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Understanding Glycogen Storage Disease Type 1b and its impacts.Liver involvement in glycogen storage disease -
We identified that most patients did not develop cardiomyopathy or neuromuscular complications during follow—up of up to Seven of these patients received liver transplantation from living donors, which included five heterozygous and three ABO—incompatible donors, and no mortality or morbidity associated with heterozygosity has yet been observed 3 , 24 , 27 , 32 , One of these patents was a 3.
In one patient who underwent liver transplantation for heart failure due to cardiomyopathy, and her heart failure was restored during 6 mo follow—up 3. Remarkably, there was resorption of amylopectin on myocardial biopsy in one patient after liver transplantation The mechanism of this decrease of abnormal glycogen remains unclear It may have been due to migration of donor cells from the liver allograft to the recipient heart and microchimerism 5 , However, the prognosis is grave when extrahepatic manifestations of GSD IV develop, especially cardiomyopathy Accordingly, it is a major concern that liver transplantation may only improve the hepatic function of individuals with GSD IV, and extrahepatic manifestations might develop post—transplantation and result in poor prognosis.
Amylopectin is not soluble, and the enzyme defect is present in other affected organs such as muscle, heart or nervous system. Amylopectin accumulation in other affected tissues might progress after transplantation. Postoperative extrahepatic progression of the disease caused by amylopectin accumulation in other affected tissues might be a potential risk for these individuals.
We identified only one patient with heart failure before transplantation. The evaluation of pretransplant cardiac function is not a predicting factor of poor outcome in this situation.
Of the four patients who died of cardiac failure after liver transplantation, all preoperative heart function was normal, but they developed cardiac amylopectionosis, attributed to accumulation of amylopectin in cardiac muscle.
The patients died 2. In three of those four patients, autopsy showed that cardiomyocytes contained massive PAS—positive, diastase-resistant inclusions 25 , In the fourth patient, postoperative myocardial biopsy showed PAS—positive, amylase—resistant deposits in cardiomyocytes up to 9 mo following liver transplantation In another patient, cardiomyopathy was discovered by postmortem examination after he died from respiratory and circulatory failure secondary to sepsis 2.
Myocardial biopsy is a potential predictor of cardiac functional prognosis after transplantation, but the number of amylopectin—like deposits related to progressive fatal cardiac failure needs to be defined. Further, long-term follow-up is necessary to evaluate possible cardiac or neuromuscular complications To further evaluate this risk, patients with GSD IV need careful assessment of heart, liver, and muscle before and after liver transplantation.
Heart transplantation has been suggested in cases with severe cardiac involvement. Patients with progressive cardiomyopathy and myocardial involvement confirmed by myocardial biopsy secondary to GSD IV may be candidates for cardiac transplantation. The experience with cardiac transplantation for GSD IV is insufficient.
Only three patients are known to have undergone cardiac transplantation for extrahepatic progression related to GSD IV 37 — Two patients were transplanted successfully and in good condition during follow—up. The third one died due to infectious complications after orthoptic heart transplantation.
Evaluation of the genotype—phenotype correlation in GSD IV may be helpful, which may provide valuable information in decision-making and help us to better understand the outcome of liver transplantation 6 , Liver transplantation remains the only therapeutic option for treatment of hepatic manifestation of GSD IV.
Our review shows that all GSD IV patients who survived had normal liver function after liver transplantation. Selection of patients with GSD IV for liver transplantation should be alert to extrahepatic progression, as the cardiomyopathy may lead to fatal complications.
Consideration of combined liver—heart transplantation and careful assessment of cardiac function even in the absence of evidence of clinical decompensation appears warranted for patients with GSD IV.
Histopathological studies of myocardial tissues and evaluation of the correlation between genotype—phenotype and the condition may predict the degree of severity and assist with treatment decisions. ML identified all the cases to be included, analyzed and interpreted the data and drafted the manuscript.
L-YS reviewed the manuscript. Both authors read and approved the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Andersen DH. Familial cirrhosis of the liver with storage of abnormal glycogen. Lab Invest. PubMed Abstract Google Scholar. Magoulas PL, El-Hattab AW, Roy A, Bali DS, Finegold MJ, Craigen WJ.
