Treatment trials in Niemann-Pick type C disease.

Niemann-Pick type C (NPC) disease is a genetically determined neurodegenerative metabolic disease. It belongs to the lysosomal storage diseases and its main cause is impaired cholesterol transport in late endosomes or lysosomes. It is an autosomal recessive inherited disease that results from mutations in the NPC1 or NPC2 genes. The treatment efforts are focused on the slowing its progression. The only registered drug, devoted for NPC patients is Miglustat. Effective treatment is still under development. NPC disease mainly affects the nervous system, and the crossing of the blood-brain barrier by medicines is still a challenge, therefore the combination therapies of several compounds are increasingly being worked on. The aim of this paper is to present the possibilities in treatment of Niemann-Pick type C disease. The discussed research results relate to animal studies.

Laboratory diagnosis of the Niemann-Pick type C disease: an inherited neurodegenerative disorder of cholesterol metabolism.

Niemann-Pick type C disease (NPC) is a genetically determined neurodegenerative metabolic disease resulting from the mutations in the NPC1 or NPC2 genes. It belongs to the lysosomal storage diseases and its main cause is impaired cholesterol transport in late endosomes or lysosomes. NPC is inherited in an autosomal recessive trait. Due to the wide range in age of onset, often unspecific clinical picture and varying dynamics of disease progression, the diagnosis is very difficult and long-lasting. The most characteristic visceral symptoms are hepato- or hepatosplenomegaly, which may appear independently of neurological or psychiatric symptoms at various stages of the disease. Available biochemical biomarkers should be tested as early as possible in patients presenting with hepato- or hepatosplenomegaly, long-lasting cholestatic jaundice in neonates or infantile patients, as well as in individuals at any age with: vertical supranuclear gaze palsy (VSGP), ataxia, dystonia, frontotemporal dementia and untreatable schizophrenia or psychosis. Research on biomarkers which can detect NPC patients (Cholestan-3ß, 5α, 6ß-triol, 7-ketocholesterol, lysosphingomyelin isoforms and bile acid metabolites) is still ongoing, although they are not specific for the NPC disease only. This mini review describes currently used diagnostic methods.

Gene expression profile in patients with Gaucher disease indicates activation of inflammatory processes.

Gaucher disease (GD) is a rare inherited metabolic disease caused by pathogenic variants in the GBA1 gene. So far, the pathomechanism of GD was investigated mainly in animal models. In order to delineate the molecular changes in GD cells we analysed gene expression profile in cultured skin fibroblasts from GD patients, control individuals and, additionally, patients with Niemann-Pick type C disease (NPC). We used expression microarrays with subsequent validation by qRT-PCR method. In the comparison GD patients vs. controls, the most pronounced relative fold change (rFC) in expression was observed for genes IL13RA2 and IFI6 (up-regulated) and ATOH8 and CRISPLD2 (down-regulated). Products of up-regulated and down-regulated genes were both enriched in genes associated with immune response. In addition, products of down-regulated genes were associated with cell-to-cell and cell-to-matrix interactions, matrix remodelling, PI3K-Akt signalling pathway and a neuronal survival pathway. Up-regulation of PLAU, IFIT1, TMEM158 and down-regulation of ATOH8 and ISLR distinguished GD patients from both NPC patients and healthy controls. Our results emphasize the inflammatory character of changes occurring in human GD cells indicating that further studies on novel therapeutics for GD should consider anti-inflammatory agents.