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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.
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Deficiências do Desenvolvimento/genética , Proteínas de Drosophila/genética , Oftalmopatias Hereditárias/genética , Deficiência Intelectual/genética , Carioferinas/genética , Anormalidades Musculoesqueléticas/genética , beta Carioferinas/genética , Proteína ran de Ligação ao GTP/genética , Alelos , Sequência de Aminoácidos , Animais , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Oftalmopatias Hereditárias/metabolismo , Oftalmopatias Hereditárias/patologia , Feminino , Dosagem de Genes , Regulação da Expressão Gênica no Desenvolvimento , Genoma Humano , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Carioferinas/antagonistas & inibidores , Carioferinas/metabolismo , Masculino , Anormalidades Musculoesqueléticas/metabolismo , Anormalidades Musculoesqueléticas/patologia , Mutação , Neurônios/metabolismo , Neurônios/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Sequenciamento Completo do Genoma , beta Carioferinas/metabolismo , Proteína ran de Ligação ao GTP/metabolismoRESUMO
AIM: To develop standardized diagnostic criteria for 'infection-triggered encephalopathy syndrome (ITES)' and five specific clinical syndromes of ITES. METHOD: The draft definitions were based on existing criteria, standardized, and discussed by a panel of international experts using nominal group technique over 18 months to achieve consensus. All criteria use the same format: (1) presence of infection/fever; (2) clinical features including encephalopathy; (3) neuroradiological features on magnetic resonance imaging; (4) exclusion of other causes. RESULTS: We first highlighted differences between ITES and infectious and autoimmune encephalitis, which is the most important differential diagnosis. Consensus was achieved to define five specific ITESs: acute encephalopathy with biphasic seizures and late reduced diffusion; acute necrotizing encephalopathy; mild encephalopathy with a reversible splenial lesion; acute fulminant cerebral oedema; and acute shock with encephalopathy and multiorgan failure. Two further conditions that are currently classified as epilepsy syndromes but have similar features to ITES, namely febrile infection-related epilepsy syndrome and hemiconvulsion-hemiplegia-epilepsy syndrome, are also discussed. INTERPRETATION: The consensus definition is expected to improve awareness of this disease concept, provide diagnostic framework, and facilitate future international research and clinical trials.
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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.
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Doenças do Sistema Nervoso , Doenças Raras , Humanos , Doenças Raras/terapia , Estudos Transversais , Doenças do Sistema Nervoso/terapia , Feminino , Masculino , Austrália , Adulto , Cuidadores/psicologia , Inquéritos e Questionários , Entrevistas como Assunto , Participação dos Interessados , Pessoa de Meia-Idade , Pessoal de Saúde/psicologia , Pesquisa Translacional Biomédica , Pesquisa QualitativaRESUMO
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.
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Coreia , Distonia , Distúrbios Distônicos , Transtornos dos Movimentos , Criança , Humanos , Hipercinese , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/diagnóstico , Distúrbios Distônicos/genética , Coreia/diagnóstico , Coreia/genética , Proteínas do Tecido Nervoso , Fatores de Transcrição Forkhead , Diester Fosfórico Hidrolases , ATPase Trocadora de Sódio-Potássio , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genéticaRESUMO
BACKGROUND: ADCY5-related dyskinesia is characterized by early-onset movement disorders. There is currently no validated treatment, but anecdotal clinical reports and biological hypotheses suggest efficacy of caffeine. OBJECTIVE: The aim is to obtain further insight into the efficacy and safety of caffeine in patients with ADCY5-related dyskinesia. METHODS: A retrospective study was conducted worldwide in 30 patients with a proven ADCY5 mutation who had tried or were taking caffeine for dyskinesia. Disease characteristics and treatment responses were assessed through a questionnaire. RESULTS: Caffeine was overall well tolerated, even in children, and 87% of patients reported a clear improvement. Caffeine reduced the frequency and duration of paroxysmal movement disorders but also improved baseline movement disorders and some other motor and nonmotor features, with consistent quality-of-life improvement. Three patients reported worsening. CONCLUSION: Our findings suggest that caffeine should be considered as a first-line therapeutic option in ADCY5-related dyskinesia. © 2022 International Parkinson and Movement Disorder Society.