Diffuse reticuloendothelial system involvement in type IV glycogen storage disease with a novel GBE1 mutation: a case report and review.
Hum Pathol. doi: PubMed Abstract CrossRef Full Text Google Scholar. Aksu T, Colak A, Tufekcioglu O. Cardiac involvement in glycogen storage disease type iv: two cases and the two ends of a spectrum. Case Rep Med. Fernandez C, Halbert C, De Paula AM, Lacroze V, Froissart R, Figarella-Branger D, et al.
Non-lethal neonatal neuromuscular variant of glycogenosis type IV with novel GBE1 mutations. Muscle Nerve. Dainese L, Adam N, Boudjemaa S, Hadid K, Rosenblatt J, Jouannic JM, et al.
Glycogen storage disease type IV and early implantation defect: early trophoblastic involvement associated with a New GBE1 mutation. Pediatr Dev Pathol. Moses SW, Parvari R. The variable presentations of glycogen storage disease type IV: a review of clinical, enzymatic and molecular studies.
Curr Mol Med. Bruno C, van Diggelen OP, Cassandrini D, Gimpelev M, Giuffre B, Donati MA, et al. Clinical and genetic heterogeneity of branching enzyme deficiency glycogenosis type IV.
Lamperti C, Salani S, Lucchiari S, Bordoni A, Ripolone M, Fagiolari G, et al. Neuropathological study of skeletal muscle, heart, liver, and brain in a neonatal form of glycogen storage disease type IV associated with a new mutation in GBE1 gene.
J Inherit Metab Dis. Shin YS. Glycogen storage disease: clinical, biochemical, and molecular heterogeneity. Semin Pediatr Neurol. Cenacchi G, Papa V, Costa R, Pegoraro V, Marozzo R, Fanin M, et al.
Update on polyglucosan storage diseases. Virchows Arch. Davis MK, Weinstein DA. Pediatr Transplant. Bao Y, Kishnani P, Wu JY, Chen YT. Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene.
J Clin Invest. Greene HL, Brown BI, McClenathan DT, Agostini RJ, Taylor SR. A new variant of type IV glycogenosis: deficiency of branching enzyme activity without apparent progressive liver disease. McConkie-Rosell A, Wilson C, Piccoli DA, Boyle J, DeClue T, Kishnani P, et al.
Last updated: December 23, Years published: , , , , , , , , NORD gratefully acknowledges Deeksha Bali, PhD, Professor, Division of Medical genetics, Department of Pediatrics, Duke Health; Co-Director, Biochemical Genetics Laboratories, Duke University Health System, and Yuan-Tsong Chen, MD, PhD, Professor, Division of Medical Genetics, Department of Pediatrics, Duke Medicine; Distinguished Research Fellow, Academia Sinica Institute of Biomedical Sciences, Taiwan for assistance in the preparation of this report.
Glycogen storage diseases are a group of disorders in which stored glycogen cannot be metabolized into glucose to supply energy and to maintain steady blood glucose levels for the body.
Type I glycogen storage disease is inherited as an autosomal recessive genetic disorder. Glycogen storage disease type I GSDI is characterized by accumulation of excessive glycogen and fat in the liver and kidneys that can result in an enlarged liver and kidneys and growth retardation leading to short stature.
GSDI is associated with abnormalities mutations in the G6PC gene GSDIA or SLC37A4 gene GSDIB. These mutations result in enzyme deficiencies that block glycogen breakdown in affected organs causing excess amounts of glycogen and fat accumulation in the body tissues and low levels of circulating glucose in the blood.
The enzyme deficiency also results in an imbalance or excessive accumulation of other metabolites, especially lactates, uric acid and fats like lipids and triglycerides. The primary symptom of GSDI in infancy is a low blood sugar level hypoglycemia. Symptoms of GSDI usually begin at three to four months of age and include enlargement of the liver hepatomegaly , kidney nephromegaly , elevated levels of lactate, uric acid and lipids both total lipids and triglycerides , and possible seizures caused due to repeated episodes of hypoglycemia.
