8% no video), and 25% (n = 149) HINE. Overall, 19% of the cohort (n = 114/597) met criteria for high risk of CP, 57% (340/597) had at least 2 normal assessments (of neuroimaging, GMA or HINE), and 24% (n = 143/597) had insufficient assessments. CONCLUSIONS: Early CP screening was implemented across participating sites using a multimodal knowledge translation strategy. Although the COVID-19 pandemic affected recruitment rates, there was high engagement in the screening process. Reasons for engagement in early screening from parents and clinicians warrant further contextualization and investigation.

Oral corticosteroid dosage and taper duration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapse.

BACKGROUND: We sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid exposure. METHODS: In a retrospective multicentre cohort study, Cox proportional hazards models examined the relationship between corticosteroid course as a time-varying covariate and time to first relapse. Simon-Makuch and Kaplan-Meier plots identified an optimal dosing strategy. RESULTS: We evaluated 109 patients (62 female, 57%; 41 paediatric, 38%; median age at onset 26 years, (IQR 8-38); median follow-up 6.2 years (IQR 2.6-9.6)). 76/109 (70%) experienced a relapse (median time to first relapse 13.7 months; 95% CI 8.2 to 37.9). In a multivariable model, higher doses of oral prednisone delayed time to first relapse with an effect estimate of 3.7% (95% CI 0.8% to 6.6%; p=0.014) reduced hazard of relapse for every 1 mg/day dose increment. There was evidence of reduced hazard of relapse for patients dosed ≥12.5 mg/day (HR 0.21, 95% CI 0.07 to 0.6; p=0.0036), corresponding to a 79% reduction in relapse risk. There was evidence of reduced hazard of relapse for those dosed ≥12.5 mg/day for at least 3 months (HR 0.12, 95% CI 0.03 to 0.44; p=0.0012), corresponding to an 88% reduction in relapse risk compared with those never treated in this range. No patient with this recommended dosing at onset experienced a Common Terminology Criteria for Adverse Events grade >3 adverse effect. CONCLUSIONS: The optimal dose of 12.5 mg of prednisone daily in adults (0.16 mg/kg/day for children) for a minimum of 3 months at the onset of MOGAD delays time to first relapse.

The MOG antibody non-P42 epitope is predictive of a relapsing course in MOG antibody-associated disease.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) IgG seropositivity is a prerequisite for MOG antibody-associated disease (MOGAD) diagnosis. While a significant proportion of patients experience a relapsing disease, there is currently no biomarker predictive of disease course. We aim to determine whether MOG-IgG epitopes can predict a relapsing course in MOGAD patients. METHODS: MOG-IgG-seropositive confirmed adult MOGAD patients were included (n=202). Serum MOG-IgG and epitope binding were determined by validated flow cytometry live cell-based assays. Associations between epitopes, disease course, clinical phenotype, Expanded Disability Status Scale and Visual Functional System Score at onset and last review were evaluated. RESULTS: Of 202 MOGAD patients, 150 (74%) patients had MOG-IgG that recognised the immunodominant proline42 (P42) epitope and 115 (57%) recognised histidine103/serine104 (H103/S104). Fifty-two (26%) patients had non-P42 MOG-IgG and showed an increased risk of a relapsing course (HR 1.7; 95% CI 1.15 to 2.60, p=0.009). Relapse-freedom was shorter in patients with non-P42 MOG-IgG (p=0.0079). Non-P42 MOG-IgG epitope status remained unchanged from onset throughout the disease course and was a strong predictor of a relapsing course in patients with unilateral optic neuritis (HR 2.7, 95% CI 1.06 to 6.98, p=0.038), with high specificity (95%, 95% CI 77% to 100%) and positive predictive value (85%, 95% CI 45% to 98%). CONCLUSIONS: Non-P42 MOG-IgG predicts a relapsing course in a significant subgroup of MOGAD patients. Patients with unilateral optic neuritis, the most frequent MOGAD phenotype, can reliably be tested at onset, regardless of age and sex. Early detection and specialised management in these patients could minimise disability and improve long-term outcomes.

Association between cumulative maternal exposures related to inflammation and child attention-deficit/hyperactivity disorder: A cohort study.

