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The role of glycoproteins in the causes, diagnosis and treatment of Gaucher’s diseaseIntroduction Gaucher’s disease is a rare autosomal genetic disorder which is believed to be caused by the insufficient production of the lysosomal hydrolase enzyme, glycocerbrosidase. This decrease of this lysosomal enzyme therefore decreases the action of the enzyme to act on ceramide in order to break it down into glucosylceramide (which essential for the further production of gangliosides and lactosylceramides, which are responsible for the maintenance of healthy cardiovascular health, sugar homeostasis cancer prevention and normal neuronal function.
as well as used in the formation of the endomembrane and plasma membrane of eukaryotic cells). However, continued overabundance of the glycosphingolipids such as glucosylceramide, primarily within the lysosome derived from the macrophage linage. Glucosylceramide- engorged cells infiltrate various organs, this is harmful and results in Gaucher’s disease. Glycosphingolipids such a ceramide are subtypes of glycolipids known as sphingolipids as they contain amino alcohol sphingosine groups. Sphingolipids are thought to be associated with apoptotic processes, and glucosylceramide might directly activate and enhance macrophage function.
Glucocerebrosidase works by breaking down naturallyoccurring glycosphingolipid molecules found in the spleen and bone marrow, which are responsible for the cleavage of the Іglucosidic bond of the glucocerebrosidase enzyme, glucosylceramide (Cox, 2001). When glucocerebrosidase activity is low, Nacylsphingosyl1″0ІDglucoside’ and other sphingolipid metabolites, accumulate in lysosomal macrophages located in the bone marrow, spleen and liver (Nguyen, Stirnemann and Belmatoug, 2019). The collection of glycolipids leads to various symptoms associated with a lysosomal storage disease. Since glucocerebrosidase (GlcCer is a key intermediate in the biosynthetic and degradative pathways of complex glycosphingolipids (Figure 1), its accumulation in GD is likely to have severe pathological consequences.
8280409525000 -279133145047Figure 1. Pathophysiological mechanisms of Gaucher’s disease (Jmoudiak and Futerman, 2019). The sequential steps in the degradation of glycosphingolipids by lysosomal‹ ‹hydrolases‹. Gaucher Disease is also connected to the same pathway where defects in Krabbe disease, Farber disease and Niemann Disease and others occur.0Figure 1. Pathophysiological mechanisms of Gaucher’s disease (Jmoudiak and Futerman, 2019). The sequential steps in the degradation of glycosphingolipids by lysosomal‹ ‹hydrolases‹. Gaucher Disease is also connected to the same pathway where defects in Krabbe disease, Farber disease and Niemann Disease and others occur.Causes Genetic studies have shown the glucocerebrosidase acid gene (GBA) is located on the 1q21 chromosome. Researchers reported morethan 200 mutations have been gene associated with GD. Both the N370S and L444P mutations are the most prevalent mutations in the GBA gene located on the chromosome 1q21(Dandana et al., 2015). Mutations such as the N370S have been found to mostly occurs within the Caucasian population. Whereas other mutations such as the 84GG and the N370S are though to hav originated from a single founder in the Ashkenazi Jewish population. The presence the N307S mutation guarantees sufficient Glucosylcerebrosidase activity for the production of glucocerebroside in neurones, therefore, no neurological symptoms are revealed. However, the L444P mutation of the GBA gene leads to neuronopathic forms of GD disease. -38163519939000Signs and symptoms -2310063235961Figure 2. Clinical presentations and therapeutic treatments of the distinct forms of Gaucher’s disease (Thomas, Mehta and Hughes, 2014). 