RESUMO
The TRIO gene encodes a rho guanine exchange factor, the function of which is to exchange GDP to GTP, and hence to activate Rho GTPases, and has been described to impact neurodevelopment. Specific genotype-to-phenotype correlations have been established previously describing striking differentiating features seen in variants located in specific domains of the TRIO gene that are associated with opposite effects on RAC1 activity. Currently, 32 cases with a TRIO gene alteration have been published in the medical literature. Here, we report an additional 25, previously unreported individuals who possess heterozygous TRIO variants and we review the literature. In addition, functional studies were performed on the c.4394A > G (N1465S) and c.6244-2A > G TRIO variants to provide evidence for their pathogenicity. Variants reported by the current study include missense variants, truncating nonsense variants, and an intragenic deletion. Clinical features were previously described and included developmental delay, learning difficulties, microcephaly, macrocephaly, seizures, behavioral issues (aggression, stereotypies), skeletal problems including short, tapering fingers and scoliosis, dental problems (overcrowding/delayed eruption), and variable facial features. Here, we report clinical features that have not been described previously, including specific structural brain malformations such as abnormalities of the corpus callosum and ventriculomegaly, additional psychological and dental issues along with a more recognizable facial gestalt linked to the specific domains of the TRIO gene and the effect of the variant upon the function of the encoded protein. This current study further strengthens the genotype-to-phenotype correlation that was previously established and extends the range of phenotypes to include structural brain abnormalities, additional skeletal, dental, and psychiatric issues.
Assuntos
Microcefalia , Malformações do Sistema Nervoso , Humanos , Fenótipo , Mutação , Mutação de Sentido Incorreto , Microcefalia/genéticaRESUMO
In this paper we reframe febrile seizures, which are viewed as a symptom of an underlying brain disorder. The general observation is that a small cohort of children will develop febrile seizures (2-5% in the West), while the greater majority will not. This suggests that the brain that generates a seizure, in an often-mild febrile context, differs in some ways from the brain that does not. While the underlying brain disorder appears to have no significant adverse implication in the majority of children with febrile seizures, serious long-term outcomes (cognitive and neuropsychiatric) have been recently reported, including sudden death. These adverse events likely reflect the underlying intrinsic brain pathology, as yet undefined, of which febrile seizures are purely a manifestation and not the primary cause. A complex interaction between brain-genetics-epigenetics-early environment is likely at play. In view of this emerging data, it is time to review whether febrile seizures are a single entity, with a new and multidimensional approach needed to help with predicting outcome. WHAT THIS PAPER ADDS: A febrile seizure is due to a brain's aberrant response to high temperature. Problems in a small group of children are now being identified later in life. There is no clear correlation between duration or other characteristics of febrile seizures and subsequent mesial temporal sclerosis.
Assuntos
Encefalopatias , Disfunção Cognitiva , Epilepsia , Transtornos Mentais , Convulsões Febris , Encefalopatias/complicações , Pré-Escolar , Disfunção Cognitiva/etiologia , Epilepsia/etiologia , Humanos , Lactente , Transtornos Mentais/etiologia , Convulsões Febris/complicações , Convulsões Febris/etiologia , Convulsões Febris/fisiopatologiaRESUMO
The neuronal ceroid lipofuscinoses (NCLs) form a group of autosomal recessively inherited neurodegenerative disorders that mainly affect children. Ten NCL forms can be distinguished by age at onset, clinicopathologic features, and genetics. In eight of these forms, the underlying genes have been identified. At present, approximately 10% of all patients do not fall into one of the eight known genetic forms of NCL. We have identified two Asian families with two novel homozygous mutations in the CLN5 gene. In the first Pakistani family, two children developed symptoms of an early juvenile NCL. After exclusion of mutations in genes known to be associated with this age of onset in families from many different countries (CLN1, CLN2, CLN3, CLN6, CLN8 and CLN10) SNP array-based homozygosity mapping led to the identification of a novel homozygous mutation c.1072_1073delTT (p.Leu358AlafsX4) in CLN5. In the second Afghan family, two children developed symptoms of a late infantile NCL. The mutation c.1137G>T (p.Trp379Cys) in CLN5 was identified. The affected children in these families represent the first reported CLN5 patients originating in Asian sibships. Expression analysis showed that mutant p.Leu358AlafsX4 CLN5 is truncated and lacks a used N-glycosylation site at Asn401. The missense mutation p.Trp379Cys affected neither the size nor glycosylation of the CLN5 protein. Double immunofluorescence microscopy showed that while the wild-type CLN5 protein is localized in lysosomes, both mutant CLN5 proteins are retained in the endoplasmic reticulum rather than reaching the lysosome.
