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Insulin Signaling Modulates Neuronal Metabolism
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Qian Huang, Jialin Fu, Kelly Anne Borges, Weikang Cai
Glucose can be stored as an energy reserve in the form of glycogen when in excess. This is also true in the brain (Figure 3.1). Glycogen in the brain was first observed and reported by Koizumi and Shiraishi using biochemical assay and electron microscopy in the 1970s (84, 85). However, the glycogen appears to be present exclusively in astrocytes (86–89). Although healthy neurons express the glycogen synthase required for glycogen synthesis, glycogen is hardly detected in neurons in experimental settings (90, 91). This is likely due to the constant high rate of utilization of glycogen in neurons (92). Any resident glycogen stock within the neurons may be exhausted during the sample tissue collection and processing. In addition, the protein targeting glycogen (PTG), a potent activator of the glycogen synthesis, is rapidly degraded in neurons, resulting in low basal glycogen synthesis (90). Although it is technically challenging to detect and assess glycogen storage in neurons, disrupted glycogen synthesis/degradation results in neural dysfunction and behavioral deficit in pathological conditions like hypoxia (93) or inherited genetic diseases with abnormal glycogen storage, such as Pompe disease and Lafora disease (90, 93–96), indicating the importance of regulated neuronal glycogen storage for normal neuronal development and function.
Tyrosine Phosphatases as New Treatment Targets in Acute Myeloid Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
I. Hubeek, K. Hoorweg, J. Cloos, Gertjan J. L. Kaspers
PTPs exert key regulatory functions, and it is therefore no surprise that they have been linked to various diseases. Inactivating mutations in PTPs have been correlated with genetic disorders like lafora disease and the autoimmune disease, systemic lupus erythematosus. In cancer, many PTPs act as tumor suppressor genes and are mutated or underexpressed in different tumors. Interestingly, PTPs are also able to enhance disease, which means that inhibition of PTPs could be of considerable therapeutic interest (36). In cancer, Cdc25 stimulates the cell cycle and enhances proliferation. The receptor phosphatase CD45 is involved in many autoimmune diseases and allergic reactions. The inhibition of CD45 is especially likely to be a successful approach for the treatment of Alzheimer’s disease (37). PTP inhibition could also constitute a valuable strategy against infectious diseases. Many bacteria like Salmonella typhimurium and Yersinia Pestis use either their own PTPs or host-derived PTPs to infect their host or escape from immune response (38). Another area, which would benefit from a PTP inhibitor, is the treatment of type 2 diabetes and obesity. PTP1B appears to be a very promising target for the treatment of these disorders (39).
Classification of The Epilepsies
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Henri Gastaut, Benjamin G. Zifkin
Many specific progressive disorders may give rise to secondary generalized epilepsy. In their early stages, they can be confused with the nonspecific Lennox-Gastaut syndrome or even with a benign, primary generalized epilepsy. These progressive encephalopathies include the ceroid lipofuscinoses, especially infantile Bielschowsky-Jansky disease; and Lafora disease and subacute sclerosing panencephalitis, found in the older child and adolescent. These are discussed in Appendix II of the 1985 ILAE proposal.21
Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy
Published in Journal of Neurogenetics, 2021
Elizabeth A. Burke, Morgan Sturgeon, Diane B. Zastrow, Liliana Fernandez, Cameron Prybol, Shruti Marwaha, Edward P. Frothingham, Patricia A. Ward, Christine M. Eng, Laure Fresard, Stephen B. Montgomery, Gregory M. Enns, Paul G. Fisher, Lynne A. Wolfe, Brian Harding, Blake Carrington, Kevin Bishop, Raman Sood, Yan Huang, Abdel Elkahloun, Camilo Toro, Alexander G. Bassuk, Matthew T. Wheeler, Thomas C. Markello, William A. Gahl, May Christine V. Malicdan
We examined the transcriptional changes in 6-month-old homozygous mutant (kctd7−/−) zebrafish by performing expression array analysis. A comparison of the transcriptional profiles of the kctd7−/− mutants and wild-type clutch mates (kctd7+/+) revealed a pattern of global gene dysregulation that clearly differentiates the two genotypes (Figure 3(C), Figure S4, and Table S1). The most significant difference occurred in genes that regulate apoptosis. Another important difference was seen in genes associated with seizure-related disorders (Figure 3(D) and Tables S2–S6). For example, one gene upregulated in kctd7−/−, that is, cdkn1a, has been shown to be upregulated in epileptic cortex samples (Chang et al., 2016). The expression of epm2a, the gene associated with progressive myoclonic epilepsy type 2 A/Lafora disease, was downregulated. Gadd45g, a sensitive indicator of damage to cellular DNA, was upregulated in kctd7−/− fish; similar findings have been observed in rat brains following kainic acid-induced seizures (Henshall, Sinclair, & Simon, 1999).