0Figure 2. Clinical presentations and therapeutic treatments of the distinct forms of Gaucher’s disease (Thomas, Mehta and Hughes, 2014). Researchers have identified three forms of Gaucher’s disease, categorised by the absence, presence and severity of neurological complications. Within each form of Gaucher’s, there are a large range of symptoms that can vary from person to person. Type 1 GD is the most common form of Gaucher disease, with a prevalence of 1:50,000 in the population, with as high as 1 in 850 in the Ashkenazi Jewish population (Baris, Cohen and Mistry, 2014). Clinical manifestations of GD1 mostly occur in childhood and is characterized by clinical or radiographic evidence of bone disease (Pastores and Hughes, 2000), other symptoms such as; unexplained thrombocytopenia (bruising easily due to low levels of platelets in the blood), chronic fatigue due to anaemia and hepatosplenomegaly (abnormally enlarged liver and or spleen) caused by the accumulation GL-1 macrophages in the liver and spleen, while accumulation in the bone marrow in conjunction which hypersplenism leads to cytopenia (Cappellini et al., 2018; Baris, Cohen and Mistry, 2014). Type 2 Gaucher’s disease exhibits itself within the first few months after birth and is shortly followed by death within the 2 years. Symptoms of type 2 Gaucher’s include irregular accumulations of fluid in at least two foetal compartments in utero’ (Derderian et al., 2015). Newborns with type 2 GD may appear to have congenital ichthyosis (skin abnormality) which presents itself in the form of thick, shiny, scale like skin.3651256700 -346075165067Figure 3. Microscopic image of macrophage cells normally found in patients diagnosed with gaucher’s disease. Gaucher cells unique appearance resembles that of wrinkled tissue paper or crumpled silk. (Lichtman, M., 2016)0Figure 3. Microscopic image of macrophage cells normally found in patients diagnosed with gaucher’s disease. Gaucher cells unique appearance resembles that of wrinkled tissue paper or crumpled silk. (Lichtman, M., 2016)The hydrolysis of glucosylceramide to ceramide is believed to play an important role in the formation and maintanence of epidermal permeability barrier (Berra, et al., 2000). It is believed that this symptom of type 2 gaucher’s disease arises due to the different ratios of ceramides to glucosylceramides in the outer layer of skin (Stone, 2000). This symptom leads to higher levels of ceramide as a result of the failure to hydrolyse glucosylceramide to ceramide. Other symptoms of type 2 GD include hepatosplenomegaly, neurological involvement, thrombocytopenia and anaemia, (Bodamer et al., 2002). Gaucher’s type 3 GD disease is the neuropathic form of the disease characterised by the affect it has in the central nervous system. Individuals diagnosed with this type of GD show symptoms before the age of two years old, with the disease having a slow progressive course, that may lead to the individual’s survival into the third or fourth decade (Pastores GM, Hughes DA, 2000). According to (Suwannarat et al., 2007) type 3 is further subdivided into; Gaucher’s type 3a,3b and 3c. Type 3a, symptoms include minor hepatosplenomegaly and early onset of neurological symptoms, including seizures, crossed eye (strabismus) and Isolated horizontal supranuclear gaze palsy’ (Patterson et al., 1993). Type 3b is characterised by hepatosplenomegaly, skeletal abnormalities, supranuclear gaze palsy, a later development of seizures and diminished intelligence. Type 3 correlates to the build-up of calcium around the aorta and mitral valve of the heart (Patterson et al., 1993). Llittle is known about the molecular mechanism by which GlcCer accumulation leads to neuropathology in types 2 and 3 gaucher’s disease. Cox, 2001, finding a definitive explanation for the development of neuropathic forms of gauchers disease will be challenging, (Cox, 2001) suggested that failure to degrade glycosphingolipids present in brain tissue to be a factor in the onset of neuropathic forms of gaucher’s disease, moreover, the accumulation of Gaucher’s cells around adventitial spaces in cerebral blood vessels due to the uptake of circulating glucosylceramide present in the blood may be a contributory factor.Diagnosis of Gaucher’s diseaseThe definitive diagnosis of Gaucher’s disease is done by determining the activity of glucocerebrosidase. According to a patient analysis conducted by (Dandana et al., 2015) conducting smear tests taken from the spleen of a patient suspected to have Gaucher’s disease found macrophages with large, pale and distinctly fibrous cytoplasm. These macrophages were also found with small nucleoli found with an eccentric nucleus (Lee et al., 1996). These are the characteristic appearance of diseased cells with GD (figure 2) GD cells can be compared with normal variations of monocytes in order to revive a proper