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Lysosomal, sterol and lipid disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Batten disease consists of a group of disorders comprising four main clinical types as well as several other variant forms. In the infantile form, there is a build-up of lipofuscins, which are composed of fats and proteins, in the body. This form is caused by a deficiency of the palmitoyl protein thioesterase (PPT) enzyme, as a result of which, storage material known as granular osmiophilic deposits (GROD) accumulates in the brain and other body tissues, leading to severe deterioration.
New discoveries in progressive myoclonus epilepsies: a clinical outlook
Published in Expert Review of Neurotherapeutics, 2018
Shweta Bhat, Subramaniam Ganesh
Broadly, almost all the gene products or proteins identified to be defective in NCLs can be grouped under one broad functional category: that they are involved in cellular homeostatic processes, involving proteolysis (autophagy, lysosome, and proteasomal degradation) and lipid metabolism. Two of the proteins are vesicular membrane proteins (CLN-4 and CLN-14), and the other localizing on the endosomal (CLN-6 and CLN-8) or lysosomal compartments (CLN-1, CLN-2, CLN-3, CLN-5, CLN-7, CLN-10, CLN-12, and CLN-13). Proteins encoded by CLN-10 and CLN-13 are lysosomal soluble proteins. Despite the progress made in identifying and characterizing the genes involved in NCLs, the precise mechanism underlying the individual NCL phenotype is still unknown. What is known is that the deficiency of any of the functional protein invariably leads to accumulation of ceroid-lipopigments, subunit c of mitochondrial ATP synthase or sphingolipid activator proteins A and D in lysosomes leading to neurodegeneration and associated CNS aberrations. Palmitoyl-protein thioesterase 1 (PPT1) coded by CLN-1, the Tripeptidyl-peptidase 1 (TPP1) coded by CLN-2, a transmembrane protein coded by CLN-3, Cysteine-string protein alpha (CSPα)/DNAJC5 coded by CLN-4 are demonstrated to be involved in synaptic endo or exocytosis, normal neurotransmission, and apoptosis. Apart from this general involvement, individual, protein-specific functions are also reported. For example, Cathepsin D (Aspartyl endopeptidase) and Cathepsin F (Cysteine protease) encoded by CLN-10 and CLN-13 are thought to play a role in apoptosis, autophagy, and proteasomal and lipoprotein degradation, respectively. A detailed description of cellular functions of these proteins can be found elsewhere [63,66], and summary is provided in Table 2.
Batten disease: an expert update on agents in preclinical and clinical trials
Published in Expert Opinion on Investigational Drugs, 2020
Margaux C. Masten, Jonathan W. Mink, Erika F. Augustine
CLN1 disease is caused by a mutation in CLN1 resulting in a nonfunctional palmitoyl-protein thioesterase-1 (PPT1) enzyme. Pre-clinical mouse data showed that intrathecal administration of recombinant PPT1 enzyme reduced the amount of storage material and had a significant effect on lifespan and motor function in CLN1−/- mice [10]. Collaborations Pharmaceuticals (https://www.collaborationspharma.com/pipeline, 7/13/2020) is developing a clinical trial for ERT in CLN1 disease.
Progress in gene and cell therapies for the neuronal ceroid lipofuscinoses
Published in Expert Opinion on Biological Therapy, 2018
Anthony Donsante, Nicholas M Boulis
Lönnqvist et al. treated three CLN1 disease patients between the ages of 4 and 11 months with allogeneic BMT or umbilical cord blood and followed them for 2–4 years. In one patient, cerebrospinal fluid (CSF) levels of palmitoyl protein thioesterase 1 (PPT1) reach normal 4 years after transplant. Although all three patients showed decline over time, the authors suggested that there might have been a transient amelioration of the disease [19].