Carbohydrate Storage Diseases

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Carbohydrate Storage Disease

Carbohydratesrefer to sugars. Sugars can be either complex or simple. Sucrose isan example of a simple sugar that is made up of two simpler onesknown as fructose and glucose. Lactose is another type of sugar,which comprises of galactose and glucose. Enzymes break down bothlactose and glucose so that the body can easily absorb as well as usethem. Examples of carbohydrates include pasta, rice, and bread. If aprotein (enzyme) that is required to break down a particular sugar isdeficient, the sugar may accumulate and cause problems in the body.Key symptoms encompass tiredness, low blood sugar, and weakness.Since there are different proteins (enzymes), which are responsiblefor the breakdown and production of glycogen, there are numerousdisorders of carbohydrate storage as well. The purpose of this paperis to discuss two most prevalent carbohydrate storage illnesses,namely, type I and type II.

Carbohydratestorage diseases are categorized in accordance with an enzymemalfunction or deficiency as well as the body part that is affectedby the disorder. Carbohydrate storage illnesses mostly affect themuscles and the liver. Nonetheless, some disorders affect otherparts, for example, the heart, kidney, bowel, nervous system, andblood vessels.1Thus,the different types include type XI, 0, II, V, III, IV, VII, and IX.

BiochemicalMechanism Von Gieke’s Disease

VonGieke’s disease, also known as type I, is the most prevalent of thecarbohydrate storage diseases. It is categorized under GSD (glycogenstorage diseases). The glucose-6-phosphatase enzyme causes GSD I. Itimpairs the liver’s ability to breakdown glycogen into glucose.Additionally, it causes acute hypoglycemia, especially during fastingand leads to augmented glycogen levels in the kidneys and the liver.The mechanism whereby glucose is synthesized fromglucose-6-phosphatase entails a number of different steps. First,glucose-6-phosphatase has to be moved from the cytosol (place ofsynthesis) via gluconeogenesis to the lumen, which is found withinthe endoplasmic reticulum. Inside the endoplasmic reticulum, thephosphate removal occurs via ER-localized glucose 6-phosphate. Then,the glucose is moved back to cytosol along with the inorganicphosphate. Defects during the process of releasing glucose fromglucose-6-phosphatase cause increased cytosolic glucose 6-phosphatethat results into augmented glycogen levels and resulting excessivestorage.1,2

Description of Drugs

VonGierke’s disease has no cure, but it can be managed by treating keysymptoms of the illnesses. Some of the drug targets includeAllopurunol, Lipid-lowering Medications, and ACE inhibitors.

Allopurinol is a xanthine oxidase’s inhibitor, which is utilized toprevent increased uric acid within the bloodstream. In other words,it causes less uric acid synthesis. It is employed to inhibit goutafter dietary therapy does not entirely normalize the concentrationlevels of the uric acid. The drug acts on catabolism of purineswithout disrupting purine biosynthesis. It decreases uric acidproduction through inhibiting its biochemical reactions before itsformation.4

Lipid-loweringmedications include statins and fibrates, which are utilized to lowerthe levels of lipids, especially when there is good control ofmetabolism. Statins refer to a group of drugs that help reducelow-density lipoprotein cholesterol in the bloodstream. Fibratesdenote to a set of amphipathic carboxylic acids, which are utilizedto treat different metabolic disorders, especiallyhypercholesterolemia.4

ACE inhibitors are utilized to cure microalbuminuria, which is aninitial renal dysfunction indicator. ACE inhibitors preventAngiotensin II synthesis, which is an element that results in musclecontraction around blood vessels, thus narrowing them. Narrow bloodvessels cause hypertension. ACE inhibitors allow blood vessels todilate and reduce blood pressure. Reduced hypertension enables theheart to pump blood easily and enhance its functionality.Additionally, it reduces the kidney disease progression by slowingdiabetes and hypertension. 4

Biochemical Mechanism of Pompe’sDisease

Pompe’sdisease also known as typeIIis a disorder wherein GAA is absent or is insufficient. GAAdeficiency causes a gradual increase of lysosomes’ glycogen in bodytissues where skeletal and cardiac muscles are severely damaged.Researchers have identified three forms of Pompe disease that vary inseverity as well as at the age they develop. These types arenon-classic infantile-onset, classic infantile-onsite, and lateonset. Symptoms range from severe skeletal muscle and hypertrophiccardiomyopathy in babies to moderately weakened forms that occur as agradual myopathy that does not involve the cardiac muscles. Thedefect in lysosomal GAA affects lysosomal-modified glycogendegradation unlike the deficiencies in other GSDs, which affect thesynthesis of glycogen or energy production regulation.5

