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1.
PLoS One ; 15(12): e0242367, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33320867

RESUMO

BACKGROUND: The signs and symptoms of Zika virus infection are usually mild and self-limited. However, the disease has been linked to neurological complications such as Guillain-Barré syndrome and peripheral nerve involvement, and also to abortion and fetal deaths due to vertical transmission, resulting in various congenital malformations in newborns, including microcephaly. This review aimed to describe the o signs and symptoms that characterize the congenital Zika syndrome. METHODS AND FINDINGS: A systematic review was performed with a protocol and described according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The search strategy yielded 2,048 studies. After the exclusion of duplicates and application of inclusion criteria, 46 studies were included. The main signs and symptoms associated with the congenital Zika syndrome were microcephaly, parenchymal or cerebellar calcifications, ventriculomegaly, central nervous system hypoplasia or atrophy, arthrogryposis, ocular findings in the posterior and anterior segments, abnormal visual function and low birthweight for gestational age. CONCLUSIONS: Zika virus infection during pregnancy can cause a series of changes in the growth and development of children, while impacting the healthcare system due to the severity of cases. Our findings outline the disease profile in newborns and infants and may contribute to the development and updating of more specific clinical protocols.


Assuntos
Síndrome de Guillain-Barré/diagnóstico , Transmissão Vertical de Doença Infecciosa , Malformações do Sistema Nervoso/diagnóstico , Complicações Infecciosas na Gravidez/virologia , Infecção por Zika virus/transmissão , Desenvolvimento Infantil/fisiologia , Feminino , Síndrome de Guillain-Barré/virologia , Humanos , Lactente , Recém-Nascido , Malformações do Sistema Nervoso/fisiopatologia , Malformações do Sistema Nervoso/virologia , Gravidez , Síndrome , Zika virus/patogenicidade , Infecção por Zika virus/complicações , Infecção por Zika virus/congênito , Infecção por Zika virus/virologia
2.
C R Biol ; 343(1): 9-21, 2020 Jun 05.
Artigo em Francês | MEDLINE | ID: mdl-32720483

RESUMO

DNA replication is an extremely complex process, involving thousands of replication forks progressing along chromosomes. These forks are frequently slowed down or stopped by various obstacles, such as secondary DNA structures, chromatin-acting proteins or a lack of nucleotides. This slowing down, known as replicative stress, plays a central role in tumour development. Complex processes, which are not yet fully understood, are set up to respond to this stress. Certain nucleases, such as MRE11 and DNA2, degrade the neo-replicated DNA at the level of blocked forks, allowing the replication to restart. The interferon pathway is a defense mechanism against pathogens that detects the presence of foreign nucleic acids in the cytoplasm and activates the innate immune response. DNA fragments resulting from genomic DNA metabolism (repair, retrotransposition) can diffuse into the cytoplasm and activate this pathway. A pathological manifestation of this process is the Aicardi-Goutières syndrome, a rare disease characterized by chronic inflammation leading to neurodegenerative and developmental problems. In this encephalopathy, it has been suggested that DNA replication may generate cytosolic DNA fragments, but the mechanisms involved have not been characterized. SAMHD1 is frequently mutated in the Aicardi-Goutières syndrome as well as in some cancers, but its role in the etiology of these diseases was largely unknown. We show that cytosolic DNA accumulates in SAMHD1-deficient cells, particularly in the presence of replicative stress, activating the interferon response. SAMHD1 is important for DNA replication under normal conditions and for the processing of stopped forks, independent of its dNTPase activity. In addition, SAMHD1 stimulates the exonuclease activity of MRE11 in vitro. When SAMHD1 is absent, degradation of neosynthesized DNA is inhibited, which prevents activation of the replication checkpoint and leads to failure to restart the replication forks. Resection of the replication forks is performed by an alternative mechanism which releases DNA fragments into the cytosol, activating the interferon response. The results obtained show, for the first time, a direct link between the response to replication stress and the production of interferons. These results have important implications for our understanding of the Aicardi-Goutières syndrome and cancers related to SAMHD1. For example, we have shown that MRE11 and RECQ1 are responsible for the production of DNA fragments that trigger the inflammatory response in cells deficient for SAMHD1. We can therefore imagine that blocking the activity of these enzymes could decrease the production of DNA fragments and, ultimately, the activation of innate immunity in these cells. In addition, the interferon pathway plays an essential role in the therapeutic efficacy of irradiation and certain chemotherapeutic agents such as oxaliplatin. Modulating this response could therefore be of much wider interest in anti-tumour therapy.