Assuntos
Povo Asiático , Retículo Endoplasmático/metabolismo , Proteínas de Membrana/metabolismo , Lipofuscinoses Ceroides Neuronais/metabolismo , Proteínas/metabolismo , Irmãos , Adolescente , Animais , Povo Asiático/genética , Linhagem Celular , Criança , Pré-Escolar , DNA Complementar/genética , Evolução Fatal , Feminino , Humanos , Espaço Intracelular/metabolismo , Proteínas de Membrana Lisossomal , Masculino , Proteínas Mutantes/metabolismo , Mutação/genética , Lipofuscinoses Ceroides Neuronais/genética , Paquistão , Transporte Proteico , Tripeptidil-Peptidase 1RESUMO
We report a 3-year-old patient who presented a secondary acute neurological deterioration clinically characterized by a partial Kluver-Bucy syndrome, 1 month after the onset of herpes simplex encephalitis. This episode is unlikely due to continuation or resumption of cerebral viral replication but might be related to an immune-inflammatory process. In children, postinfectious immune-mediated encephalitis occurring after HSE are usually clinically characterized by choreoathetoid movements. This type of movement disorder was, however, not observed in this patient. On the basis of this case and a review of the literature, we hypothesize the existence of a spectrum of secondary immune-mediated process triggered by herpes simplex virus cerebral infection ranging from asymptomatic cases with diffuse white matter involvement to secondary acute neurological deteriorations with or without extrapyramidal features.
Assuntos
Encefalite por Herpes Simples/etiologia , Encefalomielite Aguda Disseminada/complicações , Síndrome de Kluver-Bucy/etiologia , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/virologia , Pré-Escolar , Encefalite por Herpes Simples/patologia , Encefalite por Herpes Simples/fisiopatologia , Encefalomielite Aguda Disseminada/patologia , Encefalomielite Aguda Disseminada/fisiopatologia , Humanos , Síndrome de Kluver-Bucy/patologia , Síndrome de Kluver-Bucy/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , SimplexvirusRESUMO
This report describes a 5-year-old male with sudden unilateral headache attacks (2-50 seconds) accompanied by conjunctival injection, lacrimation, and nasal congestion. The episodes occurred without a precipitating factor, never during sleep. Brain imaging was normal. The attacks resolved spontaneously within 5 months. This headache syndrome (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) was previously described in two other children aged 10 and 11.
Assuntos
Transtornos da Cefaleia , Pré-Escolar , Doenças da Túnica Conjuntiva/complicações , Transtornos da Cefaleia/complicações , Transtornos da Cefaleia/diagnóstico , Transtornos da Cefaleia/metabolismo , Humanos , Masculino , Muco/metabolismo , Remissão Espontânea , Lágrimas/metabolismoRESUMO
Developmental motor impairment with lower limb spasticity most commonly corresponds to cerebral palsy of the spastic diplegia type. Here we describe a 4-year-old girl whose locomotor phenotype reflects early cortico-spinal lesion at the spinal level. This child has developmental spastic paraparesis secondary to D4-D8 cord compression. We analysed her gait using the ELITE optoelectronic system and compared it to that of six normal age-matched controls and six age-matched children with leucomalacic spastic diplegia. Gait characteristics of the patient included preservation of head orientation and arm swing similar to findings in normal controls and contrasting with children with spastic diplegia. She also had truncal instability and displayed lack of selectivity in lower limb movement as in spastic diplegia and in contrast with normal controls. This may reflect differences in locomotor control between developmental spasticity of cerebral and spinal origin. The latter might correspond to spinal palsy defined as abnormal movement and posture secondary to non-progressive pathological processes affecting the immature spinal cord.