Continued low blood sugar can lead to delayed growth and development and muscle weakness. Affected children typically have doll-like faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen.
High lipid levels can lead to the formation of fatty skin growths called xanthomas. Other conditions that can be associated with untreated GSD1 include; osteoporosis, delayed puberty, gout arthritis caused by accumulation of uric acid , kidney disease, pulmonary hypertension high blood pressure in the arteries that supply the lungs , hepatic adenoma benign liver tumors , polycystic ovaries in females, an inflammation of the pancreas pancreatitis , diarrhea and changes in brain function due to repeated episodes of hypoglycemia.
Impaired platelet function can lead to a bleeding tendency with frequent nose bleeds epistaxis. In general GSD type Ib patients have similar clinical manifestations as type Ia patients, but in addition to the above mentioned manifestations, GSDIb is also associated with impaired neutrophil and monocyte function as well as chronic neutropenia after the first few years of life, all of which result in recurrent bacterial infections and oral and intestinal mucosal ulcers.
Early diagnosis and effective treatment can result in normal growth and puberty and many affected individuals live into adulthood and enjoy normal life activities. Many female patients have had successful pregnancies and childbirth.
Type I glycogen storage disease is associated with abnormalities in two genes. This type of GSDI is termed glycogen storage disease type Ia.
This type of GSDI is termed glycogen storage disease type Ib. Both these enzyme deficiencies cause excess amounts of glycogen along with fats to be stored in the body tissues. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent.
If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk is the same for males and females.
Type I glycogen storage disease occurs in approximately 1 in , births. The prevalence of GSDI in Ashkenazi Jews is approximately 1 in 20, This condition affects males and females in equal numbers in any given population group.
Symptoms of the following disorders can be similar to those of glycogen storage disease type I. Detailed evaluations may be useful for a differential diagnosis:. Forbes or Cori disease GSD-III is one of several glycogen storage disorders that are inherited as autosomal recessive traits.
Symptoms are caused by a lack of the enzyme amylo-1,6 glucosidase debrancher enzyme. This enzyme deficiency causes excessive amounts of an abnormally digested glycogen the stored form of energy that comes from carbohydrates to be deposited in the liver, muscles and, in some cases, the heart.
In the first few months some symptoms may overlap with GSDI elevated lipids, hepatomegaly, low glucose. Andersen disease GSD-IV also known as glycogen storage disease type IV; This GSD is also inherited as an autosomal recessive trait.
In most affected individuals, symptoms and findings become evident in the first few years of life. Such features typically include failure to grow and gaining weight at the expected rate failure to thrive and abnormal enlargement of the liver and spleen hepatosplenomegaly.
Hers disease GSD-VI is also called glycogen storage disease type VI. It usually has milder symptoms than most other types of glycogen storage diseases. It is caused by a deficiency of the enzyme liver phosphorylase.
Hers disease is characterized by enlargement of the liver hepatomegaly , moderately low blood sugar hypoglycemia , elevated levels of acetone and other ketone bodies in the blood ketosis , and moderate growth retardation. Symptoms are not always evident during childhood, and children are usually able to lead normal lives.
However, in some instances, symptoms may be severe. Glycogen storage disease IX is caused due to deficiency of phosphorylase kinase enzyme PK enzyme deficiency.
The disorder is characterized by slightly low blood sugar hypoglycemia. Excess amounts of glycogen the stored form of energy that comes from carbohydrates are deposited in the liver, causing enlargement of the liver hepatomegaly.
Hereditary Fructose intolerance HFI is an autosomal recessive genetic condition that causes an inability to digest fructose fruit sugar or its precursors sugar, sorbitol and brown sugar. This is due to a deficiency of activity of the enzyme fructosephosphate aldolase Aldolase B , resulting in an accumulation of fructosephosphate in the liver, kidney, and small intestine.
Fructose and sucrose are naturally occurring sugars that are used as sweeteners in many foods, including many baby foods. This disorder can be life threatening in infants and ranges from mild to severe in older children and adults.
GSD type I is diagnosed by laboratory tests that indicate abnormal levels of glucose, lactate, uric acid, triglycerides and cholesterol. Molecular genetic testing for the G6PC and SLC37A4 genes is available to confirm a diagnosis. Molecular genetic testing can also be used for carrier testing and prenatal diagnosis.