Assuntos
Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Interferons/metabolismo , Malformações do Sistema Nervoso/fisiopatologia , Proteína 1 com Domínio SAM e Domínio HD/metabolismo , DNA , Replicação do DNA , Humanos , RecQ Helicases/metabolismo
3.
Crit Care ; 23(1): 323, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623658

RESUMO

BACKGROUND: Most deaths of comatose survivors of out-of-hospital sudden cardiac arrest result from withdrawal of life-sustaining treatment (WLST) decisions based on poor neurological prognostication and the family's intention. Thus, accurate prognostication is crucial to avoid premature WLST decisions. However, targeted temperature management (TTM) with sedation or neuromuscular blockade against shivering significantly affects early prognostication. In this study, we investigated whether heart rate variability (HRV) analysis could prognosticate poor neurological outcome in comatose patients undergoing hypothermic TTM. METHODS: Between January 2015 and December 2017, adult patients with out-of-hospital sudden cardiac arrest, successfully resuscitated in the emergency department and admitted to the intensive care unit of the Niigata University in Japan, were prospectively included. All patients had an initial Glasgow Coma Scale motor score of 1 and received hypothermic TTM (at 34 °C). Twenty HRV-related variables (deceleration capacity; 4 time-, 3 geometric-, and 7 frequency-domain; and 5 complexity variables) were computed based on RR intervals between 0:00 and 8:00 am within 24 h after return of spontaneous circulation (ROSC). Based on Glasgow Outcome Scale (GOS) at 2 weeks after ROSC, patients were divided into good outcome (GOS 1-2) and poor outcome (GOS 3-5) groups. RESULTS: Seventy-six patients were recruited and allocated to the good (n = 22) or poor (n = 54) outcome groups. Of the 20 HRV-related variables, ln very-low frequency (ln VLF) power, detrended fluctuation analysis (DFA) (α1), and multiscale entropy (MSE) index significantly differed between the groups (p = 0.001), with a statistically significant odds ratio (OR) by univariate logistic regression analysis (p = 0.001). Multivariate logistic regression analysis of the 3 variables identified ln VLF power and DFA (α1) as significant predictors for poor outcome (OR = 0.436, p = 0.006 and OR = 0.709, p = 0.024, respectively). The area under the receiver operating characteristic curve for ln VLF power and DFA (α1) in predicting poor outcome was 0.84 and 0.82, respectively. In addition, the minimum value of ln VLF power or DFA (α1) for the good outcome group predicted poor outcome with sensitivity = 61% and specificity = 100%. CONCLUSIONS: The present data indicate that HRV analysis could be useful for prognostication for comatose patients during hypothermic TTM.


Assuntos
Determinação da Frequência Cardíaca/métodos , Malformações do Sistema Nervoso/etiologia , Parada Cardíaca Extra-Hospitalar/complicações , Parada Cardíaca Extra-Hospitalar/mortalidade , Prognóstico , Adulto , Idoso , Área Sob a Curva , Feminino , Escala de Resultado de Glasgow , Determinação da Frequência Cardíaca/instrumentação , Humanos , Japão/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Malformações do Sistema Nervoso/mortalidade , Malformações do Sistema Nervoso/fisiopatologia , Parada Cardíaca Extra-Hospitalar/epidemiologia , Estudos Prospectivos , Curva ROC , Estatísticas não Paramétricas , Fatores de Tempo
4.
Am J Med Genet A ; 179(9): 1799-1814, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31294918

RESUMO

Sacral agenesis is a rare birth defect characterized by partial or complete absence of the sacrum. We sought to (a) describe case characteristics, (b) estimate birth prevalence, and (c) identify risk factors for nonsyndromic sacral agenesis using data from the National Birth Defects Prevention Study (NBDPS). The NBDPS was a population-based, case-control study involving pregnancies with estimated dates of delivery from October 1997 through December 2011. We estimated birth prevalence using all NBDPS eligible cases. Using self-reported maternal exposure information, we conducted multivariable logistic regression analysis to identify potential risk factors overall and among women without diabetes. The birth prevalence of sacral agenesis was 2.6/100,000 live births. In the multivariable analysis, multifetal pregnancy, pre-existing Type 1 diabetes, and pre-existing Type 2 diabetes were positively and significantly associated with sacral agenesis, albeit estimates were imprecise. Preexisting Type 1 diabetes was the strongest risk factor (adjusted odds ratio = 96.6, 95% confidence interval = 43.5-214.7). Among women without diabetes, periconceptional smoking was positively and significantly associated with sacral agenesis. Our findings underscore the importance of smoking cessation programs among women planning pregnancy and the importance of better understanding the role of glycemic control before and during pregnancy when designing interventions for primary prevention of sacral agenesis.


