Genetics of pediatric epilepsy Hani, Abeer J; Mikati, Husam M; Mikati, Mohamad A
The Pediatric clinics of North America,
06/2015, Letnik:
62, Številka:
3
Journal Article
Recenzirano
As the genetic etiologies of an expanding number of epilepsy syndromes are revealed, the complexity of the phenotype genotype correlation increases. As our review will show, multiple gene mutations ...cause different epilepsy syndromes, making identification of the specific mutation increasingly more important for prognostication and often more directed treatment. Examples of that include the need to avoid specific drugs in Dravet syndrome and the ongoing investigations of the potential use of new directed therapies such as retigabine in KCNQ2-related epilepsies, quinidine in KCNT1-related epilepsies, and memantine in GRIN2A-related epilepsies.
Pediatric epileptic encephalopathies represent a clinically challenging and often devastating group of disorders that affect children at different stages of infancy and childhood. With the advances ...in genetic testing and neuroimaging, the etiologies of these epileptic syndromes are now better defined. The various encephalopathies that are reviewed in this article include the following: early infantile epileptic encephalopathy or Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, West syndrome, severe myoclonic epilepsy in infancy (Dravet syndrome), Landau-Kleffner syndrome, Lennox-Gastaut syndrome, and epileptic encephalopathy with continuous spike-and-wave during sleep. Their clinical features, prognosis as well as underlying genetic etiologies are presented and updated.
The past few years have witnessed increasing interest in devising programs to enhance early childhood development. We review current understandings of brain development, recent advances in this ...field, and their implications for clinical interventions. An expanding body of basic science laboratory data demonstrates that several interventions, including environmental enrichment, level of parental interaction, erythropoietin, antidepressants, transcranial magnetic stimulation, transcranial direct current stimulation, hypothermia, nutritional supplements, and stem cells, can enhance cerebral plasticity. Emerging clinical data, using functional magnetic resonance imaging and clinical evaluations, also support the hypothesis that clinical interventions can increase the developmental potential of children, rather than merely allowing the child to achieve an already predetermined potential. Such interventions include early developmental enrichment programs, which have improved cognitive function; high-energy and high-protein diets, which have increased brain growth in infants with perinatal brain damage; constraint-induced movement therapy, which has improved motor function in patients with stroke, cerebral palsy, and cerebral hemispherectomy; and transcranial magnetic stimulation, which has improved motor function in stroke patients.
In this article, we review the treatment options for the pediatric epileptic encephalopathies and provide an update on the new and emerging therapies targeted at the underlying pathophysiology of ...many of these syndromes. We illustrate how the identification of the specific genetic and autoimmune causes has made possible the evaluation and development of novel, better targeted therapies, as and at times, avoidance of potentially offending agents.
Abstract We describe two boys whose distinct and remarkable clinical pictures suggested the possibility of anti- N -methyl- d -aspartate receptor antibody encephalitis. Both patients responded to ...immunotherapy, but neither manifested that antibody. Patient 1 exhibited florid encephalopathy with psychotic manifestations including inappropriate affect, intermittent delirium, visual hallucinations, severe anorexia, agitation, paranoid ideation, and abnormal electroencephalogram results. He responded to intravenous immunoglobulin, with steady improvement over 3 months to almost complete remission for 1 year, followed by a relapse that again responded, more quickly, to intravenous immunoglobulin. A second relapse occurred 1 month later, and again responded to intravenous immunoglobulin. Patient 2 exhibited progressive, severely debilitating limb dystonia that worsened over 1.5 years, with milder psychiatric symptoms including mood instability, aggressiveness, impulsivity, and depression. When he developed thymic hyperplasia 1.5 years into his illness, he underwent a thymectomy, and improved significantly on a regimen of plasmapheresis and intravenous immunoglobulin. Patients presenting with symptoms suggestive of autoimmune encephalitis, but without antibodies, may still respond to immunotherapy.
