Chitotriosidase activity as additional biomarker in the diagnosis of lysosomal storage diseases.

N V Olkhovych,

doi:10.15407/ubj88.01.069

Abstract

To date, several genetic variants that lead to a deficiency of chitotriosidase activity have been described. The duplication of 24 bp (dup24bp) in exon 10 of the CHIT1 gene, which causes a complete loss of enzymatic activity of the gene product, is the most common among the European population. The aim of the study was to evaluate the possibility of using chitotriosidase activity as an additional biomarker in diagnosis of lysosomal storage diseases (LSDs) in Ukraine, to determine this parameter in blood plasma of the patients with various lysosomal diseases and to assess the effect of the presence of dup24bp in the CHIT1 gene on this parameter. It has been shown that chitotriosidase activity in blood plasma is a convenient additional biochemical marker in the diagnosis of some LSDs, namely Gaucher disease, Niemann-Pick disease A, B, C and GM1-gangliosidosis. Reference ranges of the normal chitotriosidase activity were determined in blood plasma of Ukrainian population and found to be 8.0-53.1 nmol 4-methylumbelliferone/h·ml of plasma. The total allele frequency of the dup24bp in the CHIT1 gene in Ukrainian population was determined, which amounted to 0.26 (323/1244) that is higher than in European population. It was indicated that moleculargenetic screening of dup24bp in the CHIT1 gene is a necessary stage in a protocol for the laboratory diagnosis of Gaucher disease, Niemann-Pick disease A, B, C as well as GM1-gangliosidosis to avoid incorrect diagnosis.

Highlights

Chitinases (3.2.1.14) are enzymes, the main function of which is to degrade chitin
It has been shown that individuals who have a pronounced deficiency in chitotriosidase activity are characterized by increased susceptibility to chitin-containing pathogens such as Wuchereria bancroftifilarial, Plasmodium falciparum malaria, Cryptococcus neoformans and Candida albicans [4]
A significant increase in chitotriosidase activity is observed upon some lysosomal storage diseases (LSDs), which are inherited metabolic disorders caused by defective functioning of specific lysosomal hydrolases and accompanied by the accumulation of undegraded intracellular metabolites [9]

Summary

Introduction

Chitinases (3.2.1.14) are enzymes, the main function of which is to degrade chitin. Mammalian chitinases belong to the glycosyl hydrolase 18 family (GH-18) and are characterized by both endochitinase activity (that is, they cleave randomly chitin polymer into oligosaccharides of varyinglengths) and exochitinase activity (they cleave off N-acetylglucosamine monosaccharide from the end of chitin polymer) [1]. It has been shown that individuals who have a pronounced deficiency in chitotriosidase activity are characterized by increased susceptibility to chitin-containing pathogens such as Wuchereria bancroftifilarial, Plasmodium falciparum malaria, Cryptococcus neoformans and Candida albicans [4]. Taking into account that CHIT1 is the most active in macrophages, it has been shown that hyper production of the enzyme occurs upon various chronic inflammatory processes such as atherosclerosis, idiopathic juvenile rheumatoid arthritis, inflammatory intestinal disorders, granulomatous and fibrotic interstitial lung diseases and others [5,6,7,8]. A significant increase in chitotriosidase activity is observed upon some lysosomal storage diseases (LSDs), which are inherited metabolic disorders caused by defective functioning of specific lysosomal hydrolases and accompanied by the accumulation of undegraded intracellular metabolites [9]. The immune response to chronic accumulation of undegraded substrates leads to the development of chronic inflammation accompanied by the macrophages activation and increased secretion by these cells of large amounts of various inflammatory mediators, including chitotriosidase [11]

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