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Glucocerebrosidase cleaves a glucose off the end of glucosylceramide and converts it into CeramideIn the case of Gaucher's Disease, the enzyme is disfunctional and there is an accumulation of Glucosylceramide. Interestingly it's not the accumulation of Glucosylceramide that causes problems, it the accumulation of Glucosylceramide byproducts like psychosine and glucocerebroside.When Macrophages eat other cells they accumulate lipids and need to traffic and process those lipids correctly. Typically these Sphingolipids get trafficked to the Golgi but instead, they are mistargeted to lysosomes. The accumulation of abnormal lipids pushes the nucleus to the side and results in what is known as a Gaucher cell. The Gaucher cells then accumulate in key organs like the spleen and the liver.There are also neurological issues that arise with the imbalance of Glucosylceramide but the issues with the Gaucher cells typically present themselves first.Glucocerebrosidase as lysosomal proteins that need to be delivered to the lysosome to effectively operate. To reach their destination, the enzyme is recognized by its glycosylation patterns typically through a M6P mechanism. Macrophages have lectin-like receptors that recognize the enzyme and uptakes them and trafficks them to the lysosome. As a result, it would be found that it was incredibly important that these enzymes are produced as glycoproteins.This is from the patent from Taliglucerase alfa which shows a high level description of the processing of the glycosylation of the different production methods. With the development of recombinant methods, the careful carbohydrate remodeling was necessary for the efficacy of the drug.A brief timeline of this research. The disease was discovered in 1882. The enzyme was isolated in 1966. The original placenta extraction method was developed in 1974 and the original clinical trial occurred then. It wasn't until 1990 when the glycosylated form of Glucocerebrosidase was developed and Ceredase was approved. Recombinant Cerezyme was approved in 1995. Velaglucerase alfa was approved in 2010 and the plant derived Taliglucerase alfa was approved in 2012.All of the other lipid storage disorders work under the same principle. Damage to the synthesis of Sphingolipids result in the accumulation of certain products and that imbalance causes disease.This also seems like a good article Imiglucerase in the treatment of Gaucher disease: a history and perspective

There have been a number of important bottlenecks in human populations but population sizes were probably never less than several thousand and there has been a lot of time to recover from them. Some scientists have suspected that non-African groups may have more genetic defects than African groups on account of the very modest number of people that founded non-African peoples (possibly 10,000 people very roughly 50,000 years ago). You can read more here: http://www.pnas.org/content/109/44/17758.full.pdfStay tuned. Scientists are making real progress and we may have better answers within in the next decade.But you can find evidence for genetic defects from more recent bottlenecks in certain populations.One example is Ashkenazi Jews. Although there are now more than 10 million around the world, they apparently descend from a group of as small 350 people or so roughly 25 to 32 generations ago. There are several recessive diseases like Tay-Sachs disease and Gaucher disease which are much more common in people of this ethnicity than in other groups. You can read a technical report here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1216062/). Here’s a nontechnical article: Ashkenazi Jews descend from 350 people, scientists sayAnother example is the Amish (Pennsylvania Dutch) who currently number more than 50,000 in Lancaster County. The Amish in America descend from roughly 80 ancestors 10 generations ago (250 years). There are several recessive genetic disorders that are more common among the Amish than in other Americans. Geneticists and medical professionals have been interested in helping these people and learning from them. You can read a technical description here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077314/ and here is a more readable account: Genetic disease is ravaging Lancaster County's Amish, and helping to change medicine for all of us .There are almost certainly other, less well documented, populations like these.

Approximately 600 years ago, give or take a century, the Ashkenazi people were reduced to a very small number. The reason for this isn’t known, nor the exact date; we only know from genetic evidence how many generations it has been since it occurred. In this period, their numbers became so small that all future Ashkenazi would be descended from a mere handful of people. Obviously, for several generations at least, this resulted in people marrying close relatives. It is estimated no Askhenazi today is further removed than a 6th cousin from all others.Inbreeding increases the odds that the same recessive gene will appear in both parents, hence increasing the odds that a particular genetic disease will manifest. Ashkenazi Jews have a higher incidence than other populations of a number of conditions, of which the BCRA mutation, which causes breast cancer, is but one. They are also more likely than your average person to suffer from:Bloom syndrome. Babies with this disease are born small and remain shorter than normal as they grow. Their skin may look red, and they have more lung and ear infections than children normally have.Canavan disease. This disease gradually destroys brain tissue.Cystic fibrosis. This disease causes very thick mucus in the lungs and problems with digesting food.Familial dysautonomia (FD). People with this problem cannot feel pain, they sweat a lot, and they have trouble with speech and coordination.Fanconi anemia. People with this problem do not have enough blood cells and have problems with the heart, kidneys, arms, or legs. They also are more likely to get cancer.Gaucher disease. This disease causes a type of fat called glucocerebroside to build up in certain cells of the liver, spleen, and bone marrow.Mucolipidosis IV. This problem causes the nervous system to deteriorate, or break down, over time.Niemann-Pick disease (type A). This disease causes a type of fat called sphingomyelin to build up in cells of the liver, spleen, lymph nodes, and bone marrow.Tay-Sachs disease. This disease causes a type of fat called ganglioside to build up in the cells of the brain and nervous system.Torsion dystonia. People with this problem have ongoing spasms that twist the muscles in their arms, legs, and sometimes their body. Testing for this condition may not always be done.(ufmohealth.org)