BackgroundIn recent years clinical evidence has emphasized the importance of the mtDNA genetic background that hosts a primary pathogenic mutation in the clinical expression of mitochondrial disorders, but little experimental confirmation has been provided. We have analyzed the pathogenic role of a novel homoplasmic mutation (m.15533 A>G) in the cytochrome b (MT-CYB) gene in a patient presenting with lactic acidosis, seizures, mild mental delay, and behaviour abnormalities.MethodologySpectrophotometric analyses of the respiratory chain enzyme activities were performed in different tissues, the whole muscle mitochondrial DNA of the patient was sequenced, and the novel mutation was confirmed by PCR-RFLP. Transmitochondrial cybrids were constructed to confirm the pathogenicity of the mutation, and assembly/stability studies were carried out in fibroblasts and cybrids by means of mitochondrial translation inhibition in combination with blue native gel electrophoresis.Principal FindingsBiochemical analyses revealed a decrease in respiratory chain complex III activity in patient's skeletal muscle, and a combined enzyme defect of complexes III and IV in fibroblasts. Mutant transmitochondrial cybrids restored normal enzyme activities and steady-state protein levels, the mutation was mildly conserved along evolution, and the proband's mother and maternal aunt, both clinically unaffected, also harboured the homoplasmic mutation. These data suggested a nuclear genetic origin of the disease. However, by forcing the de novo functioning of the OXPHOS system, a severe delay in the biogenesis of the respiratory chain complexes was observed in the mutants, which demonstrated a direct functional effect of the mitochondrial genetic background.ConclusionsOur results point to possible pitfalls in the detection of pathogenic mitochondrial mutations, and highlight the role of the genetic mtDNA background in the development of mitochondrial disorders.
Background: The ketogenic diet (KD) is an effective treatment against drug-resistant epilepsy in children. The KD is a diet rich in fats that produces anticonvulsant and neuroprotective effects that reduces seizures and improves the cognitive state. Nevertheless, it can produce side effects that sometimes can be serious. Further, the effect on growth is quite controversial when used for an extended period of time. The aim of this paper was to assess the effectiveness, side effects, and repercussions in the development of children who have been treated with a KD for more than 2 years. Methods: Observational descriptive study of 26 pediatric patients on a KD, with data collection at baseline, at 3, 6, and 12 months, and then once a year. Number of seizures, type of seizures, anti-seizure drugs, anthropometry, side effects, and alterations in laboratory assessment were monitored. Results: In every assessment, about 60%–75% of the patients experienced a reduction in number of seizures of over 90%, and at least 50% experienced side effects, of which digestive issues, alteration in the lipid metabolism, and hypercalciuria were the most common. The KD significantly affected height after 2 years of treatment. Conclusions: The KD is an effective treatment for drug-resistant epilepsy. Its side effects, although common, are very mild; therefore, this constitutes a very safe treatment for children of all ages. More studies are needed to identify and prevent potential causes of growth retardation in children on the KD.
Status Epilepticus (SE) is a potential and relatively common complication of epileptic seizures. Traditionally, SE was defined as 30 minutes of continuous seizure activity or a series of seizures without return to full consciousness between the seizures. As a practical rule, it is admitted that all patients arriving at the emergency room suffering from epileptic seizures could have SE and should be treated accordingly. It is well known that the longer an attack has lasted, the more difficult it is to control in the next 5 to 10 minutes. On the other hand, once an attack has lasted for over 5 to 10 minutes, it is unlikely to cease spontaneously. Ambulatory intervention should focus on this "therapeutic interval" in acute attacks with the use of first-line drugs such as the intramuscular, rectal, oral, and/or intranasal application of benzodiazepines (BZD). Treatment of SE is a medical emergency, which should include 3 priority objectives: (1) to stop the seizures; (2) to maintain internal homeostasis; and (3) to treat possible complications. Current consensus is that a BZD, notably lorazepam or diazepam, is the initial class of drug for the treatment of SE. Phenytoin, fosphenytoin, or valproate generally is agreed upon as the next drugs to be administered. Failure to respond to optimal BZD and phenytoin loading operationally defines refractory SE.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.