LysosomalGAA hydrolyzes both alpha-1, 6 and alpha-1, 4-glucose linkages foundin the lysosome’s low pH environment. As said before, the enzymeshortage causes glycogen buildup within the cytoplasm and lysosomes,leading to the destruction of tissues.6The effects may spread to vesicle systems, which are connected tolysosomes as well as may affect receptors, for example, glucosetransporter 4, which surround the organelles. Enzyme activity isrelated to genotype and is minimal or absent in individuals withinfantile-phenotype as well as variably decreased in those withlate-onset phenotype.7

Drug Descriptions

AlglucosidaseAlfa is an enzyme, which treats infantile-onset Pompe disease. It isan enzyme replacement therapy drug. It contains acidalpha-glucosidase, a human enzyme, which is lacking in patients withPompe illness. Additionally, it aids with glycogen absorption anddigestion. The drug is available on doctor’s prescription. 8

Myozymeis a type of GAA. It comprises of an enzyme, which occurs naturallyin healthy people’s body. The enzyme may lack in some people due toa genetic illness. It aids in replacing the missing enzyme inindividuals without it. Myozyme is used to treat Pompe disorder inchildren and adults. It has shown to enhance ventilator-free survivalparticularly in individuals with Pompe disease’s infantile-onset. 8

Lumizymeis an ERT (enzyme replacement therapy). It offers an exogenous GAAsource, which is a crucial lysosomal enzyme, which is absent ordeficient in individuals suffering from Pompe disease, resulting inthe accumulation of intralysosomal glycogen. It is intended forpatients with late non-infantile onset Pompe illness.8

Conclusively, this essay has outlined different types of carbohydratestorage disorders. It has defined carbohydrate storage disorders asillnesses that are caused by an enzyme deficiency. The paper hasfurther discussed two carbohydrate storage illnesses namely, VonGierke’s disease and Pompe’s disease by looking into theirbiochemical mechanisms and drug targets. Both diseases have no cure,but they can be properly managed. Enzyme deficiency in Von Gierke’sillness makes the liver unable to break down glucose. Drug targetsfor type I include Allopurinol, lipid-lowering medications, and ACEinhibitors while those for Pompe encompass Alglucosidase Alfa,Myozyme, and Lumizyme intravenous. Other than use of drugs, themanagement of these illnesses requires proper nutritional management,exercises, and supportive therapies. Type I is easy to manage andsymptoms can be alleviated by reducing sugar intake.

ReferenceList

  1. Derks T, van Rijn M. Lipids in hepatic glycogen storage diseases: pathophysiology, monitoring of dietary management and future directions.&nbspJournal Of Inherited Metabolic Disease&nbsp[serial online]. May 201538(3):537-543. Available from: MEDLINE, Ipswich, MA. Accessed November 3, 2016.

  2. Bhattacharya K, Mundy H, Lilburn M, Champion M, Morley D, Maillot F. A pilot longitudinal study of the use of waxy maize heat modified starch in the treatment of adults with glycogen storage disease type I: a randomized double-blind cross-over study.&nbspOrphanet Journal Of Rare Diseases&nbsp[serial online]. February 15, 201510:18. Available from: MEDLINE, Ipswich, MA. Accessed November 3, 2016.

  3. Boers S, Visser G, Smit P, Fuchs S. Liver transplantation in glycogen storage disease type I.&nbspOrphanet Journal Of Rare Diseases&nbsp[serial online]. April 20149(1):2-18. Available from: Academic Search Complete, Ipswich, MA. Accessed November 3, 2016.

  4. Bali D, Chen Y, Austin S, Goldstein J. Glycogen storage disease type I.&nbspNcbinlmnihgov. 2016. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1312/. Accessed November 4, 2016.

  5. van der Ploeg A, Reuser A. Pompe`s disease.&nbspLancet (London, England)&nbsp[serial online]. October 11, 2008372(9646):1342-1353. Available from: MEDLINE, Ipswich, MA. Accessed November 3, 2016.

