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The ubiquitin-proteasome system mediates the degradation of a wide variety of proteins. Proteasome dysfunction is associated with neurodegenerative diseases and neurodevelopmental disorders in humans. Here we identified mutations in PSMC5, an AAA ATPase subunit of the proteasome 19S regulatory particle, in individuals with neurodevelopmental disorders, which were initially considered as variants of unknown significance. We have now found heterozygotes with the following mutations: P320R (6 individuals), R325W, Q160A, and one nonsense mutation at Q69. We focused on understanding the functional consequence of PSMC5 insufficiency and the P320R mutation in cells and found that both impair proteasome function and activate apoptosis. Interestingly, the P320R mutation impairs proteasome function by weakening the association between the 19S regulatory particle and the 20S core particle. Our study supports that proteasome dysfunction is the pathogenic cause of neurodevelopmental disorders in individuals carrying PSMC5 variants.
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Variants in the FIG4 gene, which encodes a phosphatidylinositol-3,5-bisphosphatase lead to obstruction of endocytic trafficking, causing accumulation of enlarged vesicles in murine peripheral neurons and fibroblasts. Bi-allelic pathogenic variants in FIG4 are associated with neurological disorders including Charcot-Marie-Tooth disease type-4J (CMT4J) and Yunis-Varón syndrome (YVS). We present four probands from three unrelated families, all homozygous for a recurrent FIG4 missense variant c.506A>C p.(Tyr169Ser), with a novel phenotype involving features of both CMT4J and YVS. Three presented with infant-onset dystonia and one with hypotonia. All have depressed lower limb reflexes and distal muscle weakness, two have nerve conduction studies (NCS) consistent with severe sensorimotor demyelinating peripheral neuropathy and one had NCS showing patchy intermediate/mildly reduced motor conduction velocities. All have cognitive impairment and three have swallowing difficulties. MRI showed cerebellar atrophy and bilateral T2 hyperintense medullary swellings in all patients. These children represent a novel clinicoradiological phenotype and suggest that phenotypes associated with FIG4 missense variants do not neatly fall into previously described diagnoses but can present with variable features. Analysis of this gene should be considered in patients with central and peripheral neurological signs and medullary radiological changes, providing earlier diagnosis and informing reproductive choices.
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Doença de Charcot-Marie-Tooth/genética , Displasia Cleidocraniana/genética , Displasia Ectodérmica/genética , Flavoproteínas/genética , Predisposição Genética para Doença , Deformidades Congênitas dos Membros/genética , Micrognatismo/genética , Monoéster Fosfórico Hidrolases/genética , Idade de Início , Doença de Charcot-Marie-Tooth/complicações , Doença de Charcot-Marie-Tooth/patologia , Criança , Pré-Escolar , Displasia Cleidocraniana/complicações , Displasia Cleidocraniana/patologia , Distonia/complicações , Distonia/genética , Distonia/patologia , Displasia Ectodérmica/complicações , Displasia Ectodérmica/patologia , Feminino , Genótipo , Humanos , Deformidades Congênitas dos Membros/complicações , Deformidades Congênitas dos Membros/patologia , Masculino , Micrognatismo/complicações , Micrognatismo/patologia , Hipotonia Muscular/complicações , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Mutação/genética , Linhagem , FenótipoRESUMO
Drug-resistant epilepsy (DRE) occurs in 20%-30% of children with epilepsy with significant impact on their quality of life. Management of this group of children has greatly improved in the recent years with streamlining of epilepsy surgery services and associated quaternary multimodal evaluation. This article provides a review of DRE in children and management based on recent evidence and published opinion. We have also presented an algorithmic approach to the child with possible DRE.