Liver biopsy can also be used to prove specific enzyme deficiency for GSD Ia. Treatment GSDI is treated with a special diet in order to maintain normal glucose levels, prevent hypoglycemia and maximize growth and development. Frequent small servings of carbohydrates must be maintained during the day and night throughout the life.
Calcium, vitamin D and iron supplements maybe recommended to avoid deficits. Frequent feedings of uncooked cornstarch are used to maintain and improve blood levels of glucose. Allopurinol, a drug capable of reducing the level of uric acid in the blood, may be useful to control the symptoms of gout-like arthritis during the adolescent years.
Human granulocyte colony stimulating factor GCSF may be used to treat recurrent infections in GSD type Ib patients. Liver tumors adenomas can be treated with minor surgery or a procedure in which adenomas are ablated using heat and current radiofrequency ablation.
People with glycogen storage disorders often work with physical and occupational therapists to build strength and promote proper development. These therapies can help you or your child with motor skills for tasks of daily living. Weakened muscles and developmental delays related to glycogen storage disorders can impact speech.
Our speech pathologists use speech therapy to teach children how to make the correct mouth movements to improve their spoken words and language acquisition. Surgery may be necessary if the liver, heart, or digestive tract is affected by the disease.
If serious damage occurs, organ transplants may be recommended. We use family history and medical tests to diagnose glycogen storage diseases. Prenatal testing is also available.
The following tests may be ordered. May be used to monitor the health of the liver, kidneys, and muscles, and ensure proper blood sugar levels. Can uncover the presence of disease-causing genetic changes. It is used to check for certain disease markers and hereditary traits. Tissue samples taken from the liver and muscle are studied to look for disease or abnormal cell function.
Contrast-enhanced ultrasound, CT, and MRI create detailed pictures of the size, structure, and function of organs and vessels. This nonsurgical alternative to a liver biopsy uses ultrasound to check for liver stiffness from scarring, called liver fibrosis.
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Glycogen is the form of sugar your body stores in your liver and muscles Glycoen future energy needs. Glycogen storage diseases are complex genetic Djsease in which certain involvemnet -- ones involved in Stress-free living glycogen involvemenr breaking it storag into lnvolvement for your body to use -- are missing or don't work correctly. This can result in liver, heart, muscle, and respiratory problems. While there is no cure, our team of internationally recognized experts uses special diets and medical treatments to manage these diseases and their symptoms. We work you or your child to improve growth, development, and health. Our physical and occupational therapists and speech pathologists may also work with you to develop muscle strength and improve other weaknesses.Last gllycogen December 23, Dtorage published:djsease,, NORD gratefully acknowledges Deeksha Bali, PhD, Professor, Division involvemetn Medical genetics, Department of Pediatrics, Duke Health; Co-Director, Glyvogen Genetics Laboratories, Glgcogen University Health System, and Yuan-Tsong Chen, Diease, PhD, Professor, Division of Medical Genetics, Department of Pediatrics, Duke Medicine; Distinguished Diseade Fellow, Academia Sinica Institute of Biomedical Sciences, Taiwan for atorage in involvemdnt preparation of gylcogen report.
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Disewse type of GSDI is ib glycogen stoeage disease type Diesase. This type of GSDI is termed glycogen storage disease type Ib. Both these enzyme deficiencies cause excess amounts of glycogen along with fats to be stored in the body tissues. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent.
If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk is the same for males and females. Type I glycogen storage disease occurs in approximately 1 inbirths. The prevalence of GSDI in Ashkenazi Jews is approximately 1 in 20, This condition affects males and females in equal numbers in any given population group.
Symptoms of the following disorders can be similar to those of glycogen storage disease type I. Detailed evaluations may be useful for a differential diagnosis:. Forbes or Cori disease GSD-III is one of several glycogen storage disorders that are inherited as autosomal recessive traits.
Symptoms are caused by a lack of the enzyme amylo-1,6 glucosidase debrancher enzyme. This enzyme deficiency causes excessive amounts of an abnormally digested glycogen the stored form of energy that comes from carbohydrates to be deposited in the liver, muscles and, in some cases, the heart.
