Glycogen storage disease type -
Diseases can disrupt glycogen metabolism secondary to the primary disease. Abnormal thyroid function—hypo- and hyperthyroidism—can manifest as myopathy with symptoms of exercise-induced muscle fatigue, cramping, muscle pain and may include proximal weakness or muscle hypertrophy particularly of the calves.
In patients with increased growth hormone, muscle biopsy includes, among other features, excess glycogen deposition. It is interesting to note, in comparison to hypothyroid myopathy, that McArdle disease GSD-V , which is by far the most commonly diagnosed of the muscle GSDs and therefore the most studied, [58] [45] [59] has as its second highest comorbidity endocrine disease chiefly hypothyroidism [60] [45] and that some patients with McArdle disease also have hypertrophy of the calf muscles.
Poor diet and malabsorption diseases such as celiac disease may lead to malnutrition of essential vitamins necessary for glycogen metabolism within the muscle cells. Malnutrition typically presents with systemic symptoms, but in rare instances can be limited to myopathy.
Exercise-induced, electrically silent, muscle cramping and stiffness transient muscle contractures or "pseudomyotonia" are seen not only in GSD types V, VII, IXd, X, XI, XII, and XIII, but also in Brody disease , Rippling muscle disease types 1 and 2, and CAV3 -related hyperCKemia Elevated serum creatine phosphokinase.
Erythrocyte lactate transporter defect formerly Lactate transporter defect, myopathy due to also includes exercise-induced, electrically silent, painful muscle cramping and transient contractures; as well as exercise-induced muscle fatigue. Limb—girdle muscular dystrophy autosomal recessive 23 LGMD R23 has calf hypertrophy and exercise-induced cramping.
a MDDGC3 has muscle hypertrophy, proximal muscle weakness, and muscle fatigue. Tubular aggregate myopathy TAM types 1 and 2 has exercise-induced muscle pain, fatigue, stiffness, with proximal muscle weakness and calf muscle pseudohypertrophy.
TAM1 has cramping at rest, while TAM2 has cramping during exercise. Treatment is dependent on the type of glycogen storage disease. Von Gierke disease GSD-I is typically treated with frequent small meals of carbohydrates and cornstarch , called modified cornstarch therapy , to prevent low blood sugar, while other treatments may include allopurinol and human granulocyte colony stimulating factor.
However, unlike GSD-I, gluconeogenesis is functional, so simple sugars sucrose, fructose, and lactose are not prohibited. A ketogenic diet has demonstrated beneficial for McArdle disease GSD-V as ketones readily convert to acetyl CoA for oxidative phosphorylation, whereas free fatty acids take a few minutes to convert into acetyl CoA.
For phosphoglucomutase deficiency formerly GSD-XIV , D-galactose supplements and exercise training has shown favourable improvement of signs and symptoms. For McArdle disease GSD-V , regular aerobic exercise utilizing " second wind " to enable the muscles to become aerobically conditioned, as well as anaerobic exercise strength training that follows the activity adaptations so as not to cause muscle injury, helps to improve exercise intolerance symptoms and maintain overall health.
Regardless of whether the patient experiences symptoms of muscle pain, muscle fatigue, or cramping, the phenomenon of second wind having been achieved is demonstrable by the sign of an increased heart rate dropping while maintaining the same speed on the treadmill.
Conversely, patients that were regularly active did not experience the typical symptoms during low-moderate aerobic exercise walking or brisk walking , but still demonstrated second wind by the sign of an increased heart rate dropping. They may show a normal heart rate, with normal or above normal peak cardio-respiratory capacity VO 2max.
Tarui disease GSD-VII patients do not experience the "second wind" phenomenon; instead are said to be "out-of-wind. Overall, according to a study in British Columbia , approximately 2. While a Mexican incidence showed 6.
Within the category of muscle glycogenoses muscle GSDs , McArdle disease GSD-V is by far the most commonly diagnosed.
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Brain: A Journal of Neurology. Human Mutation. In the liver, the accumulation of polyglucosan bodies causes hepatomegaly. While GSD 0a and GSD 0b are due to insufficient glycogen storage, most GSDs are unable to remove glucose from glycogen glycogenolysis , resulting in excess glycogen tissue storage.