BACKGROUND: Preclinical studies suggest synergistic effects of maternal inflammatory exposures on offspring neurodevelopment, but human studies have been limited. OBJECTIVES: To examine the cumulative association and potential interactions between seven maternal exposures related to inflammation and child attention-deficit/hyperactivity disorder (ADHD). METHODS: We conducted a population-based cohort study of children born from July 2001 to December 2011 in New South Wales, Australia, and followed up until December 2014. Seven maternal exposures were identified from birth data and hospital admissions during pregnancy: autoimmune disease, asthma, hospitalization for infection, mood or anxiety disorder, smoking, hypertension, and diabetes. Child ADHD was identified from stimulant prescription records. Multivariable Cox regression assessed the association between individual and cumulative exposures and ADHD and potential interaction between exposures, controlling for potential confounders. RESULTS: The cohort included 908,770 children, one-third (281,724) with one or more maternal exposures. ADHD was identified in 16,297 children (incidence 3.5 per 1000 person-years) with median age of 7 (interquartile range 2) years at first treatment. Each exposure was independently associated with ADHD, and risk increased with additional exposures: one exposure (hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.54, 1.65), two exposures (HR 2.25, 95% CI 2.13, 2.37), and three or more exposures (HR 3.28, 95% CI 2.95, 3.64). Positive interaction was found between smoking and infection. The largest effect size was found for cumulative exposure of asthma, infection, mood or anxiety disorder, and smoking (HR 6.12, 95% CI 3.47, 10.70). CONCLUSIONS: This study identifies cumulative effects of multiple maternal exposures related to inflammation on ADHD, most potentially preventable or modifiable. Future studies should incorporate biomarkers of maternal inflammation and consider gene-environment interactions.

'High hopes for treatment': Australian stakeholder perspectives of the clinical translation of advanced neurotherapeutics for rare neurological diseases.

INTRODUCTION: Advanced therapies offer unprecedented opportunities for treating rare neurological disorders (RNDs) in children. However, health literacy, perceptions and understanding of novel therapies need elucidation across the RND community. This study explored healthcare professionals' and carers' perspectives of advanced therapies in childhood-onset RNDs. METHODS: In this mixed-methodology cross-sectional study, 20 healthcare professionals (clinicians, genetic counsellors and scientists) and 20 carers completed qualitative semistructured interviews and custom-designed surveys. Carers undertook validated psychosocial questionnaires. Thematic and quantitative data analysis followed. RESULTS: Participants described high positive interest in advanced therapies, but low knowledge of, and access to, reliable information. The substantial 'therapeutic gap' and 'therapeutic odyssey' common to RNDs were recognised in five key themes: (i) unmet need and urgency for access; (ii) seeking information; (iii) access, equity and sustainability; (iv) a multidisciplinary and integrated approach to care and support and (v) difficult decision-making. Participants were motivated to intensify RND clinical trial activity and access to advanced therapies; however, concerns around informed consent, first-in-human trials and clinical trial procedures were evident. There was high-risk tolerance despite substantial uncertainties and knowledge gaps. RNDs with high mortality, increased functional burdens and no alternative therapies were consistently prioritised for the development of advanced therapies. However, little consensus existed on prioritisation to treatment access. CONCLUSIONS: This study highlights the need to increase clinician and health system readiness for the clinical translation of advanced therapeutics for RNDs. Co-development and use of educational and psychosocial resources to support clinical decision-making, set therapeutic expectations and promotion of equitable, effective and safe delivery of advanced therapies are essential. PATIENT OR PUBLIC CONTRIBUTION: Participant insights into the psychosocial burden and information need to enhance the delivery of care in this formative study are informing ongoing partnerships with families, including co-production and dissemination of psychoeducational resources featuring their voices hosted on the Sydney Children's Hospitals Network website SCHN Brain-Aid Resources.

The spectrum of functional tic-like behaviours: Data from an international registry.