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Discinesias , Transtornos dos Movimentos , Adenilil Ciclases/genética , Cafeína/uso terapêutico , Criança , Discinesias/etiologia , Discinesias/genética , Humanos , Transtornos dos Movimentos/genética , Estudos RetrospectivosRESUMO
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.
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Transtornos do Neurodesenvolvimento , Placenta , Animais , Feminino , Humanos , Inflamação/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Obesidade/metabolismo , Placenta/metabolismo , Gravidez , Receptores Toll-Like/metabolismoRESUMO
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.
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Doenças Autoimunes do Sistema Nervoso/líquido cefalorraquidiano , Doenças Autoimunes do Sistema Nervoso/tratamento farmacológico , Inibidores de Janus Quinases/farmacologia , Neopterina/líquido cefalorraquidiano , Malformações do Sistema Nervoso/líquido cefalorraquidiano , Malformações do Sistema Nervoso/tratamento farmacológico , Adolescente , Biomarcadores/líquido cefalorraquidiano , Criança , Pré-Escolar , Feminino , Humanos , Janus Quinase 1/antagonistas & inibidores , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. METHODS: In order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. RESULTS: We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. CONCLUSION: The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers.
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Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Malformações do Sistema Nervoso/genética , Polimicrogiria/genética , Tubulina (Proteína)/genética , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Vermis Cerebelar/diagnóstico por imagem , Vermis Cerebelar/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/patologia , Feminino , Predisposição Genética para Doença , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Masculino , Mutação de Sentido Incorreto/genética , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/patologia , Neuroimagem/métodos , Fenótipo , Polimicrogiria/diagnóstico por imagem , Polimicrogiria/patologia , Tubulina (Proteína)/deficiência , Adulto JovemRESUMO
AIM: To report the prevalence and clinical characteristics of children with rapid onset functional tic-like behaviours during the COVID-19 pandemic. METHODS: Single centre, retrospective cohort study of children (<18 years) referred to the tic clinic from January 2018 to July 2021. We calculate the prevalence of newly diagnosed functional tics, and compare the clinical features to chronic tic disorder/Tourette syndrome (CTD/TS). RESULTS: A total of 185 new patients were referred to the tic clinic between 2018 and 2021. There was a significant increase in the percentage of functional tics in 2020 and 2021 (2% in 2018, 5.6% in 2019, 10.6% in 2020 and 36% in 2021). Differences between functional tics (n = 22) and CTD/TS (n = 163) include female predominance (100 vs. 28%, P < 0.0001), later age of onset (mean age 13.8 vs. 6.8 years, P < 0.0001) and higher rates of anxiety/depression (95 vs. 41%, P < 0.0001). The functional tic group were more likely to present with coprolalia-like behaviours (77 vs. 10%, P < 0.0001), complex phrases (45 vs. 0.6%, P < 0.0001), copropraxia (45 vs. 2%, P < 0.0001), self-injury (50 vs. 4%, P < 0.0001), hospitalisation/emergency visits (36 vs. 2%, P < 0.0001) and school absenteeism (56 vs. 7%, P < 0.0001). A total of 18.2% of patients with functional tics reported preceding exposure to social media content involving tics. CONCLUSIONS: There is an increase in adolescent females presenting with rapid onset functional tic-like behaviours during the COVID-19 pandemic. We highlight differences in clinical features between the functional tic group and CTD/TS to aid diagnosis and management in the community. Based on our findings, we propose a mixed model of neuropsychiatric vulnerability and social media contagion in this group of adolescents with functional tics.