Paroxysmal events in children can mimic epileptic seizures, and many of them have only been recently described, or are only now being increasingly recognized. An awareness of the different mimickers ...of epilepsy and the art of history-taking will help pediatricians and neurologists differentiate epileptic from nonepileptic events. Nonepileptic paroxysms can present with drop attacks, limb or eye jerks, and abnormal postures. This review describes the different mimickers of epilepsy and focuses on their circumstances, precipitators, prodromes, pathophysiology, and other manifestations that help distinguish them from epilepsy.
Abstract Pediatric ischemic stroke still represents a burden, and more than half of the survivors will experience cognitive or motor disabilities. The objective of this study was to investigate the ...role of thrombophilia in a cohort of children with arterial ischemic stroke. The records of infants and children with clinically and radiologically confirmed stroke were reviewed. Patients with venous or perinatal stroke were not included. Thirty-three patients were diagnosed with arterial ischemic stroke. The male/female ratio was 1.75:1. The median age was 4 years. The most frequent clinical manifestations were hemiparesis (54.5%) and seizures (33.3%). Genetic thrombophilia testing was available on 24 patients. Nine of the 24 patients (37.5%) were heterozygous for factor V Leiden. None of the patients carried the factor II G20210A variant. Ten patients (41.7%) were heterozygous and 3 (12.5%) were homozygous for methylenetetrahydrofolate reductase (MTHFR) C677T variant. Fifteen patients (62.5%) had one or more genetic polymorphism. Factor V Leiden was significantly associated with arterial ischemic stroke ( P < 0.001). Stroke recurred in 2 children with multiple risk factors and MTHFR C677T mutation. Factor V Leiden is one of the major genetic risk factors for pediatric arterial ischemic stroke in Lebanon. MTHFR C677T was prevalent among patients with recurrent stroke.
Several factors, such as epilepsy syndrome, poor compliance and increased seizure frequency increase the risks of sudden unexpected death in epilepsy (SUDEP). Animal models have revealed that the ...mechanisms of SUDEP involve initially a primary event, often a seizure of sufficient type and severity, which occurs in a brain which is vulnerable to SUDEP due to either genetic or antecedent factors. This primary event initiates a cascade of secondary events starting, as some models indicate, with cortical spreading depolarization which propagates to the brainstem where it results in autonomic dysfunction. Intrinsic abnormalities in brainstem serotonin, adenosine and respiratory-control systems are also important. The tertiary event, which results from the above dysfunction, consists of either lethal central apnea, pulmonary edema, or an arrhythmia. Currently it is necessary to: (1) continue researching SUDEP mechanisms, (2) work on reducing SUDEP risk factors, and (3) address the major need to counsel families about SUDEP.
This report presents a case of short-chain acyl-coenzyme A (CoA) dehydrogenase deficiency with a previously unreported presentation with brain malformations and infantile spasms. This female infant ...developed repeated tonic clonic seizures at the age of 3½ months. She subsequently developed West syndrome at the age of 4 months. Her electroencephalogram disclosed hypsarrhythmia, and video-electroencephalographic monitoring confirmed the presence of infantile spasms. Magnetic resonance imaging revealed a small midline frontal meningocele, abnormal cortical gyration, and partial agenesis of the corpus callosum consistent with neuronal migrational disorder. Metabolic evaluation indicated ethylmalonic acidemia. Muscle biopsy with enzymatic assay of short-chain acyl-coenzyme A revealed low enzymatic activity confirming the diagnosis of short-chain acyl-coenzyme A dehydrogenase deficiency. To our knowledge, this is the first report of the coexistence of short-chain acyl-coenzyme A dehydrogenase deficiency, infantile spasms, and brain malformation. We conclude that short-chain acyl-coenzyme A dehydrogenase deficiency should be considered in the differential diagnosis of gyral abnormality, corpus callosal hypoplasia, and infantile spasms.
