China
Africa
Explore chapters and articles related to this topic
Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Adult diagnosis may require EM histology to identify inclusion bodies. White blood cells usually have characteristic inclusion bodies, so biopsies are not normally required. However, biopsies are taken of neuron dense tissues such as conjunctiva, skin, or rectal mucosa. Three different tissues should be negative to rule out inclusion body disease. If characteristic inclusion bodies are present, there are biochemical assays for PPT1, TPP1, and CTSD enzyme activity. Gene panel testing for progressive myoclonic epilepsy or storage disorders in general may also be considered based on the patient's phenotype.
Insights into ultra-low affinity lipase-antibody noncovalent complex binding mechanisms
Published in mAbs, 2022
Elizabeth Sara Hecht, Shrenik Mehta, Aaron T. Wecksler, Ben Aguilar, Nathaniel Swanson, Wilson Phung, Ananya Dubey Kelsoe, W. Henry Benner, Devin Tesar, Robert F. Kelley, Wendy Sandoval, Alavattam Sreedhara
The high sensitivity of native MS offered an opportunity to screen additional ultra-low-affinity binders from the esterase family, including palmitoyl protein thioesterase (PPT1),4 phospholipase D3 (PLD3),25 and sphingomyelin phosphodiesterase (SP)26 (Figure 2), which were previously identified as persisting in drug formulations through proteomics experiments. SP was not detected, and PPT1 and PLD3 complexes could only be observed in 100 mM ammonium acetate, rather than 50 mM. For PPT1, found at 0.6% relative abundance, binding was only achieved at a 100:1 protein:mAb solution ratio (Figure 2a). For PLD3 (Figure 2b), which exists naturally as a dimer, a 2:1 stoichiometric complex at 0.8% levels was observed in a 10:1 solution ratio. Thus, the native stoichiometric state of the esterase was shown in each case to bind a single antibody.
Emerging treatments for progressive myoclonus epilepsies
Published in Expert Review of Neurotherapeutics, 2020
Antonella Riva, Alberto Guglielmo, Ganna Balagura, Francesca Marchese, Elisabetta Amadori, Michele Iacomino, Berge Arakel Minassian, Federico Zara, Pasquale Striano
Knowing the pathogenesis of INCL and LINCL, enzyme replacement therapies (ERTs) represent the most straight-forward cytological approach. Initially, enzymes proved to be effective for non-CNS symptoms but not for neurodegeneration, because when intravenously administered they were unable to cross the blood-brain barrier (BBB); hence, in 2009 Tamaki SJ. et al. tried a novel approach. They transplanted purified human central nervous system stem cells, grown as neurospheres (hCNS-SCns), into the brains of immunodeficient Ppt−/- mouse. The rationale is to provide the deficient enzyme directly into the CNS through secretion of PPT1 by the grafted cells. As a result, the authors observed reduction of stored materials in the lysosomes, delayed loss of motor coordination and broad neuroprotection of host cells in the hippocampus and cortex. Hence, as hCNS-SCns could appropriately integrate into the brain, they could be considered as a safe, early-to-administer, therapeutic option for INCL [61].
New discoveries in progressive myoclonus epilepsies: a clinical outlook
Published in Expert Review of Neurotherapeutics, 2018
Shweta Bhat, Subramaniam Ganesh
Invariably in all the PMEs neurodegeneration at the molecular level is the hallmark feature. Oxidative stress is the major predisposing factor for neurodegeneration and epilepsy. Therefore, antioxidants have long been used in the management of PMEs. N-acetylcysteine (NAC), riboflavin, vitamin E, selenium, and zinc were shown to be useful in case of ULD [146]. Cofactors and vitamins with antioxidant properties namely coenzyme Q10 (CoQ10), L-carnitine, hydroxy-L-tryptophan are used in combination with idebenone (150 mg × 3 daily) in managing MERRF [123,128]. In addition, antioxidant sodium selenate has been reported to reduce seizure sensitivity in LD mouse model [147]. The ketogenic diet (2:1 to 4:1 fat to carbohydrate and protein) is yet another non-pharmacological treatment approach in controlling refractory epilepsy, but improvement in PMEs is limited [123,128,148]. Combinatorial therapy using antioxidants, such as vitamin E, Resveratrol, selenium, curcumin, and some chemical chaperones, such as trimethylamine N-oxide dihydride (TMAO) was reported in the management of NCL [149]. Omega 3/6 fatty acids were reported to exert protective effects in neuronal cells from mice deficient for Ppt1 (NCL1 model).