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COVID-19 , Transtornos de Tique , Tiques , Síndrome de Tourette , Adolescente , COVID-19/epidemiologia , COVID-19/terapia , Criança , Feminino , Humanos , Masculino , Pandemias , Estudos Retrospectivos , Transtornos de Tique/diagnóstico , Transtornos de Tique/epidemiologia , Transtornos de Tique/terapiaRESUMO
PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
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Transtorno do Espectro Autista , Encefalopatias , Epilepsia , Transtorno do Espectro Autista/genética , Encefalopatias/genética , Epilepsia/genética , Feminino , Genes Ligados ao Cromossomo X/genética , Humanos , Masculino , Proteínas do Tecido Nervoso , Convulsões/genéticaRESUMO
Although genetic variation is a major risk factor of neurodevelopmental disorders, environmental factors during pregnancy and early life are also important in disease expression. Animal models demonstrate that maternal inflammation causes fetal neuroinflammation and neurodevelopmental deficits, and brain transcriptomics of neurodevelopmental disorders in humans show upregulated differentially expressed genes are enriched in immune pathways. We prospectively recruited 200 sequentially referred children with tic disorders/obsessive-compulsive disorder (OCD), 100 autoimmune neurological controls, and 100 age-matched healthy controls. A structured interview captured the maternal and family history of autoimmune disease and other pro-inflammatory states. Maternal blood and published Tourette brain transcriptomes were analysed for overlapping enriched pathways. Mothers of children with tics/OCD had a higher rate of autoimmune disease compared with mothers of children with autoimmune neurological conditions (p = 0.054), and mothers of healthy controls (p = 0.0004). Autoimmunity was similarly elevated in first- and second-degree maternal relatives of children with tics/OCD (p < 0.0001 and p = 0.014 respectively). Other pro-inflammatory states were also more common in mothers of children with tics/OCD than controls (p < 0.0001). Upregulated differentially expressed genes in maternal autoimmune disease and Tourette brain transcriptomes were commonly enriched in innate immune processes. Pro-inflammatory states, including autoimmune disease, are more common in the mothers and families of children with tics/OCD. Exploratory transcriptome analysis indicates innate immune signalling may link maternal inflammation and childhood tics/OCD. Targeting inflammation may represent preventative strategies in pregnancy and treatment opportunities for children with neurodevelopmental disorders.
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Transtorno Obsessivo-Compulsivo , Transtornos de Tique , Tiques , Autoimunidade/genética , Criança , Feminino , Humanos , Imunidade Inata/genética , Recém-Nascido , Inflamação/genética , Transtorno Obsessivo-Compulsivo/genética , Gravidez , TranscriptomaRESUMO
Genetic early-onset parkinsonism presenting from infancy to adolescence (≤21 years old) is a clinically diverse syndrome often combined with other hyperkinetic movement disorders, neurological and imaging abnormalities. The syndrome is genetically heterogeneous, with many causative genes already known. With the increased use of next-generation sequencing in clinical practice, there have been novel and unexpected insights into phenotype-genotype correlations and the discovery of new disease-causing genes. It is now recognized that mutations in a single gene can give rise to a broad phenotypic spectrum and that, conversely different genetic disorders can manifest with a similar phenotype. Accurate phenotypic characterization remains an essential step in interpreting genetic findings in undiagnosed patients. However, in the past decade, there has been a marked expansion in knowledge about the number of both disease-causing genes and phenotypic spectrum of early-onset cases. Detailed knowledge of genetic disorders and their clinical expression is required for rational planning of genetic and molecular testing, as well as correct interpretation of next-generation sequencing results. In this review we examine the relevant literature of genetic parkinsonism with ≤21 years onset, extracting data on associated movement disorders as well as other neurological and imaging features, to delineate syndromic patterns associated with early-onset parkinsonism. Excluding PRKN (parkin) mutations, >90% of the presenting phenotypes have a complex or atypical presentation, with dystonia, abnormal cognition, pyramidal signs, neuropsychiatric disorders, abnormal imaging and abnormal eye movements being the most common features. Furthermore, several imaging features and extraneurological manifestations are relatively specific for certain disorders and are important diagnostic clues. From the currently available literature, the most commonly implicated causes of early-onset parkinsonism have been elucidated but diagnosis is still challenging in many cases. Mutations in â¼70 different genes have been associated with early-onset parkinsonism or may feature parkinsonism as part of their phenotypic spectrum. Most of the cases are caused by recessively inherited mutations, followed by dominant and X-linked mutations, and rarely by mitochondrially inherited mutations. In infantile-onset parkinsonism, the phenotype of hypokinetic-rigid syndrome is most commonly caused by disorders of monoamine synthesis. In childhood and juvenile-onset cases, common genotypes include PRKN, HTT, ATP13A2, ATP1A3, FBX07, PINK1 and PLA2G6 mutations. Moreover, Wilson's disease and mutations in the manganese transporter are potentially treatable conditions and should always be considered in the differential diagnosis in any patient with early-onset parkinsonism.