Assuntos
Anormalidades Múltiplas/epidemiologia , Anormalidades Congênitas/epidemiologia , Diabetes Mellitus/epidemiologia , Meningocele/epidemiologia , Malformações do Sistema Nervoso/epidemiologia , Região Sacrococcígea/anormalidades , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adulto , Estudos de Casos e Controles , Anormalidades Congênitas/genética , Anormalidades Congênitas/fisiopatologia , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/genética , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus/genética , Diabetes Mellitus/fisiopatologia , Feminino , Humanos , Recém-Nascido , Masculino , Exposição Materna , Meningocele/etiologia , Meningocele/genética , Meningocele/fisiopatologia , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , População/genética , Gravidez , Fatores de Risco , Região Sacrococcígea/fisiopatologia , Sacro/anormalidades
5.
Eur J Med Genet ; 62(8): 103704, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31207318

RESUMO

Whole exome sequencing undertaken in two siblings with delayed psychomotor development, absent speech, severe intellectual disability and postnatal microcephaly, with brain malformations consisting of cerebellar atrophy in the eldest affected and hypoplastic corpus callosum in the younger sister; revealed a homozygous intragenic deletion in VPS51, which encodes the vacuolar protein sorting-associated protein, one the four subunits of the Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes that promotes the fusion of endosome-derived vesicles with the trans-Golgi network (GARP) and recycling endosomes (EARP). This observation supports a pathogenic effect of VPS51 variants, which has only been reported previously once, in a single child with microcephaly. It confirms the key role of membrane trafficking in normal brain development and homeostasis.


Assuntos
Encéfalo/fisiopatologia , Microcefalia/genética , Malformações do Sistema Nervoso/genética , Proteínas de Transporte Vesicular/genética , Encéfalo/diagnóstico por imagem , Criança , Endossomos/genética , Feminino , Humanos , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/fisiopatologia , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/fisiopatologia , Transporte Proteico/genética , Rede trans-Golgi/genética
8.
World Neurosurg ; 126: 564-569, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30898734

RESUMO

BACKGROUND: The clinical advantage of telemetric intracranial pressure (ICP) monitoring has previously been limited by issues with inaccuracy and zero-drift. Today, 2 comparable telemetric ICP monitoring systems are available performing adequately in these parameters. The objective of this study is to identify appropriate uses of each system. METHODS: The 2 telemetric ICP monitoring systems from Raumedic (implant: Neurovent-P-tel) and Miethke (implant: Sensor Reservoir) are compared in terms of fundamental differences, sensor survival, monitoring possibilities, complications, and cost/benefit. Two illustrative cases are presented highlighting clinical advantages and disadvantages of each system. RESULTS: Both systems provide transdermal (telemetric) ICP measurements through external application of a reader unit cabled to a portable data sampler. Thereby, they allow several ICP monitoring sessions without multiple surgical insertions of a cabled ICP sensor. The Miethke implant has a high sampling frequency (40 Hz) and a long CE (Conformité Européenne) approval (3 years) but cannot be used for long-duration monitoring sessions. In comparison, the Raumedic implant has a lower sampling frequency (5 Hz) and shorter CE approval (90 days) but can be used for long-duration monitoring sessions. The standard 3-year cost for a patient with a Neurovent-P-tel is 17,380 €, and for the Sensor Reservoir it is 15,790 €. CONCLUSIONS: The Miethke system is useful in outpatient clinics where patients have sequential point measurements of ICP performed, whereas the Raumedic system is ideal for long-duration ICP monitoring outside the hospital. When choosing between the 2 systems, it must primarily be decided if the clinical situation requires long-duration monitoring sessions or continuous repeated ambulatory follow-up sessions.