Perampanel as monotherapy and adjunctive therapy for focal onset seizures, focal to bilateral tonic-clonic seizures and as adjunctive therapy of generalized onset tonic-clonic seizures
Published in Expert Review of Neurotherapeutics, 2019
Ivana Tyrlikova, Milan Brazdil, Ivan Rektor, Michal Tyrlik
There are few reports providing evidence that perampanel might be effective as adjunctive therapy of progressive myoclonic epilepsy such as Lafora disease, a fatal pharmacoresistant adolescence-onset myoclonus epilepsy. Schorlemmer et al. documented sustained seizure remission of myoclonus and generalized onset tonic-clonic seizures in a 21-year-old woman with Lafora disease [33]. In a small prospective open-label study of 10 patients (without placebo control) with genetically confirmed Lafora disease, 4 patients achieved a significant seizure reduction greater than 74% compared to baseline. However, none of the patients achieved a significant improvement in disability or cognition. Three patients discontinued the perampanel treatment due to ineffectivity or side effects [34]. In addition, reports indicated the perampanel efficacy in severe encephalopathies like Unverricht-Lundborg disease [8] and type I Sialidosis [35] were also published. Perampanel showed its efficacy in the individual cases of dentatorubral-pallidoluysian atrophy [36] and in Lance-Adams posthypoxic non-epileptic myoclonus as well [37].
An Update on Myoclonus Management
Published in Expert Review of Neurotherapeutics, 2019
Christine M. Stahl, Steven J. Frucht
In 2016, Hainque et al. conducted a randomized placebo-controlled trial of zonisamide in the treatment of myoclonus and found that it improved the action myoclonus and myoclonus-related functional disability in 24 patients studied with myoclonus-dystonia [65]. There have also been a few promising reports on the benefit of perampanel for myoclonus. In 2016, Goldsmith and Minassian studied the efficiency and tolerability of perampanel as add-on therapy in 10 patients with Lafora disease in an open-label study [66]. They found seven patients had improvement of their myoclonus; however, there was no significant change in reported functional disability scores. Three patient dropped out of the study due to side effects, although there were no serious adverse events. In 2017, Crespel et al. studied perampanel as add-on therapy in 12 patients with Unverricht-Lundborg disease in an open label study [67]. They found 10 of the 12 patients had clear improvement of myoclonus, and 5 were able to decrease other medications. Notably, three patients regained the ability to walk, while two others regained the ability to transfer. The study found, however, that the use of perampanel was limited by psychological and behavioral side effects at higher doses. In 2018, Bianchini et al. reported one case of postsurgical cortical myoclonus that was refractory to benzodiazepine and levetiracetam but resolved with perampanel [68]. Additionally, in 2018, Gil-Lopez et al. examined the effect of perampanel as add-on therapy with a retrospective observational study of 31 patients with drug-resistant myoclonic seizures. They found that after 6 months of add-on therapy with perampanel, there were 10 who were myoclonic seizure free, with an additional five patients who reported an overall reduction in the number of days with myoclonic seizures [69].