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Transtornos dos Movimentos/diagnóstico por imagem , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/genética , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/genética , Fatores Etários , Humanos , Transtornos dos Movimentos/complicações , Mutação/genética , Transtornos Parkinsonianos/complicaçõesRESUMO
Movement disorders differ in children to adults. First, neurodevelopmental movement disorders such as tics and stereotypies are more prevalent than parkinsonism, and second, there is a genomic revolution which is now explaining many early-onset dystonic syndromes. We outline an approach to children with movement disorders starting with defining the movement phenomenology, determining the level of functional impairment due to abnormal movements, and screening for comorbid psychiatric conditions and cognitive impairments which often contribute more to disability than the movements themselves. The rapid improvement in our understanding of the etiology of movement disorders has resulted in an increasing focus on precision medicine, targeting treatable conditions and defining modifiable disease processes. We profile some of the key disease-modifying therapies in metabolic, neurotransmitter, inflammatory, and autoimmune conditions and the increasing focus on gene or cellular therapies. When no disease-modifying therapies are possible, symptomatic therapies are often all that is available. These classically target dopaminergic, cholinergic, alpha-adrenergic, or GABAergic neurochemistry. Increasing interest in neuromodulation has highlighted that some clinical syndromes respond better to DBS, and further highlights the importance of "disease-specific" therapies with a future focus on individualized therapies according to the genomic findings or disease pathways that are disrupted. We summarize some pragmatic applications of symptomatic therapies, neuromodulation techniques, and some rehabilitative interventions and provide a contemporary overview of treatment in childhood-onset movement disorders. © 2019 International Parkinson and Movement Disorder Society.
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Doenças Autoimunes do Sistema Nervoso/terapia , Tomada de Decisão Clínica , Estimulação Encefálica Profunda , Dietoterapia , Terapia Genética , Fatores Imunológicos/uso terapêutico , Erros Inatos do Metabolismo/terapia , Transtornos dos Movimentos/terapia , Agonistas alfa-Adrenérgicos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Doenças Autoimunes do Sistema Nervoso/complicações , Toxinas Botulínicas Tipo A/uso terapêutico , Canabinoides/uso terapêutico , Terapia Baseada em Transplante de Células e Tecidos , Quelantes/uso terapêutico , Ácido Quenodesoxicólico/uso terapêutico , Criança , Suplementos Nutricionais , Dopaminérgicos/uso terapêutico , Terapia de Reposição de Enzimas , GABAérgicos/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Erros Inatos do Metabolismo/complicações , Inibidores da Monoaminoxidase/uso terapêutico , Transtornos dos Movimentos/etiologia , Fármacos Neuromusculares/uso terapêutico , Compostos Organofosforados/uso terapêutico , Pterinas/uso terapêuticoRESUMO
BACKGROUND: Tics are conceptualized as a sensorimotor phenomenon with a premonitory urge typically described by patients. As observed in other neurodevelopmental disorders, we have observed sensory dysregulation symptoms, such as tactile hypersensitivity to clothing, in children with tic disorders; however, formal clinical research in this area is limited. OBJECTIVE: To define the presence of sensory dysregulation symptoms in tic disorders, and their clinical associations. METHODS: Prevalence of sensory dysregulation in 102 children with tic disorders was compared to 61 age- and sex-matched healthy controls. Sensory dysregulation, executive function, and quality of life data were obtained through the Short Sensory Profile-2, Sensory Profile-2, Sensory Processing Measure, Behaviour Rating Inventory of Executive Function-2, and Strength and Difficulties Questionnaire and Pediatric Quality of Life Inventory. Tics were assessed with the Yale Global Tic Severity Scale. RESULTS: Children with tics, in the presence of comorbidity, had elevated sensory dysregulation compared to healthy controls (P < 0.001). There was a positive correlation between sensory dysregulation and global executive difficulties in children with tics and comorbidity (n = 87; rho = 0.716; P < 0.001) and a negative correlation of sensory dysregulation with quality of life (n = 87; rho = -0.595; P < 0.001). In children with tics, there was an association between sensory dysregulation and number of comorbidities (P < 0.001). CONCLUSION: In the presence of comorbidity, children with tic disorders have broad sensory dysregulation symptoms beyond the premonitory urge. There was a statistically significant association between sensory dysregulation and executive function difficulties and the presence of neurodevelopmental and psychiatric comorbidity. Sensory dysregulation can be considered neurodevelopmental symptoms, providing insight into the neurobiology of tics and opportunities for therapeutic intervention. © 2019 International Parkinson and Movement Disorder Society.
