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nodding spasm [keywords]
- Association of SCN1A gene polymorphisms with infantile spasms and adrenocorticotropic hormone responsiveness. [JOURNAL ARTICLE]
- Eur Rev Med Pharmacol Sci 2014 Sep; 18(17):2500-2506.
Infantile spasms (IS) are severe epileptic encephalopathy during infancy. The SCN1A encodes the α1 subunit of the neuronal voltage-gated sodium channels, and mutations in SCN1A have been frequently detected in idiopathic epilepsy and encephalopathy, which had similar symptoms as IS. Therefore, we investigated the association of SCN1A polymorphism with the IS and the responsiveness to adrenocorticotropic hormone (ACTH) treatment in the present study.We totally collected 113 IS patients and and 122 age-matched healthy controls. All of the subjects were Han Chinese descent, and the 113 cases were further divided into subgroups of cryptogenic and symptomatic patients. Nine tag SNPs within the SCN1A gene were selected and genotyped by the direct sequencing of PCR-amplified products. The ACTH was then applied to all of the cases.Two SNPs in high linkage disequilibrium, rs13397210 and rs760543, were significantly associated with IS under genotype model (p = 0.015). In addition, we also found that a 4-SNP haplotype (CAGC) which contains the aforementioned 2 SNPs, was associated with increased responsiveness to ACTH therapy in IS (p = 0.018, OR = 4.8) under recessive model. Of the 2 subgroups of cases, more cryptogenic patients responded to the ACTH treatment than the symptomatic patients.The results suggested that genetic variants of the SCN1A gene were associated with IS and ACTH responsiveness.
- Epileptic Encephalopathies: New Genes and New Pathways. [JOURNAL ARTICLE]
- Neurotherapeutics 2014 Sep 30.
Epileptic encephalopathies represent a group of devastating epileptic disorders that occur early in life and are often characterized by pharmaco-resistant epilepsy, persistent severe electroencephalographic abnormalities, and cognitive dysfunction or decline. Next generation sequencing technologies have increased the speed of gene discovery tremendously. Whereas ion channel genes were long considered to be the only significant group of genes implicated in the genetic epilepsies, a growing number of non-ion-channel genes are now being identified. As a subgroup of the genetically mediated epilepsies, epileptic encephalopathies are complex and heterogeneous disorders, making diagnosis and treatment decisions difficult. Recent exome sequencing data suggest that mutations causing epileptic encephalopathies are often sporadic, typically resulting from de novo dominant mutations in a single autosomal gene, although inherited autosomal recessive and X-linked forms also exist.In this review we provide a summary of the key features of several early- and mid-childhood onset epileptic encephalopathies including Ohtahara syndrome, Dravet syndrome, Infantile spasms and Lennox Gastaut syndrome. We review the recent next generation sequencing findings that may impact treatment choices. We also describe the use of conventional and newer anti-epileptic and hormonal medications in the various syndromes based on their genetic profile. At a biological level, developments in cellular reprogramming and genome editing represent a new direction in modeling these pediatric epilepsies and could be used in the development of novel and repurposed therapies.
- Optimizing the molecular diagnosis of CDKL5 gene-related epileptic encephalopathy in boys. [JOURNAL ARTICLE]
- Epilepsia 2014 Sep 29.
Mutations involving the cyclin-dependent kinase-like 5 (CDKL5) gene cause an early onset epileptic encephalopathy (EE) with severe neurologic impairment and a skewed 12:1 female-to-male ratio. To date, 18 mutations have been described in boys. We analyzed our cohort of boys with early onset EE to assess the diagnostic yield of our molecular approach.We studied 74 boys who presented early onset severe seizures, including infantile spasms and developmental delay, in the setting of EE, using Sanger sequencing, next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA).We identified alterations involving CDKL5 in four boys (5.4%) using NGS in one and MLPA in three. Three of four mutations were indicative of somatic mosaicism.CDKL5 gene mutations accounted for 5.4% of boys with early onset EE. Somatic mosaic mutations might be even more represented than germline mutations, probably because their less deleterious effect enhances viability of the male embryo. The molecular approach used for CDKL5 screening remarkably influences the diagnostic yield in boys. Diagnosis is optimized by Sanger sequencing combined with array-based methods or MLPA; alternatively, NGS targeted resequencing designed to also detect copy number alterations, may be performed.
- De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies. [JOURNAL ARTICLE]
- Am J Hum Genet 2014 Oct 2; 95(4):360-370.
Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.
- Potential for treatment of severe autism in tuberous sclerosis complex. [Journal Article, Review]
- World J Clin Pediatr 2013 Aug 8; 2(3):16-25.
The Food and Drug Administration (FDA) has approved two mechanism-based treatments for tuberous sclerosis complex (TSC)-everolimus and vigabatrin. However, these treatments have not been systematically studied in individuals with TSC and severe autism. The aim of this review is to identify the clinical features of severe autism in TSC, applicable preclinical models, and potential barriers that may warrant strategic planning in the design phase of clinical trial development. A comprehensive search strategy was formed and searched across PubMed, Embase and SCOPUS from their inception to 2/21/12, 3/16/12, and 3/12/12 respectively. After the final search date, relevant, updated articles were selected from PubMed abstracts generated electronically and emailed daily from PubMed. The references of selected articles were searched, and relevant articles were selected. A search of clinicaltrials.gov was completed using the search term "TSC" and "tuberous sclerosis complex". Autism has been reported in as many as 60% of individuals with TSC; however, review of the literature revealed few data to support clear classification of the severity of autism in TSC. Variability was identified in the diagnostic approach, assessment of cognition, and functional outcome among the reviewed studies and case reports. Objective outcome measures were not used in many early studies; however, diffusion tensor imaging of white matter, neurophysiologic variability in infantile spasms, and cortical tuber subcategories were examined in recent studies and may be useful for objective classification of TSC in future studies. Mechanism-based treatments for TSC are currently available. However, this literature review revealed two potential barriers to successful design and implementation of clinical trials in individuals with severe autism-an unclear definition of the population and lack of validated outcome measures. Recent studies of objective outcome measures in TSC and further study of applicable preclinical models present an opportunity to overcome these barriers.
- Ventriculoperitoneal shunt infection with Listeria innocua. [Journal Article]
- Pediatr Int 2014 Aug; 56(4):621-3.
Listeria species may cause life-threatening events including meningitis and invasive infection in newborns, pregnant women, older and immunodeficient people. The most common Listeria species that causes infection is L. monocytogenes. It is known that Listeria innocua has no pathogenicity. A 9-month-old baby had ventriculoperitoneal shunt and was treated with adrenocorticotropic hormone because of infantile spasms. He was brought to hospital with fever and vomiting. Upon physical examination, the patient seemed uncomfortable and had a temperature of 38.6°C. Laboratory results were as follows: hemoglobin, 6.7 g/dL; leukocyte count, 5420/mm(3) ; platelet count, 169 000/mm(3) ; and C-reactive protein, 100 mg/L (normal <5 mg/L). On analysis of cerebrospinal fluid (CSF), leukocyte count was 480/mm(3) , protein was 46 mg/dL and CSF glucose was 35 mg/dL. L. innocua was isolated in CSF culture. We describe this unusual case of ventriculoperitoneal shunt infection with L. innocua.
- m.8993T>G-Associated Leigh Syndrome with Hypocitrullinemia on Newborn Screening. [JOURNAL ARTICLE]
- JIMD Rep 2014 Sep 21.
Citrulline is among the metabolites measured by expanded newborn screening (NBS). While hypocitrullinemia can be a marker for deficiency of proximal urea cycle enzymes such as ornithine transcarbamylase (OTC), only a handful of state newborn screening programs in the United States officially report a low citrulline value for further work-up due to low positive predictive value. We report a case of a male infant who was found to have hypocitrullinemia on NBS. After excluding proximal urea cycle disorders by DNA sequencing, his NBS result was felt to be a false positive. At 4 months of age, he developed poor feeding, failure to thrive, apnea and infantile spasms with a progression to intractable seizures, as well as persistent hypocitrullinemia. He was diagnosed with Leigh syndrome due to a maternally inherited homoplasmic m.8993T>G mutation in the ATPase 6 gene. His mother, who had previously been diagnosed with cerebral palsy, was concurrently diagnosed with neuropathy, ataxia, and retinitis pigmentosa (NARP) due to heteroplasmy of the same mutation. She had progressive muscle weakness, ataxia, and speech dyspraxia. The m.8993T>G mutation causes mitochondrial ATP synthase deficiency and it is hypothesized to undermine the synthesis of citrulline by CPS1. In addition to proximal urea cycle disorders, the evaluation of an infant with persistent hypocitrullinemia should include testing for the m.8993T>G mutation and other disorders that cause mitochondrial dysfunction.