In the first few months some symptoms may overlap with GSDI elevated lipids, hepatomegaly, low glucose. Andersen disease GSD-IV also known as glycogen storage disease type IV; This GSD is also inherited as an autosomal recessive trait.
In most affected individuals, symptoms and findings become evident in the first few years of life. Such features typically include failure to grow and gaining weight at the expected rate failure to thrive and abnormal enlargement of the liver and spleen hepatosplenomegaly.
Hers disease GSD-VI is also called glycogen storage disease type VI. It usually has milder symptoms than most other types of glycogen storage diseases. It is caused by a deficiency of the enzyme liver phosphorylase. Hers disease is characterized by enlargement of the liver hepatomegalymoderately low blood sugar hypoglycemiaelevated levels of acetone and other ketone bodies in the blood ketosisand moderate growth retardation.
Symptoms are not always evident during childhood, and children are usually able to lead normal lives. However, in some instances, symptoms may be severe. Glycogen storage disease IX is caused due to deficiency of phosphorylase kinase enzyme PK enzyme deficiency.
The disorder is characterized by slightly low blood sugar hypoglycemia. Excess amounts of glycogen the stored form of energy that comes from carbohydrates are deposited in the liver, causing enlargement of the liver hepatomegaly.
Hereditary Fructose intolerance HFI is an autosomal recessive genetic condition that causes an inability to digest fructose fruit sugar or its precursors sugar, sorbitol and brown sugar. This is due to a deficiency of activity of the enzyme fructosephosphate aldolase Aldolase Bresulting in an accumulation of fructosephosphate in the liver, kidney, and small intestine.
Fructose and sucrose are naturally occurring sugars that are used as sweeteners in many foods, including many baby foods. This disorder can be life threatening in infants and ranges from mild to severe in older children and adults. GSD type I is diagnosed by laboratory tests that indicate abnormal levels of glucose, lactate, uric acid, triglycerides and cholesterol.
Molecular genetic testing for the G6PC and SLC37A4 genes is available to confirm a diagnosis. Molecular genetic testing can also be used for carrier testing and prenatal diagnosis. Liver biopsy can also be used to prove specific enzyme deficiency for GSD Ia. Treatment GSDI is treated with a special diet in order to maintain normal glucose levels, prevent hypoglycemia and maximize growth and development.
Frequent small servings of carbohydrates must be maintained during the day and night throughout the life. Calcium, vitamin D and iron supplements maybe recommended to avoid deficits. Frequent feedings of uncooked cornstarch are used to maintain and improve blood levels of glucose. Allopurinol, a drug capable of reducing the level of uric acid in the blood, may be useful to control the symptoms of gout-like arthritis during the adolescent years.
Human granulocyte colony stimulating factor GCSF may be used to treat recurrent infections in GSD type Ib patients. Liver tumors adenomas can be treated with minor surgery or a procedure in which adenomas are ablated using heat and current radiofrequency ablation. Individuals with GSDI should be monitored at least annually with kidney and liver ultrasound and routine blood work specifically used for monitoring GSD patients.
Information on current clinical trials is posted on the Internet at www. All studies receiving U. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the National Institutes of Health NIH in Bethesda, MD, contact the NIH Patient Recruitment Office:. Tollfree: TTY: Email: prpl cc. For information about clinical trials sponsored by private sources, contact: www. TEXTBOOKS Chen YT, Bali DS.
Prenatal Diagnosis of Disorders of Carbohydrate Metabolism. In: Milunsky A, Milunsky J, eds. Genetic disorders and the fetus — diagnosis, prevention, and treatment. West Sussex, UK: Wiley-Blackwell; Chen Y. Glycogen storage disease and other inherited disorders of carbohydrate metabolism.
In: Kasper DL, Braunwald E, Fauci A, et al. New York, NY: McGraw-Hill; Weinstein DA, Koeberl DD, Wolfsdorf JI. Type I Glycogen Storage Disease.
In: NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott, Williams and Wilkins; JOURNAL ARTICLES Chou JY, Jun HS, Mansfield BC.
