RESUMO
Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage-sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi-faceted complications due to haploinsufficiency of BPTF.
Assuntos
Montagem e Desmontagem da Cromatina/genética , Epilepsia/genética , Microcefalia/genética , Transtornos do Neurodesenvolvimento/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Epilepsia/fisiopatologia , Fácies , Feminino , Haploinsuficiência/genética , Humanos , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Microcefalia/fisiopatologia , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Fatores de Transcrição/genética , Adulto JovemRESUMO
Hypoxic Ischemic Encephalopathy (HIE) is the result of severe anoxic brain injury during the neonatal period and causes life-long morbidity and premature mortality. Currently, therapeutic hypothermia immediately after birth is the standard of care for clinically relevant HIE. However, therapeutic hypothermia alone does not provide complete neuroprotection and there is an urgent need for adjunctive therapies. Ischemic conditioning is an adaptive process of endogenous protection in which small doses of sub-lethal ischemia can provide a protection against a lethal ischemic event. Remote Ischemic Post-conditioning (RIPC), a form of ischemic conditioning, is highly translatable for HIE diagnosed immediately after birth as the conditioned ischemic stimulus is applied at the limb after the lethal ischemic episode. A number of studies in neonatal rats have demonstrated that RIPC is effective at reducing injury in focal cerebral ischemia models and improves neurological outcomes. In this review, we focus on the available data on HIE and its current treatment, models in HIE studies, ischemic conditioning/RIPC and its mechanism. We discuss in particular the effect of RIPC on neonatal brain with HIE. We postulate that combining RIPC with standard therapeutic hypothermia can be an attractive therapeutic approach for HIE.
RESUMO
Interictal spikes have been implicated in epileptogenesis and cognitive dysfunction in epilepsy. Unfortunately, antiepileptic drugs have shown poor efficacy in suppressing interictal discharges; novel therapies are needed. Surface charge on neuronal membranes provides a novel target for abolishing interictal spikes. This property can be modulated through the use of neuraminidase, an enzyme that decreases the amount of negatively charged sialic acid. In the present report we determined whether applying neuraminidase to brains of rats with a history of status epilepticus would reduce number of interictal discharges. Following pilocarpine-induced status epilepticus, rats received intrahippocampal injections of neuraminidase, which significantly decreased the number of interictal spikes recorded in the CA1 region. This study provides evidence that sialic acid degradation can reduce the number of interictal spikes. Furthermore, the results suggest that modifying surface charge created by negatively charged sialic acid may provide new opportunities for reducing aberrant epileptiform events in epilepsy.