The first step in glycogenolysis is the release of glucosephosphate GP from glycogen by the action of glycogen phosphorylase. GSD type V is caused by mutations in the glycogen phosphorylase gene-specific for muscle PYGM.
Mutations in the glycogen phosphorylase gene specific for the liver PYGL cause GSD type VI. Glucosephosphate in the liver is, in turn, converted to glucose by glucosephosphatase encoded by the G6PC gene. It should be noted that skeletal muscles lack glucosephosphatase and therefore do not release glucose into the blood.
GSDs type I results from genetic disorders in the metabolism of glucosephosphatase. Glucosephosphate is synthesized in the cytoplasm of hepatocytes and must be transported into the lumen of the endoplasmic reticulum ER , where it is acted upon by glucosephosphatase yielding glucose, which is transported back to the cytoplasm and then through the hepatic GLUT2 transporter into the blood.
Glucosephosphate translocase1 G6PT1 is the transporter protein that provides a GP channel between the cytoplasm and the ER. The G6PT protein is made of three subunits termed G6PT1, G6PT2, and G6PT3 Figure 2.
Mutations in the SLC37A4 gene, which encodes the G6PT1 protein, are responsible for GSD type Ib Figure 1. Fanconi-Bickel disease is a rare GSD caused by a GLUT2 deficiency due to a mutation in the SLC2A2 gene. This leads to increased glycogen storage and hepatomegaly. As mentioned above, glycogen is a branched polymer.
While glycogen phosphorylase works well at removing glucose from alpha- 1,4 -linkages, it does not work at branch points. Branch points are alpha-1,6 linkages. GSD type II is unique among GSDs because it is also classified as a lysosomal storage disease LSD.
Lysosomal storage diseases are caused by a missing or nonfunctional lysosomal enzyme. In the case of GSD II, this enzyme is lysosomal acid alpha-glucosidase encoded by the gene GAA , which breaks down glycogen into glucose for use as a cellular energy source.
Mutation in the GAA gene results in the toxic accumulation of glycogen in lysosomes. The true incidence of metabolic diseases is difficult to determine given the lack of uniform, universal screening at birth.
Individual incidence of specific GSD types is further complicated due to overlap in symptoms and the lack of standardized specific testing in most areas of the world. A study evaluating the incidence of inborn errors of metabolism in British Columbia in the s reported that the incidence of these diseases was approximately 30 cases per live births.
Approximately 2. As stated above, glycogen is the stored form of glucose and is composed of long polymers of 1,4 linked glucose with branch points via 1,6 linked glucose molecules. When these physiologic functions are defective, hypoglycemia, hepatomegaly, muscle cramps, exercise intolerance, and weakness develops.
Some disorders also affect the myocardial tissue and can lead to cardiomyopathy and cardiac conduction defects. In GSD type 1, for example, failure of glycogenolysis in the liver results in increased lactic acid production lactic acidosis due to the intracellular accumulation of glucosephosphate, which stimulates the glycolytic pathway.
GSDs are a diverse set of rare inborn errors of carbohydrate metabolism that can have variable phenotypic presentation even within the same GSD type. Obtaining a family pedigree is useful in establishing the mode of inheritance. Most GSDs show an autosomal recessive inheritance, but a few GSD type IX show an x-linked inheritance.
Patients with a defect in hepatic glycogen metabolism usually present with fasting hypoglycemia and ketosis. Their symptoms improve with glucose administration. Patients with a defect in skeletal muscle glycogen metabolism present with fatigue and exercise intolerance after short periods of moderate-intense exercise.
In rare cases, progressive weakness may be reported. This, however, is usually limited to GSD type 0, II, and IV. In rare instances, GSD type III, V, and VII can present with weakness rather than muscle cramps and, over time, develop fixed weakness. Anthropometric measurements should be obtained and graphed in all patients with GSDs to assess the overall growth pattern.
Short stature or poor linear growth, especially in a child with hypoglycemia, should warrant workup for glycogen storage disorders.
In the liver, this results in hepatomegaly with the potential for cirrhosis. Hypoglycemia is defined as a plasma concentration of glucose that results in symptoms attributable to hypoglycemia and is reversed with the administration of glucose.
There is no set plasma glucose level above which GSDs can be ruled out, particularly for children. It is important to note that neonates go through a period of transitional hypoglycemia in the first 48 hours of life, during which GSDs cannot be diagnosed.