J Inherit Metab Dis. doi: Epub Oct 7. PubMed PMID: Kishnani PS, Austin SL, Abdenur JE, Arn P, Bali DS, Boney A, Chung WK, Dagli AI, Dale D, Koeberl D, Somers MJ, Wechsler SB, Weinstein DA, Wolfsdorf JI, Watson MS; American College of Medical Genetics and Genomics.
Genet Med. Austin SL, El-Gharbawy AH, Kasturi VG, James A, Kishnani PS. Menorrhagia in patients with type I glycogen storage disease. Obstet Gynecol ;— Dagli AI, Lee PJ, Correia CE, et al. Pregnancy in glycogen storage disease type Ib: gestational care and report of first successful deliveries.
Chou JY, Mansfield BC. Mutations in the glucosephosphatase-alpha G6PC gene that cause type Ia glycogen storage disease. Hum Mutat. Franco LM, Krishnamurthy V, Bali D, et al.
Hepatocellular carcinoma in glycogen storage disease type Ia: a case series. Lewis R, Scrutton M, Lee P, Standen GR, Murphy DJ.
: Liver involvement in glycogen storage disease| Glycogen Storage Disease Type 1 (von Gierke) | Phosphoglucomutase-1 PGM1. Sforage GSD type Inovlvement, our results demonstrated that LT Joint health pain management the liver function Performance optimization software patients Nutrition myths busted Livver the metabolic outcome. Failure to thrivedeath at age ~5 years. Selection of patients with GSD IV for liver transplantation should be alert to extrahepatic progression, as the cardiomyopathy may lead to fatal complications. Received : 24 February |
| Glycogen Storage Disease | Liver transplantation normalized the liver function of stoage the Lver with GSD IV glycoten case srorage, thereby improving the survival rate and quality of life of patients. Glycogen Xisease Disease Performance optimization software Energy drinks for weight loss Print. Ekstein J, Rubin BY, Anderson, et al. A mild juvenile variant of type IV glycogenosis. Failure to thrivedeath at age ~5 years. Bruno C, van Diggelen OP, Cassandrini D, Gimpelev M, Giuffre B, Donati MA, et al. Most remarkable, eight patients were reported to had retarded growth pre—transplantation, but developed well with normal growth, after liver transplantation 2527 , |
| Choose Language | Methods to diagnose glycogen storage diseases include history and physical examination for associated symptoms, blood tests for associated metabolic disturbances, and genetic testing for suspected mutations. Retrieved 5 July Although the extrahepatic manifestations of GSD IV may still progress after transplantation, especially cardiomyopathy. Liver biopsies have confirmed signs of cirrhosis and cells with periodic acid-Schiff PAS —stained, diastase-resistant inclusions, consistent with GSD IV. PAS-positive inclusion deposits in the myocardium of ten patients with GSD IV pre-or-post liver transplantation. No mass was identified. The childhood neuromuscular subtype, which is the rarest one, has most variable course. |
Liver involvement in glycogen storage disease -
Glycogen storage disease diagnosis usually occurs in infancy or childhood as a result of the above symptoms. If your child's doctor suspects a glycogen storage diseases, he or she will ask about your child's symptoms and medical history, then perform a physical exam.
The doctor will perform tests to rule out or confirm the diagnosis. These tests may include:. Glycogen storage disease treatment will depend on the type of disease and the symptoms. The following general treatment guidelines apply to people who have glycogen storage diseases that affect the liver, or types I, III, IV, and VI.
Your child's doctor will develop a treatment regimen based on your child's specific symptoms. This next group of glycogen storage disease treatment guidelines applies to people who have glycogen storage diseases that affect the muscles, or types V and VII.
This is done by:. There is no way to prevent glycogen storage diseases. However, early treatment can help control the disease once a person has it. If you have a glycogen storage disease or a family history of the disorder, you can talk to a genetic counselor when deciding to have children.
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Children's Hospital is part of the UPMC family. UPMC Website UPMC's Story. Our Sites. Liver Disease States. Liver Transplant. Glycogen Storage Diseases GSD in Children What Is Glycogen Storage Disease? Types of Glycogen Storage Disease The main types of glycogen storage diseases in children are categorized by number and name.