Assuntos
Hipertensão Intracraniana/diagnóstico , Pressão Intracraniana/fisiologia , Manometria/métodos , Monitorização Fisiológica/métodos , Telemetria/métodos , Anormalidades Múltiplas , Adulto , Assistência Ambulatorial/economia , Assistência Ambulatorial/métodos , Derivações do Líquido Cefalorraquidiano , Criança , Desenho de Equipamento , Feminino , Humanos , Hidrocefalia/diagnóstico , Hidrocefalia/fisiopatologia , Hidrocefalia/cirurgia , Hipertensão Intracraniana/fisiopatologia , Masculino , Manometria/economia , Manometria/instrumentação , Monitorização Fisiológica/economia , Monitorização Fisiológica/instrumentação , Malformações do Sistema Nervoso/fisiopatologia , Malformações do Sistema Nervoso/cirurgia , Manejo de Espécimes , Telemetria/economia , Transdutores
9.
Gene ; 695: 12-17, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30738969

RESUMO

Microcephaly is a rare condition in which the occipitofrontal circumference in a child is more than two standard deviations below the mean of children of the same age and gender. It is mainly caused by genetic abnormalities that interfere with the growth of the cerebral cortex during early months of fetal development. We present a case of a 12 years old patient with microcephaly. To identify a possible genetic origin of the phenotype, we performed array CGH and exome sequencing in the patient. Exome sequencing revealed the presence of a de novo missense mutation in the TUBB5 gene (E401K). Mutations in the TUBB5 are mainly responsible for microcephaly but the clinical spectrum is wide, from patients with severe developmental delay, and the presence of different brain malformations, to patients with only slightly cognitive impairment and normal motor development. Our patient shows a milder phenotype than other patients carrying the same mutation. These differences in the clinical features suggest that other factors, presumably genetic or epigenetic, could be modulating clinical expressivity of TUBB5. It is therefore evident that more functional studies are needed to understand the pathology that underlies the clinical spectrum of tubulin associated disease states.


Assuntos
Deficiências do Desenvolvimento/genética , Microcefalia/genética , Malformações do Sistema Nervoso/genética , Tubulina (Proteína)/genética , Criança , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/fisiopatologia , Exoma/genética , Feminino , Humanos , Masculino , Microcefalia/diagnóstico , Microcefalia/fisiopatologia , Mutação , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/fisiopatologia
10.
J Hum Genet ; 64(4): 291-296, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30692598

RESUMO

A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia. Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis. This unusual combination of benign cerebellar findings with effects on higher functions in these two situations raises the possibility that WNT1 is involved in the pathogenesis of the associated sporadic cases as well. Finally, our patient reacted poorly to pamidronate, which appears ineffective with this form of OI, so that a lack of improvement is an indication for molecular testing that includes WNT1.


Assuntos
Sistema Nervoso Central/fisiopatologia , Deficiência Intelectual/genética , Osteogênese Imperfeita/genética , Proteína Wnt1/genética , Cistos Aracnóideos/diagnóstico por imagem , Cistos Aracnóideos/fisiopatologia , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/fisiopatologia , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Pamidronato/administração & dosagem , Pamidronato/efeitos adversos
11.
PLoS Genet ; 15(1): e1007863, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30640919

RESUMO

Many neurons are unable to regenerate after damage. The ability to regenerate after an insult depends on life stage, neuronal subtype, intrinsic and extrinsic factors. C. elegans is a powerful model to test the genetic and environmental factors that affect axonal regeneration after damage, since its axons can regenerate after neuronal insult. Here we demonstrate that diapause promotes the complete morphological regeneration of truncated touch receptor neuron (TRN) axons expressing a neurotoxic MEC-4(d) DEG/ENaC channel. Truncated axons of different lengths were repaired during diapause and we observed potent axonal regrowth from somas alone. Complete morphological regeneration depends on DLK-1 but neuronal sprouting and outgrowth is DLK-1 independent. We show that TRN regeneration is fully functional since animals regain their ability to respond to mechanical stimulation. Thus, diapause induced regeneration provides a simple model of complete axonal regeneration which will greatly facilitate the study of environmental and genetic factors affecting the rate at which neurons die.


