Generally, these NCL forms are based on disease onset and mutated gene. Currently, several mutations have been identified in more than 13 different genes all resulting in a specific form of NCL. Unfortunately, the NCLs are not limited to a single gene or genetic mutation. Given the large neurological manifestations and predominance in childhood onset, the NCLs are considered to be the most common pediatric neurodegenerative disease. Symptomatic hallmarks of the NCLs consist of but are not limited to epilepsy, tremors, retinopathy, gross and fine motor deterioration, and cognitive decline. Most commonly, NCL onset begins in childhood however in rarer occasions onset can occur in adulthood. The Neuronal Ceroid Lipofuscinoses (NCLs) are a special category of LSD and accumulate a storage material referred to as ceroid lipofuscin. All LSDs affect multiple physiological systems however, most appear to illicit a significant effect on the central nervous system (CNS). LSDs are commonly categorized according to the constituents of this accumulated material thus resulting in generalized LSD categories for example the mucopolysaccharidoses accumulate mucopolysaccharides. These deficiencies affect normal lysosomal function resulting in an accumulation of various lysosomal substrates. Ionized calcium binding adapter molecule 1 DAPI,Ĭhildren across the globe are affected by any one of more than 40 different lysosomal storage disorders (LSDs) many of them resulting from deficiencies in either a lysosomal membrane protein or lysosomal enzyme. Glyceraldehyde-3-phosphate dehydrogenase GFAP, The equipment used from the molecular, histology, and microscope cores at Sanford Research are funded by National Institutes of Health program grants P20GM103620 and P20GM103548 awarded to Sanford Research's Children's Health Research Center and Cancer Biology Research Center respectively.Ĭompeting interests: The authors have declared that no competing interests exist.Ĭlassic infantile neuronal ceroid lipofuscinosis cLINCL,Ĭlassic late infantile neuronal ceroid lipofuscinosis cJNCL,Ĭlassic juvenile neuronal ceroid lipofuscinosis TPP1, This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All data is contained within the paper and supplementary material.įunding: This work was supported by Sanford Health. Received: MaAccepted: MaPublished: May 2, 2017Ĭopyright: © 2017 Geraets et al. PLoS ONE 12(5):Įditor: Thomas Langmann, University of Cologne, GERMANY (2017) A tailored mouse model of CLN2 disease: A nonsense mutant for testing personalized therapies. Collectively, these assessments indicate that the Cln2 R207X/R207X mouse is a valid CLN2 disease model which can be used for the preclinical evaluation of all therapeutic approaches including mutation guided therapies.Ĭitation: Geraets RD, Langin LM, Cain JT, Parker CM, Beraldi R, Kovacs AD, et al. This reduction leads to the development of neurological impairment (e.g. Molecular assessment of Cln2 R207X/R207X tissues determined significant reduction in Cln2 transcript abundance and TPP1 enzyme activity. Thus, we created a mouse model that carries a mutation equivalent to the human p.R208X mutation. Nonsense mutations in CLN2 disease are frequent, the most common being CLN2 R208X. Therefore, the purpose of this study was to develop a model of CLN2 disease that allows for the assessment of all therapeutic approaches. The genotype of the original mouse model of CLN2 disease, Cln2 -/-, excludes mutation guided therapies like antisense oligonucleotides and nonsense suppression. Mutations of the CLN2 gene encoding a soluble lysosomal enzyme, tripeptidyl peptidase 1 (TPP1), cause late infantile NCL/CLN2 disease. However, the genotypes of NCL animal models determine which therapeutic approaches can be assessed. ![]() Nevertheless, preclinical and clinical trials exist for various therapies. The NCLs result in premature death due to the absence of curative therapies. Initial clinical presentation usually consists of either seizures or retinopathy but develops to encompass both in conjunction with declining motor and cognitive function. Although, adults are susceptible, the NCLs are frequently classified as pediatric neurodegenerative diseases due to their greater pediatric prevalence. The Neuronal Ceroid Lipofuscinoses (NCLs), also known as Batten disease, result from mutations in over a dozen genes.
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