- The ketogenic diet and other dietary treatments for refractory epilepsy in children. [Journal Article, Review]
- Ann Indian Acad Neurol 2014 Jul; 17(3):253-8.
The ketogenic diet is a high-fat, low-carbohydrate, and restricted protein diet that is useful in patients with refractory epilepsy. The efficacy of the ketogenic diet is better than most of the new antiepileptic drugs. Other modifications of the diet are also beneficial, such as the modified Atkins diet and the low glycemic index treatment. There is a lack of awareness of the ketogenic diet as a treatment modality for epilepsy amongst pediatricians and neurologists. In this review, the use of the ketogenic diet and other dietary treatments in refractory epilepsy is discussed. The Indian experience with the use of these dietary treatments is also briefly reviewed.
- A potential effect of ganaxolone in an animal model of infantile spasms. [JOURNAL ARTICLE]
- Epilepsy Res 2014 Sep 2.
Infantile spasms (IS), a devastating epileptic encephalopathy of infancy, involve various etiologies associated with an unknown underlying common pathophysiology. The efficacy of adrenocorticotropic hormone (ACTH) as an IS therapy suggests a role for steroid hormones in treating IS. This study used an animal model of IS to test the efficacy of ganaxolone, a synthetic neurosteroid, promoting tonic GABAA inhibition.The model of cryptogenic IS used in this study involved prenatal priming of rats with betamethasone (0.4mg/kg i.p. at 08:30 and 18:30) on gestational day 15. To test the acute effects of ganaxolone, rats were pretreated with ganaxolone (10, 25, or 50mg/kg i.p.) or vehicle (β-cyclodextrin, i.p.) 30min prior to N-methyl-d-aspartate (NMDA)-induced spasms at postnatal day 15 (P15). To mimic human conditions, another group of rats was randomly divided and repeatedly treated with ganaxolone (20mg/kg at 9:00 and 18:00 from P13-15) or vehicle after experiencing NMDA-triggered spasms at P12. Additional spasms were triggered on P13 and P15. We determined latency to the onset of spasms and the total number of spasms per 90-min observation period after the trigger at P15. On P19 and P21, behavioral tests were performed in rats with randomized repeated treatments.The 25mg/kg and 50mg/kg doses of ganaxolone significantly delayed the onset of spasms compared with the controls, and significantly decreased the number of spasms or suppressed their incidence. Ganaxolone had significant side effects in terms of sedation: all animals with the 50mg/kg dose were sleeping during the test. Randomized ganaxolone treatment for 3 days also significantly delayed the onset and decreased the number of spasms triggered by NMDA on P15, and decreased exploratory behavior after multiple NMDA triggered spasms.Ganaxolone significantly suppresses the development of spasms in the rat model of cryptogenic IS. This synthetic neurosteroid active in an animal model of IS might contribute to the current armamentarium to treat human IS.
- Epilepsy in Menkes disease: An electroclinical long-term study of 28 patients. [JOURNAL ARTICLE]
- Epilepsy Res 2014 Aug 30.
Epilepsy is a frequent and severe feature of Menkes disease (MD) but only few studies described the long-term evolution of these children. We report a series of 28 epileptic MD patients, with clinical characteristics, EEG abnormalities, brain malformations and long-term outcome.EEG, clinical characteristics and neuroimaging features in 28 MD patients were analyzed at the onset of epilepsy and after long-term follow-up (at least 4 years). We subdivided the patients into two groups: Group 1, 16 patients who received a subcutaneous copper-histidine treatment, and Group 2 including 12 patients who did not get any therapies.The large majority of our patients presented at the onset of epilepsy focal seizures (FS) and infantile spasms (IS). Five patients had recurrent status epilepticus (SE). During the follow-up, patients showed multiple seizure types: 6 patients had generalized tonic clonic seizures (GCT), 6 patients presented IS, 10 children had FS, 11 had myoclonic jerks and 3 had SE. Therapy with various antiepileptic drugs had poor efficacy, except in three patients who showed seizure disappearance with consequent discontinuation of antiepileptic therapy. There was no difference of neurological outcome among the two groups analyzed.Epilepsy in MD is a difficult to treat problem. At the onset, the most frequent type of seizures are FC and IS; in the next months, other kinds of seizures can appear. Many children are drug resistant. Institution of replacement therapy with copper-histidine seems to be not beneficial for epilepsy.