BACKGROUND AND PURPOSE: Between 2019 and 2022, there was a marked rise in adolescents/young adults seeking urgent help for functional tic-like behaviours (FTLBs). Given the global scale of this phenomenon, we aimed to pool cases from different institutions in an international registry to better characterize this spectrum and facilitate future longitudinal observation. METHODS: An international collaborative group from 10 tertiary referral centres for tic disorders collected retrospective data on FTLB patients who sought specialists' attention between the last quarter of 2019 and June 2022. An audit procedure was used for collection of data, which comprised demographics, course of presentation and duration, precipitating and predisposing factors, phenomenology, comorbidities, and pharmacological treatment outcome. RESULTS: During the study period, we collected data on 294 patients with FTLBs, 97% of whom were adolescents and young adults and 87% of whom were female. FTLBs were found to have a peak of severity within 1 month in 70% of patients, with spontaneous remissions in 20%, and a very high frequency of complex movements (85%) and vocalizations (81%). Less than one-fifth of patients had pre-existing primary tic disorder, 66% had comorbid anxiety disorders, 28% comorbid depressive disorders, 24% autism spectrum disorder and 23% attention deficit/hyperactivity disorder. Almost 60% explicitly reported exposure to tic-related social media content. The vast majority of pharmacologically treated patients did not report benefit with tic-suppressing medications. CONCLUSIONS: Our data from the largest multicentre registry of FTLBs to date confirm substantial clinical differences from primary tic disorders. Social modelling was the most relevant contributing factor during the pandemic. Future longitudinal analyses from this database may help understand treatment approaches and responsiveness.

Cervical lymph nodes and ovarian teratomas as germinal centres in NMDA receptor-antibody encephalitis.

Autoantibodies against the extracellular domain of the N-methyl-d-aspartate receptor (NMDAR) NR1 subunit cause a severe and common form of encephalitis. To better understand their generation, we aimed to characterize and identify human germinal centres actively participating in NMDAR-specific autoimmunization by sampling patient blood, CSF, ovarian teratoma tissue and, directly from the putative site of human CNS lymphatic drainage, cervical lymph nodes. From serum, both NR1-IgA and NR1-IgM were detected more frequently in NMDAR-antibody encephalitis patients versus controls (both P < 0.0001). Within patients, ovarian teratoma status was associated with a higher frequency of NR1-IgA positivity in serum (OR = 3.1; P < 0.0001) and CSF (OR = 3.8, P = 0.047), particularly early in disease and before ovarian teratoma resection. Consistent with this immunoglobulin class bias, ovarian teratoma samples showed intratumoral production of both NR1-IgG and NR1-IgA and, by single cell RNA sequencing, contained expanded highly-mutated IgA clones with an ovarian teratoma-restricted B cell population. Multiplex histology suggested tertiary lymphoid architectures in ovarian teratomas with dense B cell foci expressing the germinal centre marker BCL6, CD21+ follicular dendritic cells, and the NR1 subunit, alongside lymphatic vessels and high endothelial vasculature. Cultured teratoma explants and dissociated intratumoral B cells secreted NR1-IgGs in culture. Hence, ovarian teratomas showed structural and functional evidence of NR1-specific germinal centres. On exploring classical secondary lymphoid organs, B cells cultured from cervical lymph nodes of patients with NMDAR-antibody encephalitis produced NR1-IgG in 3/7 cultures, from patients with the highest serum NR1-IgG levels (P < 0.05). By contrast, NR1-IgG secretion was observed neither from cervical lymph nodes in disease controls nor in patients with adequately resected ovarian teratomas. Our multimodal evaluations provide convergent anatomical and functional evidence of NMDAR-autoantibody production from active germinal centres within both intratumoral tertiary lymphoid structures and traditional secondary lymphoid organs, the cervical lymph nodes. Furthermore, we develop a cervical lymph node sampling protocol that can be used to directly explore immune activity in health and disease at this emerging neuroimmune interface.

Proxy-reported sensory measures for children and adolescents with neurodevelopmental disorders: A systematic review.