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Função Executiva , Transtornos de Sensação/fisiopatologia , Transtornos de Tique/fisiopatologia , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Comorbidade , Estudos Transversais , Deficiências do Desenvolvimento/complicações , Feminino , Humanos , Masculino , Transtornos Mentais/complicações , Prevalência , Escalas de Graduação Psiquiátrica , Qualidade de Vida , Transtornos de Sensação/complicações , Transtornos de Sensação/epidemiologia , Inquéritos e Questionários , Transtornos de Tique/complicações , Transtornos de Tique/epidemiologiaRESUMO
Epidemiological studies, animal models, and case-control studies indicate maternal immune activation may be an important factor involved in disease expression of autism spectrum disorder (ASD), Tourette syndrome, and obsessive-compulsive disorder (OCD). We report eight children (mean age 6y 6mo [range 4-15y]; six males and two females) referred over a 2-year period with at least one of these neurodevelopmental disorders plus a maternal history of thyroid autoimmunity. Seven of eight children presented with an abrupt onset of neuropsychiatric symptoms (OCD [n=6], tics [n=5], and/or psychosis [n=1]), associated with an autistic or global regression. Four children had a pre-existing diagnosis of ASD. Six presentations were preceded by infection, and symptoms followed a relapsing-remitting course in seven children. All children responded to immunomodulatory treatment as indicated by a reduction in psychiatric symptoms, and seven children were also managed with conventional treatment with additional improvement. We propose that maternal autoimmunity can activate fetal microglia or alter transcription of neurodevelopmental vulnerability and/or immune genes in utero, and is an environmental factor that increases the expression and severity of neurodevelopmental problems, and susceptibility to deteriorations after infectious or stress stimuli. WHAT THIS PAPER ADDS: Maternal thyroid autoimmunity may represent a risk factor for neuropsychiatric disorders in offspring. Atypical neuropsychiatric features in these children may be due to maternal immune activation in utero.
AUTOINMUNIDAD MATERNA TIROIDEA ASOCIADA CON TRASTORNOS NEUROPSIQUIÁTRICOS DE INICIO AGUDO Y REGRESIÓN GLOBAL EN LA DESCENDENCIA: Los estudios epidemiológicos, los modelos animales y los estudios de casos y controles indican que la activación inmune materna puede ser un factor importante involucrado en la expresión de la enfermedad del trastorno del espectro autista (TEA), el síndrome de Tourette y el trastorno obsesivo compulsivo (TOC). Informamos ocho niños (edad media 6 años de edad y 6 meses [rango 4-15 años]; 6 varones y 2 mujeres) remitidos durante un período de 2 años con al menos uno de estos trastornos del desarrollo neurológico más un historial materno de autoinmunidad tiroidea. Siete de ocho niños presentaron un inicio brusco de síntomas neuropsiquiátricos (TOC [n = 6], tics [n = 5] y / o psicosis [n = 1]), asociados con una regresión autista o global. Cuatro niños tenían un diagnóstico preexistente de TEA. Seis presentaciones fueron precedidas por infección, y los síntomas siguieron un curso de recaídas y remisiones en siete niños. Todos los niños respondieron al tratamiento inmunomodulador según lo indicado por una reducción en los síntomas psiquiátricos, y siete niños también fueron tratados con tratamiento convencional con una mejora adicional. Proponemos que la autoinmunidad materna puede activar la microglía fetal o alterar la transcripción de la vulnerabilidad del desarrollo neurológico y / o los genes inmunes en el útero, y es un factor ambiental que aumenta la expresión y la gravedad de los problemas del desarrollo neurológico, y la susceptibilidad a deterioros después de estímulos infecciosos o estresantes.