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Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/terapia , Epilepsia/diagnóstico , Epilepsia/terapia , Convulsões/terapia , Anticonvulsivantes/uso terapêutico , Criança , Diagnóstico Diferencial , Dieta Cetogênica , Humanos , Convulsões/etiologia , Estimulação do Nervo VagoRESUMO
BACKGROUND: Idiopathic intracranial hypertension (IIH) is a potentially disabling condition. There is a lack of evidence and national guidance on how to diagnose and treat paediatric IIH, leading to variation in clinical practice. We conducted a national Delphi consensus via the Children's Headache Network to propose a best-practice diagnostic and therapeutic pathway. METHODS: The Delphi process was selected as the most appropriate methodology for examining current opinion among experts in the UK. 104 questions were considered by 66 healthcare professionals, addressing important aspects of IIH care: assessment, diagnosis, treatment, follow-up and surveillance. General paediatricians, paediatric neurologists, ophthalmologists, opticians, neuroradiologists and neurosurgeons with a clinical interest or experience in IIH, were invited to take part. RESULTS: The Delphi process consisted of three rounds comprising 104 questions (round 1, 67; round 2, 24; round 3 (ophthalmological), 13) and was completed between March 2019 and August 2021. There were 54 and 65 responders in the first and second rounds, respectively. The Delphi was endorsed by the Royal College of Ophthalmologists, which engaged 59 ophthalmologists for round 3. CONCLUSIONS: This UK-based Delphi consensus process reached agreement for the management of paediatric IIH and has been endorsed by the Children's Headache Network and more broadly, the British Paediatric Neurology Association. It provides a basis for a pragmatic clinical approach. The recommendations will help to improve clinical care while minimising under and over diagnosis.
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Consenso , Técnica Delphi , Pseudotumor Cerebral , Humanos , Criança , Pseudotumor Cerebral/diagnóstico , Pseudotumor Cerebral/terapia , Pseudotumor Cerebral/complicações , Adolescente , Reino Unido , Guias de Prática Clínica como AssuntoRESUMO
AIM: This study explored inter-rater reliability, discriminative, construct and predictive validity of the Neurobehavioral Assessment of the Preterm Infant (NAPI) in a gestational-age-based cohort. METHODS: The NAPI was conducted at 35 weeks post-menstrual age for 170 infants born <32 weeks. Cognitive and motor development was assessed at 2 years using the Mental Development Index (MDI) and Psychomotor Development Index (PDI) of Bayley Scales of Infant Development-II for 159 infants. RESULTS: Only NAPI motor and irritability scores were significantly different between very (29-3 w) and extremely preterm (<28 w) infants. Results regarding construct validity were variable: there were weak correlations between NAPI motor scores and gestational age (r = -0.23; p = 0.003), days in NICU (r = -0.24; p = 0.001); NAPI alertness scores and days in NICU (r = -0.16; p = 0.037); and NAPI irritability scores and gestational age (r = 0.21; p = 0.006). There were no significant associations with other markers of adverse outcome. Only NAPI irritability scores were correlated with MDI scores (r = -0.16; p = 0.040) but accounted for little additional variance after adjustment for neonatal factors (ΔR(2) = 0.035; p = 0.012). CONCLUSION: We found little evidence of the utility of the NAPI as a measure of short-term neurobehavioural function or for predicting neurodevelopmental outcomes in very preterm infants. It may have greater predictive power when used serially to detect delayed neurobehavioural maturation.
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Desenvolvimento Infantil , Recém-Nascido Prematuro/psicologia , Testes Neuropsicológicos , Pré-Escolar , Cognição , Feminino , Seguimentos , Humanos , Recém-Nascido , Humor Irritável , Masculino , Destreza Motora , Variações Dependentes do Observador , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is one of the most well-known mitochondrial diseases, with most cases attributed to m.3243A>G. MELAS syndrome patients typically present in the first two decades of life with a broad, multi-systemic phenotype that predominantly features neurological manifestations--stroke-like episodes. However, marked phenotypic variability has been observed among paediatric patients, creating a clinical challenge and delaying diagnoses. METHODS: A literature review of paediatric MELAS syndrome patients and a retrospective analysis in a UK tertiary paediatric neurology centre were performed. RESULTS: Three children were included in this case series. All patients presented with seizures and had MRI changes not confined to a single vascular territory. Blood heteroplasmy varied considerably, and one patient required a muscle biopsy. Based on a literature review of 114 patients, the mean age of presentation is 8.1 years and seizures are the most prevalent manifestation of stroke-like episodes. Heteroplasmy is higher in a tissue other than blood in most cases. CONCLUSION: The threshold for investigating MELAS syndrome in children with suspicious neurological symptoms should be low. If blood m.3243A>G analysis is negative, yet clinical suspicion remains high, invasive testing or further interrogation of the mitochondrial genome should be considered.