AIM: To determine the quality and utility of proxy-reported sensory measures for children and adolescents with neurodevelopmental disorders (such as autism spectrum disorder, attention-deficit/hyperactivity disorder, movement disorders, and intellectual disability). METHOD: We systematically searched 11 databases. We applied the updated Consensus-based Standards for the selection of health Measurement INstruments (COSMIN) Risk of Bias checklist and criteria for good measurement properties to evaluate instrument development and psychometric properties. Findings were summarized using a COSMIN adaptation of Grading of Recommendations, Assessment, Development and Evaluations. RESULTS: From 11 databases, 6748 articles were screened. Ninety-one full-length articles were reviewed after removing excluded studies and manual searches conducted by two reviewers. Data were extracted for 12 measures from 20 articles. Of the 12 measures, only three provided sufficient data to evaluate content validity and psychometric measurement properties. The Participation and Sensory Environment Questionnaire-Home (PSEQ-H) was the only measure that satisfied moderate content validity and moderate-to-high quality for measurement properties. These properties included: structural validity, hypothesis testing for construct validity, internal consistency, reliability, and measurement error. INTERPRETATION: One measure, the PSEQ-H, met eight criteria for good measurement properties. To facilitate evidence-informed clinical decision-making, all psychometric properties of all 12 sensory-based, proxy-reported measures were presented. The importance of consumer engagement in measure development and the need for ongoing evaluation of measures against contemporaneous standards is recommended. WHAT THIS PAPER ADDS: Three measures provided studies on content validity and psychometric measurement properties. The Participation and Sensory Environment Questionnaire-Home had moderate quality for content validity studies and high-to-moderate quality evidence for psychometric properties. The Participation and Sensory Environment Questionnaire was the only measure that included consumer involvement through qualitative interviews and pilot testing. Consumer involvement in measure development is important for content validity. Ongoing evaluation of measures against contemporaneous standards is recommended.

Clinical features associated with epilepsy occurrence, resolution, and drug resistance in children with cerebral palsy: A population-based study.

AIM: To investigate clinicoradiological features associated with epilepsy, its resolution, and drug resistance in children with cerebral palsy (CP). METHOD: Data were gathered from the New South Wales/Australian Capital Territory CP Register, encompassing children with CP born between 2003 and 2015 (n = 1916). Clinical features and the severity of impairments were compared among three groups: children with current epilepsy (n = 604), those with resolved epilepsy by age 5 years (n = 109), and those without epilepsy (n = 1203). Additionally, a subset of the registry cohort attending Children's Hospital Westmead (n = 256) was analysed to compare epilepsy and treatment characteristics between drug-responsive (n = 83) and drug-resistant groups (n = 147) using logistic regression and hierarchical cluster analysis. RESULTS: Manual Ability Classification System levels IV and V, intellectual impairment, and vision impairment were found to be associated with epilepsy in children with CP on multivariable analysis (p < 0.01). Moderate to severe intellectual impairment and bilateral spastic CP were independent positive and negative predictors of epilepsy persistence at the age of 5 years respectively (p < 0.05). Microcephaly and multiple seizure types were predictors of drug-resistant epilepsy (area under the receiver operating characteristic curve of 0.83; 95% confidence interval 0.77-0.9). Children with a known genetic cause (14%) and CP epilepsy surgery group (4.3%) formed specific clinical subgroups in CP epilepsy. INTERPRETATION: Our study highlights important clinical associations of epilepsy, its resolution, and treatment response in children with CP, providing valuable knowledge to aid in counselling families and identifying distinct prognostic groups for effective medical surveillance and optimal treatment.

Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy.

Primary mitochondrial diseases are a group of genetically and clinically heterogeneous disorders resulting from oxidative phosphorylation (OXPHOS) defects. COX11 encodes a copper chaperone that participates in the assembly of complex IV and has not been previously linked to human disease. In a previous study, we identified that COX11 knockdown decreased cellular adenosine triphosphate (ATP) derived from respiration, and that ATP levels could be restored with coenzyme Q10 (CoQ10 ) supplementation. This finding is surprising since COX11 has no known role in CoQ10 biosynthesis. Here, we report a novel gene-disease association by identifying biallelic pathogenic variants in COX11 associated with infantile-onset mitochondrial encephalopathies in two unrelated families using trio genome and exome sequencing. Functional studies showed that mutant COX11 fibroblasts had decreased ATP levels which could be rescued by CoQ10 . These results not only suggest that COX11 variants cause defects in energy production but reveal a potential metabolic therapeutic strategy for patients with COX11 variants.

Diagnosis and analysis of unexplained cases of childhood encephalitis in Australia using metatranscriptomic sequencing.