Assuntos
Axônios , Proteínas de Caenorhabditis elegans/genética , MAP Quinase Quinase Quinases/genética , Proteínas de Membrana/genética , Regeneração Nervosa/genética , Malformações do Sistema Nervoso/genética , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Diapausa/genética , Diapausa/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Necrose/genética , Necrose/patologia , Malformações do Sistema Nervoso/fisiopatologia , Malformações do Sistema Nervoso/reabilitação , Células Receptoras Sensoriais/metabolismo , Tato/genética
13.
Cerebellum ; 18(3): 309-319, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30460543

RESUMO

Bilateral volume reduction in the caudate nucleus has been established as a prominent brain abnormality associated with a FOXP2 mutation in affected members of the 'KE family', who present with developmental orofacial and verbal dyspraxia in conjunction with pervasive language deficits. Despite the gene's early and prominent expression in the cerebellum and the evidence for reciprocal cerebellum-basal ganglia connectivity, very little is known about cerebellar abnormalities in affected KE members. Using cerebellum-specific voxel-based morphometry (VBM) and volumetry, we provide converging evidence from subsets of affected KE members scanned at three time points for grey matter (GM) volume reduction bilaterally in neocerebellar lobule VIIa Crus I compared with unaffected members and unrelated controls. We also show that right Crus I volume correlates with left and total caudate nucleus volumes in affected KE members, and that right and total Crus I volumes predict the performance of affected members in non-word repetition and non-verbal orofacial praxis. Crus I also shows bilateral hypo-activation in functional MRI in the affected KE members relative to controls during non-word repetition. The association of Crus I with key aspects of the behavioural phenotype of this FOXP2 point mutation is consistent with recent evidence of cerebellar involvement in complex motor sequencing. For the first time, specific cerebello-basal ganglia loops are implicated in the execution of complex oromotor sequences needed for human speech.


Assuntos
Cerebelo/fisiopatologia , Fatores de Transcrição Forkhead/genética , Transtornos da Linguagem/genética , Transtornos da Linguagem/fisiopatologia , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Mutação Puntual , Adulto Jovem
14.
Am J Med Genet A ; 179(1): 13-19, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30549416

RESUMO

Intellectual disability (ID), a genetically and clinically heterogeneous disorder, affects 1%-3% of the general population and is a major health problem, especially in developing countries and in populations with a high frequency of consanguineous marriage. Using whole exome sequencing, a homozygous missense variation (c.3264G>C, p.W1088C) in a plausible disease causing gene, GPR126, was identified in two patients presenting with profound ID, severe speech impairment, microcephaly, seizures during infancy, and spasticity accompanied by cerebellar hypoplasia. The role of GPR126 in radial sorting and myelination in Schwann cells suggests a mechanism of pathogenesis for ID. Involvement of GPR126 in lethal congenital contracture syndrome 9 has been identified previously, but this is the first report of a plausible candidate gene, GPR126, in ID.


Assuntos
Predisposição Genética para Doença , Deficiência Intelectual/genética , Receptores Acoplados a Proteínas-G/genética , Adolescente , Cerebelo/anormalidades , Cerebelo/fisiopatologia , Consanguinidade , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Genes Recessivos/genética , Humanos , Lactente , Deficiência Intelectual/fisiopatologia , Masculino , Microcefalia/genética , Microcefalia/fisiopatologia , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Linhagem , Células de Schwann/patologia , Convulsões/genética , Convulsões/fisiopatologia , Distúrbios da Fala/genética , Distúrbios da Fala/fisiopatologia , Sequenciamento Completo do Exoma
15.
Orphanet J Rare Dis ; 13(1): 128, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-30064458

RESUMO

Complex neurodevelopmental disorders need multi-disciplinary treatment approaches for optimal care. The clinical effectiveness of treatments is limited in patients with rare genetic syndromes with multisystem morbidity. Emotional and behavioural dysregulation is common across many neurodevelopmental disorders. It can manifest in children across multiple diagnostic groups, including those on the autism spectrum and in rare genetic syndromes such as Rett Syndrome (RTT). There is, however a remarkable scarcity in the literature on the impact of the autonomic component on emotional and behavioural regulation in these disorders, and on the longer-term outcomes on disorder burden.RTT is a debilitating and often life-threatening disorder involving multiple overlapping physiological systems. Autonomic dysregulation otherwise known as dysautonomia is a cardinal feature of RTT characterised by an imbalance between the sympathetic and parasympathetic arms of the autonomic nervous system. Unlocking the autonomic component of emotional and behavioural dysregulation would be central in reducing the impairment seen in patients with RTT. In this vein, Emotional, Behavioural and Autonomic Dysregulation (EBAD) would be a useful construct to target for treatment which could mitigate burden and improve the quality of life of patients.RTT can be considered as a congenital dysautonomia and because EBAD can give rise to impairments occurring in multiple overlapping physiological systems, understanding these physiological responses arising out of EBAD would be a critical part to consider when planning treatment strategies and improving clinical outcomes in these patients. Biometric guided pharmacological and bio-feedback therapy for the behavioural and emotional aspects of the disorder offers an attracting perspective to manage EBAD in these patients. This can also allow for the stratification of patients into clinical trials and could ultimately help streamline the patient care pathway for optimal outcomes.The objectives of this review are to emphasise the key issues relating to the management of EBAD in patients with RTT, appraise clinical trials done in RTT from the perspective of autonomic physiology and to discuss the potential of EBAD as a target for clinical trials.