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Acidose Láctica , Síndrome MELAS , Acidente Vascular Cerebral , Acidose Láctica/genética , Criança , Humanos , Síndrome MELAS/diagnóstico , Síndrome MELAS/genética , Síndrome MELAS/patologia , Estudos Retrospectivos , Convulsões , Acidente Vascular Cerebral/genéticaRESUMO
OBJECTIVE: Cannabidiol is efficacious as an adjunctive treatment in children with epilepsy associated with Dravet and Lennox-Gastaut syndromes. As its role is currently adjunctive, we reviewed the interactions of cannabidiol with other antiseizure medications (ASMs). METHODS: A search of Cochrane, Pubmed and Embase databases from January 2015 to April 2020 was performed. All original research papers discussing interactions between cannabidiol and ASMs were included. Bibliographies of review articles were searched to identify further papers. Adverse events and side effects were excluded. RESULTS: Cannabidiol interacts with ASMs through both pharmacokinetic and pharmacodynamic mechanisms. Thirty studies were identified (eighteen observational cohort studies, two randomised-control trials, three case reports/series, three animal studies, two briefing reports, an analysis of cohort data and a clinical trial simulation). There is potential for pharmacokinetic interactions between CBD and brivaracetam, clobazam, eslicarbazepine, lacosamide, gabapentin, oxcarbazepine, phenobarbital, potassium bromide, pregabalin, rufinamide, sirolimus/everolimus, stiripentol, tiagabine, topiramate and zonisamide. Pharmacodynamic interactions were identified for clobazam, valproate and levetiracetam. An animal study identified that the brain concentration of ASMs may be altered while the serum concentration remains the same. CONCLUSION: Pharmacokinetic and pharmacodynamic interactions exist between cannabidiol and ASMs. The cytochrome p450 system in particular has been implicated in pharmacokinetic interactions, although not exclusively. The existing literature is limited for some ASMs by studies having relatively small cohorts. As increasing numbers of patients use cannabidiol, specialists need to monitor closely for interactions clinically and with blood levels when required.
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Canabidiol/uso terapêutico , Animais , Anticonvulsivantes/uso terapêutico , Clobazam/uso terapêutico , Interações Medicamentosas , Humanos , Síndrome de Lennox-Gastaut/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Children and adolescents treated with antiepileptic drugs are known to have problems with bone metabolism, bone mineral density loss, and 2-3 times the fracture risk of healthy controls. We reviewed the literature regarding bone mineral density in children with epilepsy and vitamin D therapy in children treated with anti-epileptic drugs. Studies of bone mineral density markers in children with epilepsy have mostly found little significant difference in bone mineral density markers in children with epilepsy. They have been limited by small sample size and many of the studies have not corrected for confounding factors such as comorbidities, mobility, nutrition, and obesity. Studies of vitamin D therapy in children with epilepsy have shown little evidence of effect and have been similarly limited by lack of stratification with regard to confounding factors. There is a need for larger studies, using clinically significant outcomes such as fractures, including at risk populations such as symptomatic generalised epilepsy, impaired mobility, and polytherapy. At the present time in the absence of good evidence to the contrary, there remains concern that children with epilepsy are at risk of poor bone health and that vitamin D therapy may be beneficial. As low-dose vitamin D supplementation (400 IU per day) is now recommended for healthy children and it is biologically feasible that children with epilepsy may be at higher risk of clinically significant deficiency, it is important that neurologists ensure that low-dose vitamin D supplementation should be prescribed and compliance followed up in children with epilepsy.
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There has been a long-held belief that outcomes for babies born at moderate and late preterm gestations do not differ substantially from those of infants born at full term. This has recently been challenged by studies highlighting an increased risk of adverse neonatal outcomes, and of poorer cognitive, behavioural and educational outcomes in this population. Data about the effects of birth at moderate and late preterm gestations on later health outcomes are limited, but emerging evidence suggests that ongoing physical health may also be worse in those born just a few weeks before full term. This review summarises the available evidence, considers the factors influencing health outcomes and discusses the implications for the planning and provision of children's health care services.
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Saúde/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Doenças do Prematuro/epidemiologia , Transtornos Respiratórios/epidemiologia , Criança , Pré-Escolar , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Estudos Longitudinais , Readmissão do Paciente/estatística & dados numéricosRESUMO
Cerebral cavernous malformations (CCMs) are vascular malformations causing seizures and cerebral hemorrhages. We report a 20-month old male with multiple CCMs associated with Krev interaction trapped 1 (KRIT1) c.845 + 1 G > C heterozygous transversion mutation. This case demonstrates the importance of molecular genetic analysis in cases of multiple CCM.