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.

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Purpose: To assess the relationship between serum inflammatory markers (interleukin 6, high sensitivity C-reactive protein [hsCRP] and chitotriosidase activity) and the extent of carotid atherosclerotic lesions in subjects with various types of dementia. Methods: Four hundreds persons with dementia (166 diagnosed as probable Alzheimer's disease, 85 as vascular dementia [VaD], 149 as mixed dementia [MD] and 180 controls) were observed. In all persons carotid intima-media thickness (IMT) was measured and all were subjected to a general medical and neurological evaluation, neuroimaging examination (computed tomography and magnetic resonance) and comprehensive neuropsychological examination. The pro-inflammatory markers interleukin-6 (IL-6) and hsCRP, and anti-inflammatory markers (paraoxonase-1 activity and HDL cholesterol level), were determined in blood serum. Chitotriosidase activity -an indicator of chronic macrophage activation -was also determined. Results: A higher frequency of carotid atherosclerosis was observed in the whole group of dementia and in the VaD and MD groups as compared to the controls. A significant positive correlation of IMT with the inflammatory indicators IL-6 and hsCRP was found. A negative correlation of IMT with inflammatory markers (paraoxonase-1 activity and HDL cholesterol level) was observed. Chitotriosidase activity was significantly elevated, as compared with the controls, in the whole group with dementia and in the MD group, and depended on the degree of carotid stenosis. Conclusions: Serum IL-6, hsCRP and chitotriosidase activity can be considered as markers of the extent of carotid arteriosclerosis in dementia, especially in patients with dementia with vascular lesions. High chitotriosidase activity may indicate chronic macrophage activation in the course of dementia development.

Ceroid lipofuscinosis type 3 (CLN3) is an autosomal recessive, neurodegenerative metabolic disease. Typical clinical symptoms include progressive visual loss, epilepsy of unknown etiology and dementia. Presence of lipofuscin deposits with typical pattern of ‘fingerprints’ and vacuolized lymphocytes suggest the diagnosis of CLN3. Cause of CLN3 are mutations in the CLN3 gene, among which the most frequently found is the large deletion 1.02 kb spreading on exons 7 and 8. We present 4 patients from 2 families, in whom the deterioration of visual quality and acuity was observed as first clinical sign, when they were a few years old and it was successively accompanied by symptoms of neurologic deterioration (like generalized convulsions with consciousness impairment). In all patients the 1.02 kb deletion in the CLN3 gene was detected in homo- or heterozygosity with other CLN3 pathogenic variant. Ultrastructural studies revealed abnormal structures corresponding to ‘fingerprint’ profiles (FPPs) in conjunctival endothelial cells. It should be emphasized that in patients with blindness of unknown cause the diagnosis of ceroid lipofuscinosis should be considered and in older children—especially CLN3. The facility of the analysis for the presence of 1.02 kb deletion and economic costs are a solid argument for intensive use of this test in the diagnostic procedure of CLN3.