Author(s):
Hammerschmidt, Tatiane Grazieli ; Encarnação, Marisa ; Lamberty Faverzani, Jéssica ; de Fátima Lopes, Franciele ; Oliveira, Fabiano Poswar de ; Fischinger Moura de Sousa, Carolina ; Ribeiro, Isaura ; Alves, Sandra ; Giugliani, Roberto ; Regla Vargas, Carmen
Date: 2023
Persistent ID: http://hdl.handle.net/10400.18/8912
Origin: Repositório Científico do Instituto Nacional de Saúde
Subject(s): Lysosomal Storage Diseases; Niemann-Pick type C; Miglustat; Neurodegeneration; Next Generation Sequencing; Inherited Disease; Rare Disease; Doenças Lisossomais de Sobrecarga; Niemann Pick tipo C; Genética Humana; Doenças Genéticas
Description
Niemann-Pick type C1 (NPC1) is a fatal inherited disease, caused by pathogenic variants in NPC1 gene, which leads to intracellular accumulation of non-esterified cholesterol and glycosphingolipids. This accumulation leads to a wide range of clinical manifestations, including neurological and cognitive impairment as well as psychiatric disorders. The pathophysiology of cerebral damage involves loss of Purkinje cells, synaptic disturbance, and demyelination. Miglustat, a reversible inhibitor of glucosylceramide synthase, is an approved treatment for NPC1 and can slow neurological damage. The aim of this study was to assess the levels of peripheric neurodegeneration biomarkers of NPC1 patients, namely brain-derived neurotrophic factor (BDNF), platelet-derived growth factors (PDGF-AA and PDGF-AB/BB), neural cell adhesion molecule (NCAM), PAI-1 Total and Cathepsin-D, as well as the levels of cholestane-3β,5α,6β-triol (3β,5α,6β-triol), a biomarker for NPC1. Molecular analysis of the NPC1 patients under study was performed by next generation sequencing (NGS) in cultured fibroblasts. We observed that NPC1 patients treated with miglustat have a significant decrease in PAI-1 total and PDGF-AA concentrations, and no alteration in BDNF, NCAM, PDGF-AB/BB and Cathepsin D. We also found that NPC1 patients treated with miglustat have normalized levels of 3β,5α,6β-triol. The molecular analysis showed four described mutations, and for two patients was not possible to identify the second mutated allele. Our results indicate that the decrease of PAI-1 and PDGF-AA in NPC1 patients could be involved in the pathophysiology of this disease. This is the first work to analyze those plasmatic markers of neurodegenerative processes in NPC1 patients.