  6. Jamil S, Ahmed S, Tariq M. Acid maltase deficiency–Pompe`s disease.&nbspJPMA. The Journal Of The Pakistan Medical Association&nbsp[serial online]. August 201161(8):821-823. Available from: MEDLINE, Ipswich, MA. Accessed November 3, 2016.

  7. Pellegrini N, Laforet P, Lofaso F, et al. Respiratory insufficiency and limb muscle weakness in adults with Pompe`s disease.&nbspThe European Respiratory Journal&nbsp[serial online]. December 200526(6):1024-1031. Available from: MEDLINE, Ipswich, MA. Accessed November 3, 2016.

  8. Harmatz P. Enzyme replacement therapies and immunogenicity in Lysosomal storage diseases: Is there a pattern?.&nbspClinical Therapeutics. 201537(9):2130-2134. doi:10.1016/j.clinthera.2015.06.004.

Carbohydrate Storage Diseases

The human body is a complex faculty that requires many substances torun the various processes within it. These substances have differentcompositions in their natural state, but they are assimilated andabsorbed into the system of the body to provide the necessary drivingpower for the body.1They include proteins, carbohydrates,fats, mineral salts and vitamins. This discussion narrows down toCarbohydrates and the effects of those stored within the human body.The paper seeks to discuss the biochemical basis of carbohydratestorage diseases as well as the basis of their treatments.

Carbohydrate serves many functions in the human body. It isintroduced into the body and converted to glucose which is thenconverted into various simpler forms, for instance, glycogen, whichis the type of carbohydrate stored in the liver and the muscles.2Glucose is essential in fat synthesis, functioning of the Red bloodcells, the central nervous system, and the brain. It also stands inas the immediate carbohydrate energy stored in the muscles and theliver and the functioning of the muscles.

The process of conversion of the raw carbohydrates into complexmolecules which are readily utilized and stored by the body isbiochemical, driven by chemicals synthesized in different pathwayswithin the body. The conversion of glucose into glycogen requiresenzymes which are protein in nature and needs their building blocksto be stable. Any hitch in the biochemical pathway for the conversionof glucose into glycogen paves the way for the development ofcarbohydrate deficient or excessive sugar diseases.3, 4Glycogen stored in the liver serves the purpose of blood sugarregulation while those stored in the muscles is used for the workingthe muscles and they increase the sizes of the associated muscles.

Galactosemia

Galactosemia is a disorder that affects the manner in which the bodybreaks down some of its sugars and to be specific galactose.2Thebreakdown of galactose, aided by the presence ofgalactose-1-phosphate uridyl transferase. In its absence, theaccumulation of galactose builds and becomes toxic. Breakdown ofgalactose takes place in a series of reactions referred to as theLeloir pathway. Galactose exists in two forms in the body accordingto stoichiometry, α-D-galactose and β-D-galactose. The Leloirpathway utilizes the α-D-galactose which is then epimerizedtoglucose-1-phosphate in the presence of transfer of UDP fromUDP-glucose catalyzed by galactose-phosphate uridyl transferaseenzyme. Insufficiency or lack of this enzyme leads to the developmentof a medical condition known as Galactosemia.2 There aretwo forms of this condition where one is inherited from the autosomalrecessive genes from the parents while the other one is thebiochemical variant form.

The symptoms associated with this condition are poor feeding habits,bleeding problems, diarrhea, and vomiting. The accumulation ofgalactose can lead to inflammation of the storage sites for thecarbohydrates like the liver, failure of the kidney, cataracts of theeye and stunted growth of the individuals associated with thedisease. The first step to treating this disease is by eliminatingall the forms of milk and dairy products from the diet of the sickindividual and routine testing to check for the accumulation oferythrocyte galactose-1-phosphate. At the infantile stages, babiesshould get metabolized milk sugars.

Treatment is not easy, though, at the tissue level, organ transplantcan be done to restore normal metabolism. At the gene level, genetherapy can be done to replace the defective gene with a normal gene.At RNA level, antisense-mediated exon skipping can be done to inhibitthe processing of the defective gene. This condition brings about thebuildup of uric acid in the body. Therefore, Sodium benzoate issupplied to bind the glutamine compound to minimize the toxicitylevels in the body of the person with the condition

Glycogen storage diseases

Glycogen storage diseases are diseases that inhibit the metabolism ofglycogen. And they affect the liver and the muscles.3Thesymptoms of these diseases include weakness, tiredness, low sugarlevels. Glycogen comprises of many molecules of glucose. The glycogenstorage disorders are diseases that result from the lack of orabnormal functioning of the enzymes or the proteins that make themup.