Encephalitis is most often caused by a variety of infectious agents identified through diagnostic tests utilizing cerebrospinal fluid. We investigated the clinical characteristics and potential aetiological agents of unexplained encephalitis through metagenomic sequencing of residual clinical samples from multiple tissue types and independent clinical review. Forty-three specimens were collected from 18 encephalitis cases with no cause identified by the Australian Childhood Encephalitis study. Samples were subjected to total RNA sequencing ('metatranscriptomics') to determine the presence and abundance of potential pathogens, and to describe the possible aetiologies of unexplained encephalitis. Using this protocol, we identified five RNA and two DNA viruses associated with human infection from both non-sterile and sterile sites, which were confirmed by PCR. These comprised two human rhinoviruses, two human seasonal coronaviruses, two polyomaviruses and one picobirnavirus. Human rhinovirus and seasonal coronaviruses may be responsible for five of the encephalitis cases. Immune-mediated encephalitis was considered likely in six cases and metatranscriptomics did not identify a possible pathogen in these cases. The aetiology remained unknown in nine cases. Our study emphasizes the importance of respiratory viruses in the aetiology of unexplained child encephalitis and suggests that non-central-nervous-system sampling in encephalitis clinical guidelines and protocols could improve the diagnostic yield.

Insights into the genetic architecture underlying complex, critical congenital heart disease.

Congenital heart disease (CHD) has a multifactorial aetiology, raising the possibility of an underlying genetic burden, predisposing to disease but also variable expression, including variation in disease severity, and incomplete penetrance. Using whole genome sequencing (WGS), the findings of this study, indicate that complex, critical CHD is distinct from other types of disease due to increased genetic burden in common variation, specifically among established CHD genes. Additionally, these findings highlight associations with regulatory genes and environmental "stressors" in the final presentation of disease.

The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: CANDLE/PRAAS, SAVI and AGS.

OBJECTIVE: Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of 'points to consider' to improve diagnosis, treatment and long-term monitoring of patients with these rare diseases. METHODS: Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates and an allied healthcare professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires and consensus methodology, 'points to consider' to guide patient management were developed. RESULTS: The Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI and AGS. CONCLUSION: These points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment and management of patients with CANDLE/PRAAS, SAVI and AGS and aim to standardise and improve care, quality of life and disease outcomes.

Complement Activation Is a Prominent Feature of MOGAD.

Myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated diseases (MOGADs) account for a substantial proportion of pediatric and adult patients who present with acquired demyelinating disorders. Its pathogenesis and optimal therapy are incompletely understood. We profiled systemic complement activation in adult and pediatric patients with MOGAD compared with patients with relapse-onset multiple sclerosis, patients with neuromyelitis optica spectrum disorder, and pediatric control and adult healthy donors. Proteins indicative of systemic classical and alternative complement activation were substantially increased in patients with MOGAD compared to control groups. Elevated levels were detected in both adult and pediatric cases and across all clinical syndromes. Complement inhibition should be explored for its therapeutic merit in patients with MOGAD. ANN NEUROL 2021;90:976-982.

Leucine-Rich Glioma-Inactivated 1 versus Contactin-Associated Protein-like 2 Antibody Neuropathic Pain: Clinical and Biological Comparisons.

Pain is a under-recognized association of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. Of 147 patients with these autoantibodies, pain was experienced by 17 of 33 (52%) with CASPR2- versus 20 of 108 (19%) with LGI1 antibodies (p = 0.0005), and identified as neuropathic in 89% versus 58% of these, respectively. Typically, in both cohorts, normal nerve conduction studies and reduced intraepidermal nerve fiber densities were observed in the sampled patient subsets. In LGI1 antibody patients, pain responded to immunotherapy (p = 0.008), often rapidly, with greater residual patient-rated impairment observed in CASPR2 antibody patients (p = 0.019). Serum CASPR2 antibodies, but not LGI1 antibodies, bound in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia, suggesting pathophysiological differences that may underlie our clinical observations. ANN NEUROL 2021;90:683-690.

The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders.

BACKGROUND AND OBJECTIVE: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders. METHODS: Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria. RESULTS: One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders; and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P < 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia. CONCLUSIONS: This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Emerging evidence of Toll-like receptors as a putative pathway linking maternal inflammation and neurodevelopmental disorders in human offspring: A systematic review.