Duration of fasting that leads to symptoms of hypoglycemia is an important element of history that must be obtained.
A short duration of fasting that results in typical symptoms suggests glycogen storage disorder type I or III. Hypoglycemia should be documented by measuring serum glucose levels. In patients where hypoglycemia is suspected, a diagnostic fasting glucose test can be performed but should only be considered in a monitored inpatient setting.
Patients with glycogen storage disease type III also have elevated creatine kinase levels. Patients with type I disorder will also present with elevated liver enzyme and uric acid levels. Triglyceredemia is also common. Urinary myoglobin levels can be detected in patients with GSDs as well, particularly in those affected by GSDs that primarily affect the skeletal muscles.
Although specific genetic testing is now available for diagnosing most GSDs, histologic examination of liver or muscle biopsy is still used in specific scenarios. In GSD type 0, a liver biopsy will show decreased hepatic glycogen and can make a definitive diagnosis for this disease.
Muscle biopsies will reveal diastase-sensitive vacuoles and positive for periodic acid-Schiff PAS and acid phosphatase in GSD type IV.
In addition, the biopsy will reveal subsarcolemmal deposits of glycogen detected with periodic acid-Schiff PAS stain. Molecular genetic testing is noninvasive and, for the most part, available for diagnosing these rare genetic disorders. In some cases, they have eliminated the need for invasive muscle and liver biopsies.
The genetic foci of mutations for these disorders are outlined in the following chart. Key goals are to treat or avoid hypoglycemia, hyperlactatemia, hyperuricemia, and hyperlipidemia. Hypoglycemia is avoided by consuming starch, and an optimal, physically modified form is now commercially available.
Hyperuricemia is treated with allopurinol and hyperlipidemia with statins. Some GSDs like GSD type II can now be treated with enzyme replacement therapy ERT , using recombinant alglucosidase alfa, which degrades lysosomal glycogen.
There is ongoing research to use ERT with other forms of GSDs. Liver transplantation should be considered for patients with certain GSDs with progressive hepatic forms that have progressed to hepatic malignancy or failure. Though liver failure and hypoglycemia may be corrected with liver transplantation, cardiomyopathy associated with the GSD will not be corrected and may continue to progress.
Glucagon is only effective in insulin-mediated hypoglycemia and will not be helpful in patients who present with hypoglycemia secondary to a GSD. With early diagnosis and proper management, the prognosis of most GSDs is good. Rarely, end-stage renal disease requiring kidney transplantation may occur in patients with GSD type Ib.
Hypoglycemia-associated seizures and cardiac arrest can occur in early childhood. whereas in GSD type Ib, recurrent bacterial infections secondary to neutropenia will be seen. Cardiomyopathy and limb-girdle dystrophy can be seen in patients with GSD type II.
Hypertrophic cardiomyopathy is a classic complication of GSD type III. Growth retardation and short status are also seen in GSD type IX a, b, c, d and GSD type XII, but a cognitive-developmental delay is also a feature in the latter.
Patient and parent education about the dietary modifications and frequency of feeding is of utmost importance in optimizing the clinical outcomes for patients affected with these diseases.
Depending on the type of GSD affecting the patient, specific instruction will be required. Patients and parents will need specific education to monitor for signs of hypoglycemia and the increased need for glucose or carbohydrate during an acute illness such as an infection.
In patients with GLUT2 deficiency, additional education regarding oral replacement of electrolytes lost via the kidneys is essential. GSDs are a group of complex metabolic disorders best managed by an interprofessional team of clinicians, nurses, pharmacists, and dietitians.
Registered dieticians and specialty nurses play a key role in educating patients and their caregivers to ensure hypoglycemia is avoided. This not only ameliorates the risk of hypoglycemia-associated complications but also prevents long-term disease sequelae in most GSDs. Specialty pharmacists play a pivotal role in managing GSD type II to ensure enzyme replacement therapy is carried out adequately and that the medication is administered under optimal circumstances.
Primary care clinicians, which include physicians and mid-level practitioners, and pediatricians, in coordination with specialists, help ensure patients have adequate growth and function with minimal risk of severe complications such as renal or liver failure. All interprofessional team members should be vigilant in monitoring these patients and alert the other team embers if any complications develop or the patient's condition worsens; this requires meticulous documentation and open communication between everyone on the care team.