Assuntos
Emoções/fisiologia , Síndrome de Rett/fisiopatologia , Síndrome de Rett/psicologia , Ensaios Clínicos como Assunto , Humanos , Malformações do Sistema Nervoso/fisiopatologia , Malformações do Sistema Nervoso/psicologia , Qualidade de Vida
16.
BMJ Open ; 8(7): e022190, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-30037879

RESUMO

INTRODUCTION: Cerebral palsy (CP), an umbrella term for non-progressive conditions of cerebral origin resulting in motor impairments, is collectively the most common cause of physical disability in childhood. Cerebral and/or non-cerebral congenital anomalies are present in 15%-40% of children with CP. In order to identify effective prevention strategies for this substantial proportion of CP, a comprehensive understanding of the epidemiology of these congenital anomalies is required. International collaboration is needed, as previous attempts have fallen short due to a lack of power, since the anomalies are individually rare and CP comprises many clinical descriptions. The aim of this study is to generate new knowledge about the aetiologies of CP through a focused investigation into the role of congenital anomalies. METHODS AND ANALYSIS: This collaborative, population-based data linkage study includes nine geographic regions (six in Europe, three in Australia) served by both congenital anomaly and CP registers. Register data for children with CP (both with and without congenital anomalies) and children with specific congenital anomalies (without CP) born between 1991 and 2009 will be linked and de-identified within each region. The resulting linked data sets will be quality assured, recoded, harmonised and then pooled into one data set. Analysis of the combined data set will include: frequencies/proportions of congenital anomalies and outcomes (type of CP, severity, impairments); descriptive analyses comparing timing of congenital anomaly development and brain injury/abnormality responsible for CP; ORs to calculate the odds of CP following a specific congenital anomaly; and identification of anomalies on causal pathways to CP. ETHICS AND DISSEMINATION: Ethics approval for this collaborative study, The Comprehensive CA-CP Study, has been obtained from the Cerebral Palsy Alliance Human Research Ethics Committee (EC00402). Study findings will be disseminated at conferences and published in peer-reviewed journals, and recommendations will be made regarding the collection and classification of congenital anomaly data by CP registers.


Assuntos
Paralisia Cerebral/epidemiologia , Anormalidades Congênitas/epidemiologia , Malformações do Sistema Nervoso/epidemiologia , Paralisia Cerebral/complicações , Paralisia Cerebral/fisiopatologia , Pré-Escolar , Anormalidades Congênitas/etiologia , Anormalidades Congênitas/fisiopatologia , Bases de Dados Factuais , Europa (Continente)/epidemiologia , Feminino , Humanos , Lactente , Armazenamento e Recuperação da Informação , Masculino , Malformações do Sistema Nervoso/etiologia , Malformações do Sistema Nervoso/fisiopatologia , Prevalência , Sistema de Registros , Estudos Retrospectivos
17.
Pediatr Neurol ; 83: 3-13, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29778488

RESUMO

Nervous system development is quadradimensional. Both normal ontogenesis and developmental malformations are explained in the context of the fourth dimension, timing. Timing of the onset of either the genetic expression of a mutation or an epigenetic event that may be teratogenic is primordial in determining morphogenesis and the forms of malformations with their functional consequences. Multiple genotypes may cause similar phenotypes or a single genotype with different degrees of retained normal genetic expression may result in variable phenotypes. In this treatise, examples are presented of these principles, including both delayed and precocious maturation of processes such as synaptogenesis that may be out of synchrony with other simultaneous processes of neuronal maturation. In postzygotic somatic mosaicism, timing of onset determines not only the character but also the extent of a lesion; focal cortical dysplasia IIb and hemimegalencephaly are the same disease, both sharing activation of the mTOR pathway as the primary mechanism; the difference is timing of onset within the 33 mitotic cycles of the periventricular neuroepithelium. Genetic expression often follows gradients along the 3 axes of the neural tube. Defective gradients often can be identified by their morphological result without knowing the precise mutation. Upregulation in the vertical axis produces hyperplasia or duplication of either dorsal or ventral structures, whereas downregulation yields hypoplasia or fusion in the midline of bilateral structures. Disorders of segmentation or neuromere formation in the neural tube are increasingly recognized as another pathogenesis of cerebral dysgenesis. Our recent investigations show the participation of the U-fibre layer beneath FCD in epileptic networks because of neuronal dispersion with elaborate synaptic plexi and a barrier to deep heterotopia.