diagnosis of GD disease. In order to receive a diagnosis of Gaucher’s disease, doctors may also choose to conduct a blood test called a beta-glucosidase leukocyte (BGL) test in order to assess the activity of the enzyme and diagnose Gaucher disease.Standard and investigational therapies of Gaucher’s diseaseThere are many possible investigational therapies for treating the three different types of gaucher’s disease. In order to treat type 1 GD, (Pastores et al., 2004) suggested the use of Enzyme replacement therapy (ERT) with mannose-terminated glucocerebrosidase’ reverses or improves many symptoms of type 1 Gaucher disease. Enzymes such as mannose terminated glucocerebrosidase’ inhibit the enzyme glucosylceramide synthase, which as seen from figure 1 is the first enzyme in the reaction cascade which ends with the synthesis of glucocerbroside. The aim of this treatment is to decrease the rate of glucerebrosidase synthesis and as a result reduce the glucocerebroside enzyme activity (Neufeld EF., 2006). On the other hand, because of the disease’s uncertainty and severity it is difficult to commence with the treatment. Also presenting potential promise is gene therapy, this would be the first line of treatment for Gaucher’ s disease. Gene therapy studies using mice have proven very successful, for example, intravenous administration of vectors containing the human elongation factor 1± promoter were administered to wildtype mice, this resulted in increased GlcCerase activity that persisted for over 20 weeks (Hong et al, 2004). However, the likelihood of gene therapy becoming a viable option for GD in the near future in human patients remains small because of the lack of successful human trials (Jmoudiak and Futerman.,2005). ConclusionWhile Gaucher disease is relatively rare, it is the most common lysosomal disorder known to date. Due to the fact Gaucher disease is caused by the mutation of single genes, of which many are known such as the L444P and N370s mutation. Dispite this, presymptomatic testing, pre-natal testing, and carrier screening have been made possible by great advances in scientific technology and has the potential to be effective in improving treatment of GD patients. Although treatment is now available, further research into the complex pathophysiology of Gaucher disease and further pharmacological therapies will need to be conducted in order to better improve the lives of individuals who suffer from this disease. Reference list Baris,, H., Cohen, I. and Mistry, P. (2014). Gaucher Disease: The Metabolic Defect, Pathophysiology, Phenotypes And Natural History. Pediatric Endocrinology Reviews, [online] 12(0-1), pp.72″81. Available at: [Accessed 20 Jan. 2019].Berra,, B., Adorni,, L., Ciuffo, R., Montorfano, G., Ra pelli,, S. and Zava, S. (2000). SKIN LIPID ABNORMALITIES IN GAUCHER’S DISEASE. J.Appl. Cosmetol., [online] 18, pp.113-123. Available at: [Accessed 9 Feb. 2019].Bodamer, O., Church, H., Cooper, A., Wraith, J., Scott, C. and Scaglia, F. (2002). Variant Gaucher disease characterized by dysmorphic features, absence of cardiovascular involvement, laryngospasm, and compound heterozygosity for a novel mutation (D409H/C16S). American Journal of Medical Genetics, [online] 109(4), pp.328-331. Available at: [Accessed 21 Jan. 2019].Cappellini, M., Cassinerio, E., Motta, I., Morello, W. and Villarubia, J. (2018). Finding and Treating Gaucher Disease Type 1 ” The Role of the Haematologist. European Oncology & Haematology, 14(1), p.50.Cox, T. (2001). 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Available at: [Accessed 21 Jan. 2019].Suwannarat, P., Keeratichamroen, S., Wattanasirichaigoon, D., Ngiwsara, L., Cairns, J., Svasti, J., Visudtibhan, A. and Pangkanon, S. (2007). Molecular characterization of type 3 (neuronopathic) Gaucher disease in Thai patients. Blood Cells, Molecules, and Diseases, [online] 39(3), pp.348-352. Available at: [Accessed 22 Jan. 2019].Thomas,, A., Mehta, A. and Hughes, D. (2014). Clinical features and presentation of sub-types of Gaucher’s disease. [image].Weiss, K., Gonzalez, A., Lopez, G., Pedoeim, L., Groden, C. and Sidransky, E. (2015). The clinical management of type 2 Gaucher disease. Molecular Genetics and Metabolism, [online] 114(2), pp.110-122. Available at: [Accessed 21 Jan. 2019].
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