The key overall goal is to avoid and treat hypoglycemia, hyperlactatemia, hyperuricemia, and hyperlipidemia. A well-coordinated interprofessional team can help manage patients with these diseases adequately and ensure they live a normal life. The development of experimental therapies, such as gene therapy, may eventually provide curative options for patients with these diseases in the future.
Glycogen Branching Polymer left Glycogen Storage Disease right Contributed by William Stone, MD. Disclosure: William Stone declares no relevant financial relationships with ineligible companies.
Disclosure: Hajira Basit declares no relevant financial relationships with ineligible companies. Disclosure: Abdullah Adil declares no relevant financial relationships with ineligible companies. This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.
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StatPearls [Internet]. Treasure Island FL : StatPearls Publishing; Jan-. Show details Treasure Island FL : StatPearls Publishing ; Jan-. Search term. Glycogen Storage Disease William L. Author Information and Affiliations Authors William L. Affiliations 1 East Tennessee State University. Continuing Education Activity Glycogen storage diseases GSDs are inherited inborn errors of carbohydrate metabolism.
Introduction Glycogen storage diseases GSDs are inherited inborn errors of carbohydrate metabolism. Etiology The etiology of GSDs is best understood by following the metabolic events leading to the synthesis glycogenesis and degradation of glycogen glycogenolysis.
Epidemiology The true incidence of metabolic diseases is difficult to determine given the lack of uniform, universal screening at birth. Pathophysiology As stated above, glycogen is the stored form of glucose and is composed of long polymers of 1,4 linked glucose with branch points via 1,6 linked glucose molecules.
History and Physical GSDs are a diverse set of rare inborn errors of carbohydrate metabolism that can have variable phenotypic presentation even within the same GSD type.
Evaluation Hypoglycemia is defined as a plasma concentration of glucose that results in symptoms attributable to hypoglycemia and is reversed with the administration of glucose. Biopsy Although specific genetic testing is now available for diagnosing most GSDs, histologic examination of liver or muscle biopsy is still used in specific scenarios.
Differential Diagnosis Charcot-Marie-Tooth disease. Prognosis With early diagnosis and proper management, the prognosis of most GSDs is good. Complications Hypoglycemia-associated seizures and cardiac arrest can occur in early childhood. Deterrence and Patient Education Patient and parent education about the dietary modifications and frequency of feeding is of utmost importance in optimizing the clinical outcomes for patients affected with these diseases.
Enhancing Healthcare Team Outcomes GSDs are a group of complex metabolic disorders best managed by an interprofessional team of clinicians, nurses, pharmacists, and dietitians.
Review Questions Access free multiple choice questions on this topic. Comment on this article. Figure Glycogen Branching Polymer left Glycogen Storage Disease right Contributed by William Stone, MD.
References 1. Hicks J, Wartchow E, Mierau G. Glycogen storage diseases: a brief review and update on clinical features, genetic abnormalities, pathologic features, and treatment. Ultrastruct Pathol. Ozen H. Glycogen storage diseases: new perspectives. World J Gastroenterol.
Kanungo S, Wells K, Tribett T, El-Gharbawy A. Glycogen metabolism and glycogen storage disorders. Ann Transl Med. Kannourakis G.
Glycogen Anti-viral treatment Ttpe Type Ib GSDIbDiwease called von Gierke disease, is Diswase inherited storrage in which the body lacks an enzyme Sustainable vegetable farming glucosephosphate translocase. GSDIb is caused by mutations in the SLC37A4 gene. A deficiency of glucosephosphate disrase impairs the body's ability to breakdown a stored form of sugar, called glycogen, into glucose. As a result, the body cannot maintain normal blood-sugar levels between meals, leading to low blood sugar hypoglycemia. Also, glycogen builds up in the body and impairs the function of the liver, the kidneys, and other organs. Children with GSDIb appear normal at birth but usually begin to show symptoms when they start to sleep longer through the night. Low blood sugar can cause tiredness, irritability, and seizures.Video
Glycogen Storage Diseases - GSD - Which glycogen storage disorder is most common? - pathology of GSD Thank Anti-viral treatment for visiting nature. Fat intake and omega- are using Glycogen storage disease type browser version with limited tye for CSS. To obtain the disezse experience, Glyclgen recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. An Erratum to this article was published on 01 September
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