Understanding Gauchers Disease


The pathogenesis of the disease is required to be known so that the manner in which it develops is identified in turn assisting the person to take precaution in avoiding to be affected by the illness. The strategies for the treatment of any disease are needed to be understood so that the individuals have knowledge regarding the treatment option to be available after being affected by the disease. In this report, the signs and symptoms along with pathogenesis of Gaucher's Disease are to be explained to inform about the factors that lead to the cause of the disease. The treatment strategies adopted for treating Gaucher's Disease is also to be discussed to help individual develop idea regarding the way they can get relieved from the illness.


Overview of Gaucher’s Disease

Gaucher’s Disease referred to the rare genetic disorder that leads accumulation of glucocerebroside which is a nature of sphingolipid into the cells and certain organs of the body mainly the spleen and liver. The presence of the disease causes the organs to enlarge which negatively affects their functioning that results individuals to experience health disorders. This is because the people affected by the disease lacks enough glucocerebrosidase enzyme which acts to beak the fatty chemical known as glucocerebroside (Mistry et al. 2017). There are three different types of Gaucher’s Disease which are mainly type 1, type 2 and type 3 (Dandana et al. 2016). The exact epidemiology of Gaucher's Disease is not available but from the left data published by the NICE, it is reported that most of the people are affected by type 1 of Gaucher's Disease. The overall frequency of occurrence of the disease is approximately 1 in 100,000 births. The NICE also informs that prevalence of type1 Gaucher’s Disease is 1 in 200,000 non-Ashkenazi Europeans that equals to 250 people present in the Wales and England (NICE, 2014).

Signs and Symptoms of Gaucher’s Disease

The people affected by type 1 Gaucher’s disease shows symptoms of enlarged spleen or liver, fatigue and bone formation issues. However, brain development in people affected by type 1 of Gaucher's disease is normal. The enlargement of the liver or spleen occurs because the cells in the organs have an excess accumulation of Gaucher cells which leads to enlarge their size. The swollen organs lead the individuals experiences pain and swollen belly which interferes with having a proper and complete meal (Alaei et al. 2018). In type 1 Gaucher’s disease, the individuals experience fatigue along with shortness of breath in some cases because of low blood counts. The accumulation of the Gaucher cells in the spleen along with bone marrow that acts to maintain and produce normal amount of blood cells are damaged in the disease resulting in presence of lower blood count among individuals (Regenboog et al. 2016). The problem in bone formation and maintenance is seen in people affected by type 1 Gaucher’s disease because the cortical bone is thinned resulting the individual experience pain in the bone joints and easy fractures of bone (Mistry et al. 2017).

The people affected by type 2 Gaucher’s disease are seen to show signs of early brain damage that worsen rapidly. The other symptoms seen among the individual include hindered ability to swallow, spasticity, enlarged liver and spleen along with seizures (Weiss et al. 2015). The brain is severely affected in type 2 of the Gaucher’s disease because the accumulation of fats occurs in the brain which disrupts its normal neurological functioning to direct the movement of the body leading individuals to experience spasticity, seizures and others (Tezuka et al. 2018). The presence of type2 Gaucher's disease is seen mostly among infants and the symptoms initiate to rise within 3 to 6 months of birth. The babies affected by type 2 of the disease do not have enough time to develop other symptoms related with the disease as they are often stillborn or experience abnormalities in the skin which makes them die within 2 years from their birth (BenHamida et al. 2015).

The type 3 Gaucher’s disease shows gradual onset of the symptoms compared to type 2 of the disease. The people affected by the disease is able to survive till adulthood with symptoms such as skeletal irregularities, poor movement and coordination, disorder in eye movement, large liver and spleen, respiratory problems and blood disorder (Grabowski et al. 2015). The bleeding problem occurs in type 2 and types 1 of the Gaucher's disease as a result of low amount of blood platelets in the body. The blood platelets have the function to ensure proper clotting of the blood during bruises and cuts (Blume et al. 2017). However, people affected by Gaucher’s disease do not have enough blood platelet which results them to experience frequent and prolonged bleeding (El-Beshlawy et al. 2017). The skeletal irregularities occur in patients with Gaucher's disease due to thinning of bones as well as interference with blood flow which results few parts of the bone to die permanently (El-Beshlawy et al. 2017).

Cause and Pathophysiology of Gaucher’s Disease

The Gaucher’s disease mainly occurs as a result of defective housekeeping gene which is mainly present for lysosomal glucocerebrosidase present on the first chromosome at cytogenetic location 1q22 (Davidson et al. 2018). The housekeeping gene is known as GBA which have the key function of producing beta-glucocerebrosidase which is an enzyme that acts to break fatty substance known as glucocerebroside into simple fat molecule called ceramide and glucose. The mutation or damage in the GBA gene leads the individuals has reduced ability to activate the beta- glucocerebrosidase. Thus, the lack of enough among of enzyme which can break fat accumulation leads the fatty chemicals to be accumulated to toxic levels in the cells. In Gaucher's Disease, the glucocerebroside which accumulates into the cell is mainly derived from the degradation as well as phagocytosis of the erythrocyte membranes and senescent leukocytes. The storage of the glycolipid leads the cells of the body to develop the characteristics Gaucher cells that are macrophages which have been engorged with lipid giving the appearance of crumpled tissue paper and displaced nuclei (Huang et al. 2015; Romero et al. 2019).