AUTOIMUNIDADE TIREÓIDE MATERNA ASSOCIADA COM DESORDENS NEUROPSIQUIÁTRICAS DE INÍCIO AGUDO E REGRESSÃO GLOBAL NA PROLE: Estudos epidemiológicos, modelos animais, e estudos de caso-controle indicam que a ativação imune materna pode ser um importante fator envolvido na expressão de doenças do transtorno do espectro autista (TEA), síndrome de Tourette, e transtorno obsessivo compulsivo (TOC). Reportamos oito crianças (média de idade 6a 6m [variação 4-15a]; 6 do sexo masculino e 2 do sexo feminino) encaminhadas em um período de 2 anos com pelo menos uma desordem neurodesenvolvimental e história de auto-imunidade tireóide materna. Sete das oito crianças apresentaram início agudo de sintomas neuropsiquiátricos (TOC [n=6], tiques [n=5], e/ou psicose [n=1]), associados com regressão autística ou global. Quatro crianças tinham diagnóstico pré-existente de TEA. Seis apresentações foram precedidas por infecção, e os sintomas seguiram um curso recorrência-remisão em sete crianças. Todas as crianças responderam ao tratamento imunomodulatório, indicado pela redução nos sintomas psiquiátricos, e sete crianças também foram abordadas com tratamento convencional, com melhora adicional. Nós propomos que a autoimunidade maternal pode ativar a microglia fetal ou alterar a transcrição de genes de vulnerabilidade neurodesenvolvimental e/ou imunes, e um fator ambiental pode aumentar a expressão e severidade de problemas neurodesenvolvimentais e suscetibilidade a deterioração após estímulo infeccioso ou estresse.
Assuntos
Transtornos de Ansiedade/imunologia , Transtorno do Espectro Autista/imunologia , Doença de Hashimoto/imunologia , Transtornos do Neurodesenvolvimento/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Glândula Tireoide/imunologia , Transtornos de Tique/imunologia , Adolescente , Transtornos de Ansiedade/psicologia , Transtorno do Espectro Autista/psicologia , Criança , Pré-Escolar , Feminino , Doença de Hashimoto/psicologia , Humanos , Masculino , Transtornos do Neurodesenvolvimento/psicologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Transtornos de Tique/psicologiaRESUMO
AIM: We used magnetic resonance imaging (MRI) to compare the neuroimaging of children with their first episode of clinical enterovirus 71-associated transverse myelitis (EV71-TM), myelin oligodendrocyte glycoprotein antibody positive transverse myelitis (MOG-TM), aquaporin-4 antibody positive transverse myelitis (AQP4-TM), transverse myelitis in multiple sclerosis (MS-TM), and unclassified transverse myelitis (UNC-TM). METHOD: We performed a retrospective blinded radiological assessment and compared the neuroimaging of 52 children (32 females, 20 males; mean age 9y 8mo, SD 5y 5mo, range 5mo-17y) presenting with their first episode of myelitis caused by EV71-TM (n=11), MOG-TM (n=10), AQP4-TM (n=9), MS-TM (n=13), and UNC-TM (n=9). RESULTS: In the EV71-TM group, lesions were distributed throughout the cord and enhancement of nerve roots (ventral and dorsal) was common. The MOG-TM group had lesions distributed throughout the cord and most commonly longitudinally extensive transverse myelitis and lesions involving the grey matter alone on axial scans. The AQP4-TM group had lesions distributed in the cervicothoracic spine, cavitation, and contrast enhancing lesions. All patients with AQP4-TM had an abnormal brain MRI scan. The MS-TM group characteristically had multiple short segment lesions of the cord involving the cervicothoracic spine. The UNC-TM group did not have distinctive spinal MRI findings but had a relative paucity of lesions on their brain MRI scans. INTERPRETATION: There are neuroimaging findings that are helpful in differentiating between myelitis associated with EV71, MOG, AQP4, and multiple sclerosis in children. These features may be useful early in the presentation of transverse myelitis while awaiting infectious/immunological testing, and/or further demyelinating events. WHAT THIS PAPER ADDS: Magnetic resonance imaging can help identify aetiologies for children presenting with a first episode of myelitis. Entervirus-71-associated myelitis lesions are distributed throughout the cord and enhancement of nerve roots is common. Lesions distributed throughout the cord are commonly seen in myelin oligodendrocyte-associated myelitis. Aquaporin-4-associated myelitis lesions are distributed in the cervicothoracic spine, cavitation and contrast enhancing lesions are common. Short segment lesions in the cervicothoracic spine are commonly seen in multiple sclerosis-associated myelitis.