Assuntos
Encéfalo/anatomia & histologia , Encéfalo/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Morfogênese/fisiologia , Malformações do Sistema Nervoso , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Morfogênese/genética , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Malformações do Sistema Nervoso/fisiopatologia
18.
Sci Rep ; 8(1): 3541, 2018 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-29476066

RESUMO

The association between Zika virus (ZIKV) infection and congenital malformations such as microcephaly in infants is a public health emergency. Although various in vivo and in vitro models are used for ZIKV research, few animal models are available for resolving the effects of maternal ZIKV infection on neonatal development. Here, we established an immunocompetent mouse model via intrauterine inoculation. Our results confirmed that ZIKV, but not dengue virus, infection caused spontaneous abortions, brain malformations, ocular abnormalities, spinal cord defects and paralysis in mouse offspring. Aside from microcephaly and hippocampal dysplasia, eye abnormalities, including microphthalmia, thinner optic nerves, damaged retinae, and deficient visual projection, were also observed following ZIKV infection. Moreover, ZIKV-infected offspring showed a loss of alpha motor neurons in the spinal cord and cerebellar malformation, which may cause paralysis. ZIKV also impaired adult neurogenesis in neonatal mice. Due to its intact immunity, our rodent model can be used to systematically evaluate the impact of ZIKV on embryonic and neonatal development and to explore potential therapies.


Assuntos
Transmissão Vertical de Doença Infecciosa , Complicações Infecciosas na Gravidez/virologia , Infecção por Zika virus/transmissão , Zika virus/patogenicidade , Animais , Animais Recém-Nascidos/virologia , Modelos Animais de Doenças , Feminino , Humanos , Hospedeiro Imunocomprometido/genética , Lactente , Camundongos , Microcefalia , Doenças do Sistema Nervoso/fisiopatologia , Doenças do Sistema Nervoso/virologia , Malformações do Sistema Nervoso/fisiopatologia , Malformações do Sistema Nervoso/virologia , Neurogênese/genética , Gravidez , Complicações Infecciosas na Gravidez/fisiopatologia , Zika virus/genética , Infecção por Zika virus/fisiopatologia , Infecção por Zika virus/virologia
19.
Hum Genet ; 137(3): 231-246, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29426960

RESUMO

Deletion and truncation mutations in the X-linked gene CASK are associated with severe intellectual disability (ID), microcephaly and pontine and cerebellar hypoplasia in girls (MICPCH). The molecular origin of CASK-linked MICPCH is presumed to be due to disruption of the CASK-Tbr-1 interaction. This hypothesis, however, has not been directly tested. Missense variants in CASK are typically asymptomatic in girls. We report three severely affected girls with heterozygous CASK missense mutations (M519T (2), G659D (1)) who exhibit ID, microcephaly, and hindbrain hypoplasia. The mutation M519T results in the replacement of an evolutionarily invariant methionine located in the PDZ signaling domain known to be critical for the CASK-neurexin interaction. CASKM519T is incapable of binding to neurexin, suggesting a critically important role for the CASK-neurexin interaction. The mutation G659D is in the SH3 (Src homology 3) domain of CASK, replacing a semi-conserved glycine with aspartate. We demonstrate that the CASKG659D mutation affects the CASK protein in two independent ways: (1) it increases the protein's propensity to aggregate; and (2) it disrupts the interface between CASK's PDZ (PSD95, Dlg, ZO-1) and SH3 domains, inhibiting the CASK-neurexin interaction despite residing outside of the domain deemed critical for neurexin interaction. Since heterozygosity of other aggregation-inducing mutations (e.g., CASKW919R) does not produce MICPCH, we suggest that the G659D mutation produces microcephaly by disrupting the CASK-neurexin interaction. Our results suggest that disruption of the CASK-neurexin interaction, not the CASK-Tbr-1 interaction, produces microcephaly and cerebellar hypoplasia. These findings underscore the importance of functional validation for variant classification.