The factors that show contribution in the neurological involvement of patients affected by type 2 and type 3 of the Gaucher’s Disease are still not known (Blume et al. 2017; Tezuka et al. 2018). However, it is determined that the building up of cytoxic glycolipids in the form of glucosylsphingosine in the brain because of reduced activity of glucocerebrosidase or neuroinflamation leads to the rise of the disease in patients affected by type 2 and type 3 of Gaucher's disease (Blume et al. 2017; Tezuka et al. 2018). The deposition of glucocerebroside in the liver spleen, bone marrow, lungs as well as others organs in the Gaucher's disease leads to the development of hepatosplenomegaly, pancytopenia, diffusive infiltration of pulmonary diseases and others (Davidson et al. 2018). The increased filtration of Gauchercells inside the bone marrow leads to bone pain, thinning of the cortex, pathological fractures, osteopenia and others (Lopez et al. 2016). Thus, it indicates that genetic factor is the only cause that leads to the development of the disease. It is reported that there is 25% chance among children to inherit two of the Gaucher's disease faulty genes and there are 50% chances that one of the faulty genes is to be inherited. There is 25% chance of inheriting neither of the mutated genes by the children from their parents during birth (genome, 2012).

Treatment strategies for Gaucher’s Disease

The strategies for the treatment of Gaucher's disease are Enzyme Replacement Therapy (ERT) and Substrate Reduction Therapy (SRT). The Enzyme Replacement Therapy (ERT) involves the process of intravenous infusion of medication for correcting the underlying lower rate of enzyme which is causing the rise of disease (Vujosevic et al. 2019). The ERT is mainly used for the treatment of patients suffering from type 1 and type 3 Gaucher's disease. In Enzyme Replacement Therapy (ERT), the mechanism involves the receptor-mediated uptake of glycoprotein through mannose receptors present on the membrane of the cell for contemplating enzyme activity deficiency seen within the lysosomal compartments of macrophages. This mechanism acts to balance the reduced level of glucocerebrosidase and they act to break glucocerebroside which the fatty elements that have accumulated in the body as a result of Gaucher's disease. The ERT is primarily regarded as the first-line of therapy used for the treatment of Gaucher's disease. The recombinant enzymes such as velaglucerase alfa or taliglucerase alfa or imiglucerase are used in ERT where they are administered into the body through intravenous injection. The dosage of the treatment is seen to usually vary from 15units/kg till 60units/kg (Smid et al. 2016; Shemesh et al. 2015) Many of the individuals affected by Gaucher’s disease on implication of ERT shows immediate response with reduction in their liver and spleen size, increased blood platelet count, less skeletal pain and solution to the episodic symptoms that are rising from the bone in the disease (Smith et al. 2016; Shemesh et al. 2015).

The patients affected by Gaucher’s disease take Enzyme Replacement Therapy (ERT) infusion after every 2 weeks and the dose is dependent on the intensity of the disease on the individual. The effect of the ERT is often seen on the patient within six months of its administration (Shemesh et al. 2015). The enzymes administered in ERT are unable to cross the Blood-Brain barrier thus it cannot be used for resolving neurological manifestations seen in case of type 2 and type 3 Gaucher’s diseased individuals. The implication of ERT is considered to be safe way of treating Gaucher’s disease and rare sensitivity reactions or anaphylaxis are seen among patients as a side effect of the therapy (Van Rossu and Holsopple, 2016; Shemesh et al. 2015). The unwanted impact which could be faced in ERT is insulin resistance and weight gain among individuals (Shemesh et al. 2015).

The Substrate Reduction Therapy (SRT) is the process in which oral medication is provided to individuals suffering from Gaucher’s disease. This therapy is not approved to be used for children or women who are pregnant or are breastfeeding (Balwani et al. 2016). In SRT, agents that reduce substrate are used for inhibiting the glucocerebroside synthesis so that improvement in the pathological building up of deposition of cognate metabolites as well as glycolipids as seen in people affected with Gaucher’s disease can be made (Kim et al. 2016). This means in SRT the glucocerebroside production is blocked in the body that is the main factor for deposition of fatty chemicals in Gaucher’s disease. The two approved SRT drugs by the Food and Drug Administration as mentioned in the National Gaucher Foundation website is eliglustat and miglustat (gaucherdisease.org, 2019). The drug which is an iminosugar has the benefit to be orally administered compared to ERT in which intravenous injections are required. The miglustat is seen to have the partial ability of crossing the blood-brain barrier and has been administered to people affected by type 3 Gaucher’s disease but not notable neurological improvement was seen (Kim et al. 2016).

In order to receive Substrate Reduction Therapy (SRT), the person affected by Gaucher’s disease has to fall under certain metabolic rate which means the body’s metabolic rate required to be such so that it is able to breakdown the medication to be absorbed and used by the body (Marshall et al. 2016). The benefit of using SRT is that the individual unlike seen in ERT do not have to travel to get the therapy as the medication can be easily taken at home. The process in SRT is less invasive and consistent dose of medication is provided for a certain time compared to gap in administration of drugs as seen in ERT which often makes the people affected the disease being restless and stop accessing the treatment (Wagner et al. 2018). The side effect of SRT is that few individuals may feel numbness on the feet and hands (Van Rossu and Holsopple, 2016; Shemesh et al. 2015).

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The above discussion informs that Gaucher’s Disease is a rare genetic condition in which deposition of fatty chemicals known as glucocerebroside is seen in the organ and cells. This results the people affected by the disease develop enlarged spleen and liver, low blood count and platelets, reduced brain development, improper coordination of hands and others. The disease occurs as a result of mutation of on the first chromosome at cytogenetic location 1q22. The strategies for treatment of Gaucher’s disease include substrate reduction therapy (SRT) and enzyme replacement therapy (ERT). The ERT process includes intravenous infusion of modified enzyme and in SRT orally medication is taken by the individual affected by Gaucher’s Disease.


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