IMÁGENES DE RESONANCIA MAGNÉTICA EN ENTEROVIRUS-71, ANTICUERPOS DE GLICOPROTEÍNA DE LA MIELINA DEL OLIGODENDROCITO, ANTICUERPOS AQUAPORIN-4, Y ESCLEROSIS MÚLTIPLE-ASOCIADA A MIELITIS EN NIÑOS: OBJETIVO: Utilizamos imágenes de resonancia magnética (IRM) para comparar la neuroimagen de los niños con su primer episodio clínico de enterovirus 71-asociado a mielitis transversa (EV71-TM), mielitis transversa con anticuerpos de glicoproteína de la mielina del oligodendrocito positivos (MOG-TM), mielitis transversa con anticuerpos aquaporin-4 positivos (AQP4-TM), mielitis transversa en esclerosis múltiple (MS-TM) y mielitis transversa no clasificada (UNC-TM). MÉTODO: Se realizó un análisis radiológico, ciego, retrospectivo y se comparó la neuroimagen de 52 niños (32 mujeres, 20 varones; con edad promedio 9 años 8 meses, La DS 5 años 5 meses, el rango de 5 meses -17 años) que presentaron su primer episodio de mielitis causada por EV71-TM (n= 11), MOG-TM (n= 10), AQP4-TM (n= 9), MS-TM (n= 13) y UNC-TM (n= 9). RESULTADOS: En el grupo de EV71-TM, fue común observar lesiones distribuidas a través de la medula con realce de las raíces de nervio (ventrales y dorsales). El grupo de MOG-TM tenía lesiones distribuidas a través de la médula, más comúnmente mielitis transversa longitudinalmente extensa y lesiones que implican solamente la sustancia gris en exploraciones axiales. El grupo AQP4-TM tenía lesiones distribuidas en la medula cervicodorsal, cavitación y lesiones con realce en el contraste. Todos Pacientes con AQP4-TM tenían una IRM cerebral anormal. El grupo de MS-TM característicamente tenía lesiones múltiples de segmentos pequeños de la medula que involucran las regiones cervical y dorsal. El grupo UNC-TM no tenía hallazgos de IRM distintivos en la medula espinal, pero tenía una relativa escasez de lesiones cerebrales IRM. INTERPRETACIÓN: Hay hallazgos de neuroimagen en niños que son útiles en diferenciar entre mielitis asociada a EV71, a MOG, a AQP4, y esclerosis múltiple. Estas características pueden ser útiles al inicio de la presentación de la mielitis transversa mientras se espera la prueba infecciosa/inmunológica y/u otros acontecimientos desmielinizantes.