Assuntos
Moléculas de Adesão Celular Neuronais/genética , Cerebelo/anormalidades , Doenças Genéticas Ligadas ao Cromossomo X/genética , Guanilato Quinases/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Malformações do Sistema Nervoso/genética , Proteínas de Ligação ao Cálcio , Moléculas de Adesão Celular Neuronais/química , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Guanilato Quinases/química , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Microcefalia/diagnóstico por imagem , Microcefalia/fisiopatologia , Mutação de Sentido Incorreto/genética , Proteínas do Tecido Nervoso/química , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/fisiopatologia , Moléculas de Adesão de Célula Nervosa , Domínios PDZ/genética , Fenótipo , Agregados Proteicos/genética , Ligação Proteica , Mapas de Interação de Proteínas/genética , Proteínas com Domínio T/genética , Domínios de Homologia de src/genética
20.
Ultrasound Obstet Gynecol ; 51(2): 199-207, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28236314

RESUMO

OBJECTIVE: To assess non-visualization of the choroid plexus of the fourth ventricle (CP-4V) as a simple, qualitative and reproducible first-trimester ultrasound feature of the posterior fossa for the prediction of central nervous system (CNS) anomalies and chromosomal defects. METHODS: First-trimester three-dimensional ultrasound datasets of the fetal brain were obtained prospectively from 65 consecutive normal singletons and retrospectively from 27 fetuses identified as having an abnormal posterior fossa on first-trimester ultrasound examination, and randomly combined to form the final study group. The stored ultrasound volumes were analyzed offline by two accredited sonologists, who were not aware of the final diagnoses. The CP-4V was assessed by multiplanar navigation and classified as visible or non-visible in its normal position depending on whether or not the echogenic structure that separates the fourth ventricle from the cisterna magna was identified in both midsagittal and axial planes. Correlation with subsequent second-trimester ultrasound, fetal magnetic resonance imaging, or postmortem or postnatal findings was performed to determine the predictive value of the first-trimester findings. RESULTS: Among the 92 ultrasound datasets analyzed, 73 (79%) were acquired transabdominally and 19 (21%) transvaginally. The CP-4V was classified as visible in 64 cases and non-visible in 28 cases, with agreement between the two observers in both sagittal and axial planes in all but one case. Twelve of the 28 (43%) fetuses with non-visible CP-4V were subsequently diagnosed as having a CNS malformation (open spina bifida (n = 6), Dandy-Walker malformation (n = 2), Blake's pouch cyst (n = 2), cephalocele (n = 1) and megacisterna magna (n = 1)). In addition, 20 of these 28 (71%) fetuses had aneuploidy (trisomy 18 (n = 10), triploidy (n = 5), trisomy 13 (n = 3), Turner syndrome (n = 1) or trisomy 21 (n = 1)). There was only one false-positive case, in which the CP-4V was classified as absent in a normal fetus. CONCLUSIONS: Non-visualization of the CP-4V in the first trimester appears to be a strong marker of posterior fossa anomalies and chromosomal defects. Qualitative evaluation of this anatomic structure is simple, feasible and reproducible, and its routine assessment during the first-trimester scan may facilitate the early detection of CNS anomalies and associated fetal aneuploidy. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.


Assuntos
Plexo Corióideo/diagnóstico por imagem , Cisterna Magna/embriologia , Fossa Craniana Posterior/anormalidades , Feto/anormalidades , Quarto Ventrículo/diagnóstico por imagem , Malformações do Sistema Nervoso/diagnóstico por imagem , Ultrassonografia Pré-Natal , Adulto , Plexo Corióideo/embriologia , Cisterna Magna/diagnóstico por imagem , Fossa Craniana Posterior/diagnóstico por imagem , Ecocardiografia Tridimensional , Feminino , Quarto Ventrículo/embriologia , Idade Gestacional , Humanos , Malformações do Sistema Nervoso/embriologia , Malformações do Sistema Nervoso/fisiopatologia , Variações Dependentes do Observador , Valor Preditivo dos Testes , Gravidez , Primeiro Trimestre da Gravidez , Estudos Prospectivos , Valores de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Espanha
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