There are many glycogen storage diseases categorized according to thetype of protein or enzyme that works in the part of the body that isaffected. Type I, Type II, Type III, Type IV, Type V up to type XI.4The most common type of glycogen storage disorder is the TypeI. It arises due to the lack of glucose-6-phosphatase enzyme which isvital for the conversion of glucose to glycogen pathway.1

The symptoms of these disorders include the slow abnormal growth ofthe patient or individual with the condition. Low blood sugar levelswhich can lead to tremors and sweating, uncoordinated anduncontrollable movements of the muscles and confusion. Enlarged liverexhibited by an enlarged abdomen. Obesity, kidney problems, bloodclotting and bleeding problems and muscle weaknesses.

The diagnosis of these disorders can be made by checking the medicalhistory of the families. There are households with an alreadyestablished history of the disease. Conducting blood tests todetermine blood sugar levels of the individuals to determine kidneyfunction and liver function is a viable way to determine the presenceof the condition. Type I can be diagnosed by blood tests for fats andurate. The purpose of doing a blood test is to measure the creatinekinase which gives the information on the potentiality of theglycogen storage disorder in affecting the muscles.4 Thisblood test can also be accompanied by blood cells count to determinethe lack of iron.

Scanning of the tummy by using abdominal ultrasound scan can show orgive the evidence of the disorder leading to the enlargement of theliver. In conducting this exercise, some gel is spread over theabdomen then an ultra-sonographer moves the probe of the scanner overthe surface of the abdomen.3, 4 High-frequency sound wavesfrom the instrument enable projection of images of the internalorgans. In the case of heart problems, it is advisable to conductechocardiogram which is ultrasound scan of the heart.

Drugs/Treatment

Glycogen storage disorders have varying treatments depending on thetype of the disease. These treatments get administered with the aimof stabilizing the energy levels within the body and blood sugarlevels. The drug, Myozyme, has been proven to be useful in thesurvival of patients with glycogen storage disorder II. The drug isadministered by intravenous infusion, 20mg/kg as a 4-hour infusionfor every two weeks. The initial infusion rate should be 1mg/kg/hwhich can then be increased to 2mg/kg/h for every 30 minutes andfinally to 7mg/kg/h with the aid of an infusion pump. When the drugis administered into the body, it works by targeting the lysosomalglycogen, and degrades it.

Liver transplant is advised for those who do not respond to thenutritional supplements. It is also recommended to administer highprotein diet to these individuals and conventional antibiotics toprotect their immune system from infection by microbes. Currently,there are trials to come up with the gene therapy treatment for thesedisorders. This method will involve the introduction of new genesinto the patient’s system to outcompete and delete the faulty genesresponsible for the diseases.

These diseases can be prevented by carrying out early pregnancy teststo determine if the unborn have the illness or the possibility ofthem being born with the disorder to prevent their deaths at earlystages of life.

Conclusion

The carbohydrate storage diseases are mostly inherited implying thatthey are genetic and trickles down the genetic lines. They cause mostof the demise of the infants if undetected and diagnosed. It’s hardto run away from the fact that the diseases are hereditary.Therefore, it is advisable to see a gene specialist to determine thelikelihood of the disorder appearing in the next generation.

References

  1. Bali, D. S., Chen, Y. T., &amp Goldstein, J. L. (2013). Glycogen storage disease type I.

  2. Dickens, F., Whelan, W. J., &amp Randle, P. J. (Eds.). (2014).&nbspCarbohydrate Metabolism: And Its Disorders. Elsevier.

  3. Galactose Metabolism. (2016). Themedicalbiochemistrypage.org. Retrieved 29 October 2016, from http://themedicalbiochemistrypage.org/galactose.php

  4. Glycogen Storage Disease (GSD). (2016). Cincinnatichildrens.org. Retrieved 29 October 2016, from https://www.cincinnatichildrens.org/health/g/gsd

  5. Glycogen Storage Disorders. Inborn errors of metabolism | Patient. (2016). Patient. Retrieved 29 October 2016, from http://patient.info/health/glycogen-storage-disorders-leaflet

  6. Innovative therapy for Classic Galactosemia — Tale of two HTS. (2016). Retrieved 29 October 2016,