IMAGEM POR RESSONÂNCIA MAGNÉTICA EM ENTEROVÍRUS-71, ANTICORPO DA GLICOPROTEÍNA DE OLIGODENDRÓCITO DA MIELINA, ANTICORPO AQUAPORINA-4, E MIELITE ASSOCIADA A ESCLEROSE MÚLTIPLA EM CRIANÇAS: OBJETIVO: Usamos imagens de ressonância funcional (IRM) para comparar as neuroimagens de crianças com o primeiro episósio de mielite transversa clínica associada a enterovírus-71 (MT-EV71), mielite transversa positiva para anticorpo da glicoproteína de oligodendrócit oda mielina (MT-GOM), mielite transversa positiva para anticorpo aquaporina-4 (MT-AQP4), mielite transversa em esclerose múltipla (MT-EM), e mielite transversa não classificada (MT-NC). MÉTODO: Realizamos uma avaliação radiológica retrospectiva cega, e comparamos a neuroimagem de 52 crianças (32 do sexo feminino, 20 do sexo masculino; média de idade 9a 8m, DP 5a 5m, variação 5m-17a) apresentando seu primeiro episódio de mielite causada por MT-EV71 (n=11), MT-GOM (n=10), MT-AQP4 (n=9), MT-EM (n=13), e MT-NC (n=9). RESULTADOS: No grupo MT-EV71, as lesões se distribuíram por toda a medula, e realces das raízes nervosas (ventrais e dorsais) eram comuns. O grupo MT-GOM teve lesões distribuídas por toda a medula, e mais comumente mielite transversa extensiva longitudinalmente e lesões envolvendo apenas a substância cinzenta nas imagens axiais. O grupo MT-AQP4 teve lesões distribuídas na coluna cérvico-torácica, cavitação, e lesões realçadas pelo contraste. Todos os pacientes com MT-AQP4 -tiveram uma IRM cerebral anormal. O grupo MT-EM caracteristicamente teve múltiplas lesões de segmentos curtos da medula envolvendo a região cérvico-torácica. O grupo MT-NC não teve achados distintivos de IRM espinhal, mas tiveram relativamente menos lesões nas imagens cerebrais. INTERPRETAÇÃO: Há achados de neuroimagem úteis para diferenciar a mielite associada com EV71, GOM, AQP4 e esclerose múltipla em crianças. Estes aspectos podem ser úteis na apresentação precoce da mielite transversa, enquanto se aguarda testes infecciosos/imunológicos, e e/ou outros eventos desmielinizantes.
Assuntos
Aquaporina 4/imunologia , Encéfalo/diagnóstico por imagem , Enterovirus Humano A/imunologia , Esclerose Múltipla/diagnóstico por imagem , Glicoproteína Mielina-Oligodendrócito/imunologia , Mielite/diagnóstico por imagem , Adolescente , Autoanticorpos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla/imunologia , Mielite/imunologia , Estudos RetrospectivosRESUMO
There is accumulating evidence that patients with functional neurological symptom disorder (FND) show activation of multiple components of the stress system-the hypothalamic-pituitary-adrenal axis, autonomic nervous system, and brain regions involved in arousal- and emotion-processing. This study aims to examine whether the immune-inflammatory component of the stress system is also activated. C-reactive protein (CRP) blood titre levels were measured in 79 children and adolescents with FND. CRP values ≥ 2 mg/L suggest low-grade inflammation. CRP values > 10 mg/L suggest a disease process. Sixty-six percent of subjects (n = 52) had CRP titres ≥ 2 mg/L. The upward shift in the distribution of CRP levels suggested low-grade inflammation (median CRP concentration was 4.60 mg/L, with 75th and 90th percentiles of 6.1 and 10.3 mg/L, respectively). Elevated CRP titres were not explained by sex, pubertal status, BMI, or medical factors. Confounder analyses suggested that history of maltreatment (χ2 = 2.802, df = 1, p = 0.094, φ = 0.190; ß = 2.823, p = 0.04) and a diagnosis of anxiety (χ2 = 2.731, df = 1, p = 0.098, φ = 0.187; ß = 4.520, p = 0.061) contributed to elevated CRP levels. Future research will need to identify the origins and locations of immune cell activation and the pathways and systems contributing to their activation and modulation. Because functional activity in neurons and glial cells-the brain's innate effector immune cells-is tightly coupled, our finding of elevated CRP titres suggests activation of the immune-inflammatory component of the brain's stress system. A more direct examination of inflammation-related molecules in the brain will help clarify the role of immune-inflammatory processes in FND.
Assuntos
Proteína C-Reativa/metabolismo , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/diagnóstico , Transtornos do Neurodesenvolvimento/sangue , Transtornos do Neurodesenvolvimento/diagnóstico , Adolescente , Ansiedade/sangue , Ansiedade/diagnóstico , Ansiedade/psicologia , Biomarcadores/sangue , Encéfalo/metabolismo , Criança , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Doenças do Sistema Nervoso/psicologia , Transtornos do Neurodesenvolvimento/psicologia , Sistema Hipófise-Suprarrenal/metabolismo , Autorrelato/normasRESUMO
OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10 mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of ≥2 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation.