It is always good to know more about our own bodies, and knowing about this particular type of disease could be very helpful for the future generations. Enzymatic disorders as the name implies are connected to malfunction of enzymes or lack of them or simply a shortage in their number, causing a disorder in the body.
My interest in Biochemistry and the body functions in general led me to this topic. After we understood enzymes in grade 10 I was curious to understand more about them, and here I am presenting you this paper with a small portion of information in the wide field of biochemistry. It is also very useful to know about these things, even though both diseases I will be talking about are genetic, we never know when we have to encounter someone suffering from them. Heck, they could even affect our children, so it's always good to know.
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By the end of this paper I expect to have a better understanding of the 2 diseases, the enzymes responsible for them, the symptoms, and treatment of both of them.
Mutations may result in the synthesis of a defective enzyme with reduced activity or in a reduced amount of a normal enzyme. In either case, the consequence is a metabolic block.
Accumulation of the substrate, depending on the site of block, may be accompanied by accumulation of one or both intermediates. Moreover, an increased concentration of intermediate 2 may stimulate the minor pathway and thus lead to an excess of M1 and M2.
Under these conditions, tissue injury may result if the precursor, the intermediates, or the products of alternative minor pathways are toxic in high concentrations. For example, in galactosemia, the deficiency of galactose-1-phosphate uridyltransferase leads to the accumulation of galactose and consequent tissue damage. In phenylketonuria, a deficiency of phenylalanine hydroxylase results in the accumulation of phenylalanine. Excessive accumulation of complex substrates within the lysosomes as a result of deficiency of degradative enzymes is responsible for a group of diseases generally referred to as lysosomal storage diseases.
2. An enzyme defect can lead to a metabolic block and a decreased amount of end product that may be necessary for normal functions. For example, a deficiency of melanin may result from lack of tyrosinase, which is necessary for the biosynthesis of melanin from its precursor, tyrosine. This results in the clinical condition called albinism.
3. Failure to inactivate a tissue-damaging substrate is best exemplified by Î±1-antitrypsin (Î±1-AT) deficiency. Patients who have an inherited deficiency of serum Î±1-AT are unable to inactivate neutrophil elastase in their lungs. Unchecked activity of this protease leads to destruction of elastin in the walls of lung alveoli, leading eventually to pulmonary emphysema
The most common of all enzyme disorders is Glucose-6-Phosphate dehydrogenase deficiency. G6PD is a cytosolic enzyme involved in metabolic processes especially those of red blood cells. It functions in the pentose phosphate pathway by supplying reducing energy to cells (Mainly erythrocytes) by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). NADPH then maintains the level of glutathione in these cells that helps protect the red blood cells-erythrocytes- against oxidative damage.
The lack of activity in G6PD is a disease called "G6PD Deficiency". The disease is an X-linked hereditary disease. Individuals with the disease may undergo nonimmune hemolytic anemia, that is the abnormal breakdown of red blood cells, in response to a number of causes, most commonly infections or exposure to certain chemicals. G6PD deficiency is also closely linked to favism, a disorder characterized by a hemolytic reaction to consumption of broad beans (Fava is Italian for broad bean). It is common confused that all people with G6PD deficiency suffer from favism, but not all people with G6PD deficiency would develop favism.
Mutations in theÂ G6PDÂ gene cause glucose-6-phosphate dehydrogenase deficiency.
TheÂ G6PDÂ gene provides instructions for making an enzyme called glucose-6-phosphate dehydrogenase. This enzyme is involved in the normal processing of carbohydrates. It also protects red blood cells from the effects of potentially harmful molecules called reactive oxygen species. Reactive oxygen species are byproducts of normal cellular functions. Chemical reactions involving glucose-6-phosphate dehydrogenase produce compounds that prevent reactive oxygen species from building up to toxic levels within red blood cells.
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If mutations in theÂ G6PDÂ gene reduce the amount of glucose-6-phosphate dehydrogenase or alter its structure, this enzyme can no longer play its protective role. As a result, reactive oxygen species can accumulate and damage red blood cells. Factors such as infections, certain drugs, or ingesting fava beans can increase the levels of reactive oxygen species, causing red blood cells to be destroyed faster than the body can replace them. A reduction in the amount of red blood cells causes the signs and symptoms of hemolytic anemia.
Researchers believe that carriers of aÂ G6PDÂ mutation may be partially protected against malaria, an infectious disease carried by a certain type of mosquito. A reduction in the amount of functional glucose-6-dehydrogenase appears to make it more difficult for this parasite to invade red blood cells. Glucose-6-phosphate dehydrogenase deficiency occurs most frequently in areas of the world where malaria is common.
Some symptoms seen are:
Appearing very pale
Sudden rise in body temperature
Rapid heart beats
Shortness of breath
Pain in the back or abdomen
Urine appears very dark, red, red-brown, brownish or tea colored
Yellow colouring of the eyes and skin (jaundice)
Spleen may be enlarged
The symptoms usually disappear when the offending food or drug is stopped.
Diagnosis of G6PD deficiency
When any of the above mentioned symptoms present themselves in a person of ethnic groups susceptible to the condition then, G6PD deficiency is suspected. In children, most cases go undetected until the child develops a health problem.
Some laboratory investigations asked for are:
Complete blood count: active G6PD shows presence of "Heinz bodies" (protein aggregates) within the red blood cells.
Liver Function Tests: done to rule out other causes of liver damage and jaundice.
Coomb's Test: to check for presence of direct antiglobulin. The results should ideally be negative as RBC breakdown isn't an auto-immune condition.
Haptaglobulin: reduced in RBC breakdown (hemolysis).
Beutler Fluorescent spot test: The conversion of nicotinamide adenine dinucleotide phosphate (NADP) to its reduced form in RBCs is the basis of diagnostic testing for the deficiency.