Inflammation is increasingly recognised to play a major role in gene-environment interactions in neurodevelopmental disorders (NDDs). The effects of aberrant immune responses to environmental stimuli in the mother and in the child can affect neuroimmune signalling that is central to brain development. Toll-like receptors (TLR) are the best known innate immune pattern and danger recognition sensors to various environmental threats. In animal models, maternal immune activation (MIA), secondary to inflammatory factors including maternal gestational infection, obesity, diabetes, and stress activate the TLR pathway in maternal blood, placenta, and fetal brain, which correlate with offspring neurobehavioral abnormalities. Given the central role of TLR activation in animal MIA models, we systematically reviewed the human evidence for TLR activation and response to stimulation across the maternal-fetal interface. Firstly, we included 59 TLR studies performed in peripheral blood of adults in general population (outside of pregnancy) with six chronic inflammatory factors which have epidemiological evidence for increased risk of offspring NDDs, namely, obesity, diabetes mellitus, depression, low socio-economic status, autoimmune diseases, and asthma. Secondly, eight TLR studies done in human pregnancies with chronic inflammatory factors, involving maternal blood, placenta, and cord blood, were reviewed. Lastly, ten TLR studies performed in peripheral blood of individuals with NDDs were included. Despite these studies, there were no studies which examined TLR function in both the pregnant mother and their offspring. Increased TLR2 and TLR4 mRNA and/or protein levels in peripheral blood were common in obesity, diabetes mellitus, depression, autoimmune thyroid disease, and rheumatoid arthritis. To a lesser degree, TLR 3, 7, 8, and 9 activation were found in peripheral blood of humans with autoimmune diseases and depression. In pregnancy, increased TLR4 mRNA levels were found in the peripheral blood of women with diabetes mellitus and systemic lupus erythematosus. Placental TLR activation was found in mothers with obesity or diabetes. Postnatally, dysregulated TLR response to stimulation was found in peripheral blood of individuals with NDDs. This systematic review found emerging evidence that TLR activation may represent a mechanistic link between maternal inflammation and offspring NDD, however the literature is incomplete and longitudinal outcome studies are lacking. Identification of pathogenic mechanisms in MIA could create preventive and therapeutic opportunities to mitigate NDD prevalence and severity.

Cerebrospinal fluid neopterin as a biomarker of treatment response to Janus kinase inhibition in Aicardi-Goutières syndrome.

Janus kinase (JAK) 1 inhibition represents a precision medicine approach in the treatment of Aicardi-Goutières syndrome (AGS), through targeting of type I interferon-mediated cell signalling. Blood interferon mRNAseq has been proposed as a biomarker of disease with utility in therapeutic monitoring. Objective cerebrospinal fluid (CSF) biomarkers tracking treatment efficacy are currently lacking. Here, we report a retrospective case series of 13 patients (median age 6y, range 2y 6mo-17y; five females, eight males) with AGS demonstrating significantly elevated CSF neopterin levels at first sampling (median 200nmol/L, range 45-2024nmol/L), compared to 13 age-matched controls with non-inflammatory neurological conditions (median 23nmol/L, range 5-34nmol/L, p<0.001). Five patients with AGS treated with JAK inhibitors demonstrated a median 81.5% reduction of CSF neopterin (range -36% to -88% change from baseline), compared to eight untreated patients with AGS demonstrating a median 7% reduction in CSF neopterin (range -63% to +117% change) (p=0.047). Our data indicate a biological effect of JAK inhibitors, and the potential role of CSF neopterin as a biomarker of treatment response.

Delivering paediatric precision medicine: Genomic and environmental considerations along the causal pathway of childhood neurodevelopmental disorders.

Precision medicine refers to treatments that are targeted to an individual's unique characteristics. Precision medicine for neurodevelopmental disorders (such as cerebral palsy, attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, Tourette syndrome, and autism spectrum disorder) in children has predominantly focused on advances in genomic sequencing technologies to increase our ability to identify single gene mutations, diagnose a multitude of rare neurodevelopmental disorders, and gain insights into pathogenesis. Although targeting specific gene variants with high penetrance will help some children with rare disease, this approach will not help most children with neurodevelopmental disorders. A 'pathway' driven approach targeting the cumulative influence of psychosocial, epigenetic, or cellular factors is likely to be more effective. To optimize the therapeutic potential of precision medicine, we present a biopsychosocial integrated framework to examine the 'gene-environment neuroscience interaction'. Such an approach would be supported through harnessing the power of big data, transdiagnostic assessment, impact and implementation evaluation, and a bench-to-bedside scientific discovery agenda with ongoing clinician and patient engagement. WHAT THIS PAPER ADDS: Precision medicine has predominantly focused on genetic risk factors. The impact of environmental risk factors, particularly inflammatory, metabolic, and psychosocial risks, is understudied. A holistic biopsychosocial model of neurodevelopmental disorder causal pathways is presented. The model will provide precision medicine across the full spectrum of neurodevelopmental disorders.