Assuntos
Transtornos Neurológicos da Marcha/etiologia , Espasticidade Muscular/etiologia , Paraplegia/etiologia , Paraplegia/fisiopatologia , Compressão da Medula Espinal/complicações , Compressão da Medula Espinal/fisiopatologia , Braço/inervação , Braço/fisiopatologia , Paralisia Cerebral/diagnóstico , Paralisia Cerebral/fisiopatologia , Pré-Escolar , Diagnóstico Diferencial , Feminino , Marcha/fisiologia , Transtornos Neurológicos da Marcha/patologia , Transtornos Neurológicos da Marcha/fisiopatologia , Movimentos da Cabeça/fisiologia , Humanos , Lactente , Recém-Nascido , Perna (Membro)/inervação , Perna (Membro)/fisiopatologia , Leucomalácia Periventricular/diagnóstico , Leucomalácia Periventricular/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Neoplasias do Mediastino/complicações , Neoplasias do Mediastino/patologia , Espasticidade Muscular/patologia , Espasticidade Muscular/fisiopatologia , Paraplegia/patologia , Equilíbrio Postural/fisiologia , Tratos Piramidais/lesões , Tratos Piramidais/fisiopatologia , Valores de Referência , Compressão da Medula Espinal/patologia , Vértebras TorácicasRESUMO
In spastic diplegia impaired postural control jeopardizes the organization of whole-body movements. We studied segmental motor patterns involved in standing up from a supine position in ten children with spastic diplegia associated with periventricular leukomalacia and 14 unimpaired children using a visual analysis scale previously devised for developmental research. This approach examines specific movement patterns in upper limbs, axis and lower limbs. We found that children with spastic diplegia use movement patterns described in normal children but with markedly reduced intra- and interindividual variability. One previously undescribed stereotyped lower limb pattern was observed in four patients. This approach can systematically characterize the limited repertoire of movement in patients with spastic diplegia and therefore contribute to a better understanding of motor control.
Assuntos
Paralisia Cerebral/fisiopatologia , Leucomalácia Periventricular/complicações , Movimento , Postura , Fenômenos Biomecânicos , Paralisia Cerebral/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Recém-Nascido , Leucomalácia Periventricular/fisiopatologia , Masculino , Destreza MotoraRESUMO
Isolated status epilepticus or severe hypoglycemia rarely causes irreversible focal neurologic deficits in children. We describe three children who presented with status epilepticus and prolonged hypoglycemia resulting in hemiplegia due to unilateral hemispheric damage. The non-vascular cortical topography of the lesions is consistent with selective neuronal necrosis, confirmed by histopathology in one patient. This suggests increased neuronal vulnerability to necrosis secondary to energy failure resulting from combination of hypoglycemia and status epilepticus.
Assuntos
Córtex Cerebral/patologia , Hipoglicemia/complicações , Estado Epiléptico/complicações , Estado Epiléptico/patologia , Dano Encefálico Crônico/complicações , Dano Encefálico Crônico/diagnóstico , Criança , Pré-Escolar , Doença Crônica , Feminino , Hemiplegia/etiologia , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , NecroseRESUMO
Visual symptomatology in childhood often presents diagnostic difficulties. Recurrent paroxysmal visual complaints, although typically associated with migraine, may also signal other disorders. We describe a 9-year-old partially sighted male with paroxysmal zoopsias resulting from Charles Bonnet syndrome. This condition is characterized by paroxysmal visual hallucinations occurring in patients with chronic visual impairment, akin to the phantom-limb phenomenon. This pediatric case is the fourth report of this condition. We have reviewed the other cases.
Assuntos
Cegueira/complicações , Alucinações/etiologia , Oftalmoplegia/complicações , Transtornos da Percepção/etiologia , Percepção Visual/fisiologia , Atrofia , Córtex Cerebral/patologia , Criança , Humanos , Imageamento por Ressonância Magnética , Masculino , SíndromeRESUMO
Acute ocular paresis, nausea, vomiting, and headaches associated with high intracranial pressure without obvious intracranial pathology are typical features of benign intracranial hypertension. We describe two young children whose presentation, initially suggestive of idiopathic or benign intracranial hypertension, evolved to comprise ophthalmoplegia, ataxia, and areflexia. This triad characterizes Miller Fisher syndrome, a clinical variant of Guillain-Barré syndrome that occurs rarely among children. In both patients, this diagnosis was supported by the clinical course and neurophysiologic findings. Plasma serology was positive for Campylobacter jejuni and anti-GQ1b antibodies in one patient and for antimyelin antibodies in the other. This report of two children with Miller Fisher syndrome presenting with intracranial hypertension adds to the findings for a similar patient treated previously, which raises the question concerning the possible role or contribution of benign intracranial hypertension in Miller Fisher syndrome.
Assuntos
Síndrome de Miller Fisher/complicações , Pseudotumor Cerebral/etiologia , Anticorpos Antibacterianos/análise , Autoanticorpos/análise , Campylobacter jejuni/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Síndrome de Miller Fisher/microbiologia , Síndrome de Miller Fisher/fisiopatologia , Bainha de Mielina/imunologiaRESUMO
Although subacute ascending paralysis without sensory involvement is typically evocative of Guillain-Barré syndrome, it can alternatively be due to infection or inflammation of the spinal cord. We describe a 16-month-old female who presented with ascending flaccid paresis after an upper respiratory tract infection. She then developed signs of upper motor neuron involvement of the lower limbs associated with upper motor neuron involvement of the upper limbs. Motor nerve conduction and electromyographic studies of upper limbs demonstrated anterior horn cell involvement. Neuroimaging was consistent with cervical myelitis, and cerebrospinal fluid polymerase chain reaction was positive for herpesvirus-1. Although association with the primary infection of the respiratory tract may be fortuitous, possible neurotropic or hematogenous spread of herpesvirus-1 to the cervical spinal cord cannot be excluded. She then developed signs of upper motor neuron involvement of the lower limbs associatred with lower motor neuron involvement of the upper limbs [corrected].
Assuntos
Vértebras Cervicais/patologia , Vértebras Cervicais/virologia , Herpes Simples/patologia , Herpesvirus Humano 1 , Mielite/patologia , Mielite/virologia , Feminino , Herpes Simples/virologia , Humanos , LactenteRESUMO
Cerebellar mutism (anarthria) is a well-described complication of posterior fossa tumor resection. It is accompanied by a characteristic behavior including irritability and autistic features. This syndrome is typically reversible within days to months. Underlying pathophysiology is unknown. We describe two children who presented with a similar clinical finding after nonsurgical cerebellar involvement, hemolytic-uremic syndrome in one and cerebellitis in the other. Postmortem pathologic findings in the first patient indicated cerebellar ischemic necrosis. Single-photon emission computed tomography in the second patient revealed diffuse cerebellar hypoperfusion with no supratentorial abnormalities, refuting a phenomenon of diaschisis between cerebellar and frontal connections. These findings confirm that this clinical syndrome may occur in a nonsurgical, nontraumatic context. They are consistent with recent integrative hypotheses explaining cerebellar anarthria.
Assuntos
Doenças Cerebelares/patologia , Cerebelo/patologia , Mutismo/patologia , Doenças Cerebelares/etiologia , Pré-Escolar , Encefalite/complicações , Feminino , Síndrome Hemolítico-Urêmica/complicações , Humanos , Imageamento por Ressonância Magnética , Mutismo/etiologiaRESUMO
Assessment of prognosis of children in hypoxic coma is difficult. The value of clinical evaluation is often limited. The usefulness of electrophysiologic tests has been documented mostly in adults and neonates and in cases of traumatic coma. We reviewed retrospectively 39 consecutive children with nontraumatic hypoxic coma to assess the prognostic value of EEG, visual, and auditory evoked potentials. Correlation between electrophysiology and neurologic outcome after mean follow-up period of 30 months was significant (r(s) = 0.6, P < 0.001). In contrast there was no correlation between Pediatric Risk of Mortality score (PRISM) and outcome (r(s) = -0.42, P = 0.8). Combining magnetic resonance imaging with electrophysiology further enhanced their prognostic value (r(s) = 0.69, P < 0.001). Neuroimaging was highly sensitive but less specific, and electrophysiologic tests were highly specific but less sensitive. We conclude that early electrophysiology can contribute to predicting outcome in pediatric hypoxic coma.
