Author(s): Rolf G Boot [[dagger]] 1 , Mariëlle J van Breemen 2 , Wouter Wegdam 3 , Richard R Sprenger 4 , Shreyas de Jong 5 , Dave Speijer 6 , Carla EM Hollak 7 , Laura Van Dussen 8 , Huub CJ Hoefsloot 9 , Age K Smilde 10 , Chris G De Koster 11 , Johannes PC Vissers 12 , Johannes MFG Aerts 13
biomarker; chitotriosidase; Gaucher disease; mass spectrometry; proteomics
In man, at least 40 distinct inherited diseases occur that are caused by impaired lysosomal catabolism, so-called lysosomal storage disorders  . The most prevalent subgroup is made up of sphingolipidoses, inherited disorders characterized by excessive accumulation of one or multiple (glyco)sphingolipids. Particularly prominent is Gaucher disease  . After the first clinical case description by Philippe Gaucher in 1882, it was soon realized this was an example of a distinct disease entity, subsequently designated Gaucher disease  . The primary storage material in Gaucher disease was identified as glucocerebroside (glucosylceramide) in 1934. This glycosphingolipid is the common intermediate in the synthesis and degradation of gangliosides and globosides  . In 1965, Patrick and Brady and colleagues independently showed that the primary defect in Gaucher disease is a marked deficiency in activity of the lysosomal enzyme glucocerebrosidase (EC 18.104.22.168) [3,4] . The Gaucher disease diagnosis can be confirmed by the demonstration of deficient glucocerebrosidase activity towards an artificial, fluorogenic substrate, 4-methyl-umbelliferyl-[beta]-D-glucoside in cells, tissues or urine samples [5,6] .
Inherited deficiencies in glucocerebrosidase result in the accumulation of its lipid substrate in the lysosomal compartment of macrophages throughout the body. Different phenotypes (types I, II and III) are generally recognized, which are differentiated on the basis of the presence or absence of neurological symptoms. More recently, it has been realized that a complete deficiency in glucocerebrosidase activity also occurs, resulting in major skin permeability abnormalities with lethal consequences either prenatally or shortly after birth  . The prevalent Gaucher phenotype is the non-neuronopathic type I Gaucher disease. Age of onset and severity of clinical manifestations are highly variable. Characteristic symptoms include splenomegaly with anemia and thrombocytopenia, hepatomegaly and bone disease. Anemia may contribute to chronic fatigue. Thrombocytopenia and prolonged clotting times can lead to an increased bleeding tendency. Atypical bone pain, pathological fractures, avascular necrosis and extremely painful bone crises may also have a great impact on the quality of life  .
The GBA1 gene encoding glucocerebrosidase is located at the chromosomal locus 1q21. Numerous mutations in the GBA1 gene have been identified in relation to Gaucher disease. It has become clear that the underlying mutations in the GBA1 gene partly correlate with the severity of disease manifestation and, in particular, development of neurological symptoms. A low residual enzyme activity in leukocytes or cultured fibroblasts is associated with a more severe disease course [8,9] . In contrast to other lysosomal glycosidases, GBA1 does not acquire mannose-6-phosphate moieties, but is sorted and transported to lysosomes by interaction with the integral membrane protein LIMP-2 [10-12] . LIMP-2 deficiency may, therefore, also result in reduced cellular GBA1 activity  . Since GBA1 requires the activator protein saposin C for efficient intralysosomal degradation of...