Treatment of G6PD deficiency
For the majority of people affected, treatment of G6PD is as simple as avoiding the triggering agent. Severely ill children may need hospitalization, oxygen support and intravenous fluids.
It is important to avoid the foods and drugs below.
Antibiotics (Sulphonamides, Co-trimoxazole (Bactrim, Septrin), Dapsone, Chloramphenicol, Nitrofurantoin, Nalidixic acid,
Antimalarials (Chloroquine, Hydroxychloroquine, Primaquine, Quinine, Mepacrine )
Chemicals (Moth Balls, napthalene, Methylene blue
Foods (Fava beans - also called broad beans)
Other drugs (Aspirin, Phenacitin, Sulphasalazine, Methyldopa, Large doses of vitamin C, Hydralazine, Procainamide, Quinidine, Some anti-cancer drugs )
Gaucher's Disease is a genetic disease in which a fatty substance (lipid) accumulates in cells and certain organs. Gaucher's disease is the most common of theÂ lysosomal storage diseases. It is a form ofÂ sphingolipidosis (a subgroup of lysosomal storage diseases), as it involves dysfunctional metabolism ofÂ sphingolipids. The disorder is characterized by bruising, fatigue, anemia, low blood platelets, and enlargement of the liver and spleen. It is caused by a hereditary deficiency of the enzymeÂ glucocerebrosidase. The enzyme acts on the fatty acid glucosylceramide. When the enzyme is defective, glucosylceramide accumulates, particularly in white blood cells, most often macrophages (mononuclear leukocytes). Glucosylceramidase can collect in theÂ spleen, liver,Â kidneys,Â lungs,Â brainÂ and bone marrow.
Symptoms: Symptoms may include enlarged spleen and liver, liver malfunction,Â skeletal disordersÂ and bone lesions that may be painful, severeÂ neurologicÂ complications, swelling ofÂ lymph nodesÂ and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin,Â anemia, low bloodÂ plateletsÂ and yellow fatty deposits on the white of the eye (sclera). Persons affected most seriously may also be more susceptible to infection. Some forms of Gaucher's disease may be treated with enzyme replacement therapy.
Causes: The disease is caused by aÂ recessive mutationÂ in a gene located onÂ chromosome 1Â and affects both males and females. About 1 in 100 people in the United States areÂ carriersÂ of the most common type of Gaucher disease. The carrier rate amongÂ Ashkenazi JewsÂ is 8.9% while the birth incidence is 1 in 450.
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The disease isÂ named afterÂ the French doctorÂ Philippe Gaucher, who originally described it in 1882.
Gaucher disease is divided into two major types-neuronopathic and non-neuronopathic disease-based on the particular symptoms of the disease. In non-neuronopathic disease most organs and tissues can be involved, but not the brain. In neuronopathic disease the brain is also involved.
Non-neuronopathic disease - Type 1 Gaucher disease
Type 1 Gaucher disease is the most common form of the disease and does not involve the central nervous system; therefore, it is also called non-neuronopathic. Although Type 1 Gaucher disease is sometimes referred to as 'adult Gaucher disease', it can affect individuals of all ages,Â Â and in hindsight, most Type 1 patients acknowledge that their first symptoms started before adulthood.Â
Type 1 Gaucher disease has a particularly wide variation in clinical signs, symptoms and disease course. In some cases, the symptoms may begin in childhood and rapidly worsen over time. In other cases, the first symptoms may only be noticed well into adulthood. There are even cases of people who are shown to have a glucocerebrosidase gene defect, but who do not show any symptoms. In general, the earlier in life the first symptoms appear, the more likely it is that the disease will be severe and will progress rapidly if left untreated.
Perhaps the most common sign of Type 1 Gaucher disease is an enlargement of the spleen. Spleen enlargement is often the initial finding and may be first recognized when a child is young.Â Skeletal symptoms of bone involvement can occur at any time in life, both in children and the elderly. Skeletal abnormalities are also very common and they are present in the majority of patients at the time of diagnosis.
Neuronopathic Gaucher disease
If brain function is affected in Gaucher disease, it can appear early in life and progress rapidly as with acute neuronopathic or Type 2 Gaucher disease; or it can appear more gradually and worsen over time, as with Type 3 or chronic neuronopathic Gaucher disease.
Type 2 Gaucher disease
Type 2 Gaucher disease is a very rare, rapidly progressive form of the disorder that affects the brain as well as the organs affected by Type 1 Gaucher disease. Formerly called 'infantile Gaucher disease', Type 2 is characterized by severe neurological involvement in the first year of life. Fewer than 1 in 100,000 newborns have Type 2 disease. This form of Gaucher disease does not appear to be concentrated within any particular ethnic group. Infants with Type 2 disease typically appear normal during the first few months of life before developing neurological signs and many of the symptoms associated with Type 1. An afflicted child usually does not live past the age of 2 years, due to the severe involvement of the brain.
Type 3 Gaucher disease
Formerly called 'juvenile Gaucher disease', Type 3 is characterized by a slowly progressive brain involvement, in addition to severe disease of the other organs typically affected by Gaucher disease. Type 3 Gaucher disease is also very rare. While not limited to any particular ethnic group, a concentrated number of cases have been reported in Sweden and a higher number of cases have been reported than in the general population in Spain and Japan.Â
We have come to the understanding that a lack of enzymes caused by genetic malfunction could cause severe disease that could eventually cause someone their life. But on the bright side, research and close study of the diseases can eventually limit the spread of the disease or eliminate it altogether.
We also learned that both G6PD deficiency and Gaucher's disease are related to metabolism, the first affecting the red blood cells, and the latter affecting the metabolism and digestion of fatty substances.