Assuntos
Coma/diagnóstico , Hipóxia Encefálica/diagnóstico , Adolescente , Criança , Pré-Escolar , Coma/fisiopatologia , Eletroencefalografia/métodos , Eletrofisiologia , Potenciais Evocados Auditivos/fisiologia , Potenciais Evocados Visuais/fisiologia , Feminino , Humanos , Hipóxia Encefálica/fisiopatologia , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos , Estatísticas não ParamétricasRESUMO
INTRODUCTION: Simple febrile seizures are generalised in onset and have a brief duration. The American Academy of Pediatrics defines this brief duration to be <15 minutes; whereas, in the UK, a maximum duration of 10 minutes is used. Simple febrile seizures do not occur more than once in 24 hours and resolve spontaneously. Complex febrile seizures are longer lasting, have focal symptoms (at onset or during the seizure), and can recur within 24 hours or within the same febrile illness. This review only deals with simple febrile seizures. About 2% to 5% of children in the US and Western Europe, and 6% to 9% of infants and children in Japan, will have experienced at least one febrile seizure by the age of 5 years. A very small number of children with simple febrile seizures may develop afebrile seizures, but simple febrile seizures are not associated with any permanent neurological deficits. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments given during episodes of fever in children (aged 6 months to 5 years) with one or more previous simple febrile seizures? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2013 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 4 RCTs or systematic reviews of RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: intermittent anticonvulsants (clobazam, diazepam, lorazepam), antipyretic drug treatments (paracetamol, ibuprofen), and conservative measures (watchful waiting, physical antipyretic measures [tepid sponging, removing clothes, cooling room, direct fanning of child]).
Assuntos
Febre/complicações , Convulsões Febris/etiologia , Convulsões Febris/terapia , Anticonvulsivantes/uso terapêutico , Europa (Continente) , Humanos , Convulsões Febris/tratamento farmacológicoRESUMO
INTRODUCTION: Simple febrile seizures are generalised in onset, last <15 minutes, and do not occur more than once in 24 hours. Complex febrile seizures are longer lasting, have focal symptoms, and can recur within 24 hours. This review only deals with simple febrile seizures. About 2% to 5% of children in the USA and Western Europe, and 6% to 9% of infants and children in Japan will have experienced at least one febrile seizure by the age of 5 years. Simple febrile seizures may slightly increase the risk of developing epilepsy, but have no known adverse effects on behaviour, scholastic performance, or neurocognition. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments given during episodes of fever in children with one or more previous simple febrile seizures? What are the effects of long-term (daily, for >1 month) anticonvulsant treatment in children with a history of simple febrile seizures? What are the effects of treatments on reducing the risk of subsequent epilepsy in children with a history of simple febrile seizures? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticonvulsants (intermittent or continuous) and antipyretic treatments (physical antipyretic measures, paracetamol, ibuprofen).
Assuntos
Anticonvulsivantes , Convulsões Febris , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Febre , Humanos , Lactente , Recidiva , Convulsões/tratamento farmacológico , Convulsões Febris/tratamento farmacológicoAssuntos
Convulsões Febris/diagnóstico , Antipiréticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Gerenciamento Clínico , Epilepsia/diagnóstico , Humanos , Recidiva , Fatores de Risco , Convulsões Febris/classificação , Convulsões Febris/tratamento farmacológico , Convulsões Febris/etiologiaRESUMO
INTRODUCTION: Simple febrile seizures are generalised in onset, last less than 15 minutes, and do not occur more than once in 24 hours. Complex seizures are longer lasting, have focal symptoms, and can recur within 24 hours. This review only deals with simple febrile seizures. About 2-5% of children in the USA and Western Europe, and 6-9% of infants and children in Japan, will have experienced at least one febrile seizure by the age of 5 years. Simple febrile seizures may slightly increase the risk of developing epilepsy, but have no known adverse effects on behaviour, scholastic performance, or neurocognition. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments given during episodes of fever in children with one or more previous simple febrile seizures? What are the effects of long-term (daily, for more than 1 month) anticonvulsant treatment in children with a history of simple febrile seizures? What are the effects of treatments on reducing the risk of subsequent epilepsy in children with a history of simple febrile seizures? We searched: Medline, Embase, The Cochrane Library and other important databases up to August 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticonvulsants (intermittent or continuous), and antipyretic treatments (physical antipyretic measures, paracetamol, ibuprofen).