Glycogen Storage Disease Symptoms Glycogen storage disease symptoms in pediatric patients depend on its type. These tests may include: Biopsy of the affected organs Blood tests and urine tests MRI scan — a test that uses magnetic waves to make pictures of the inside of the body Glycogen Storage Disease Treatment Glycogen storage disease treatment will depend on the type of disease and the symptoms.
The goal of treatment is to maintain normal blood glucose levels. This may be done with: A nasogastric infusion of glucose in infants and children under age two Dietary changes, including: In children over age two, frequent small carbohydrate feedings are given throughout the day.
This may include uncooked cornstarch. GSD type 0a is caused by defects of the hepatic isoform of glycogen synthase, encoded by GYS2 chromosome 12p Mutations of the muscle-specific isoform of glycogen synthase encoded by GYS1 gene originate GSD type 0b.
Clinically, it exhibits weakness, exercise intolerance and arrythmias without liver involvement [ 8 ]. The onset of symptoms occurs before 3. Affected toddlers are incapable of synthetizing glycogen and having adequate glycemic response to stress or fasting periods.
For this reason, they show fasting ketotic hypoglycemia, that can be either symptomatic or asymptomatic. Symptomatic hypoglycemia is revealed by pallor, sweating, hyporeactivity, lethargic state until generalized seizures [ 10 , 11 ].
After a meal or an oral glucose tolerance test OGTT , hyperglycemia and hyperlactatemia are observed [ 12 ], whereas hypoglycemia can manifest after three hours from the last feeding [ 13 ].
Patients cannot switch to gluconeogenesis rapidly enough to ensure a normal hepatic glucose output. It could be speculated that the post-prandial hyperglycemia typical of GSD type 0 suppresses the glucagon activity and that glucagon to insulin ratio remains too low to stimulate phosphoenolpyruvate carboxykinase, the rate-limiting enzyme for gluconeogenesis [ 12 ].
Fasting glucagon stimulus test may not increase glycemia as the expected, confirming the presence of poor glycogen deposits [ 14 ], with a response in the fed state not consistent among patients [ 10 ]. The presentation with post-prandial hyperglycemia and glycosuria, along with fasting ketonuria, places GSD type 0 in differential diagnosis with early phases of diabetes mellitus and Fanconi-Bickel syndrome [ 14 ].
However, ketonuria is not a constant finding and measurement of ketones in blood is preferable [ 13 ]. Hepatomegaly is not associated to this disorder [ 10 , 12 , 15 , 16 , 17 ], although a mild liver enlargement has been described in some patients [ 13 ].
Slightly different phenotypes might be related to different degrees of enzyme residual activity. Growth failure is reported [ 9 , 12 ]. The branching enzyme deficiency GBE1 gene, chromosome 3p14 causes the GSD type IV or Andersen disease.
The branching enzyme adds a segment of a minimum of six α-1,4 linked glycosyl units into an α-1,6 position; this activity is fundamental for the correct glycogen storage and degradation. Indeed, GBE1 deficiency induces the accumulation of an amylopectin-like molecule called polyglucosan, an insoluble polymer which has fewer branching points and longer outer chains than normal glycogen [ 19 ].
GSD type IV includes two hepatic subtypes the classical progressive and the non-progressive hepatic disease , three neuromuscular subtypes distinguished in the perinatal, congenital and childhood disease, depending on the age of onset and a multisystem form adult polyglucosan body disease.
Indeed, the GSD type IV has a very heterogeneous clinical presentation, ranging between myopathy, cardiomyopathy, neuropathy and liver failure variously combined [ 20 , 21 ].
The classical progressive hepatic form is characterized by an initially normal phenotype with rapid deterioration in infancy, when hepatomegaly and failure to thrive appear. Prolonged partial thromboplastin time and prothrombin time progressively develop, along with hypoalbuminemia.
Linear glycogen molecules can be metabolized, so this prevents severe hypoglycemia. Nevertheless, it may develop in the final stages of liver failure [ 23 ].
The final evolution is toward progressive fibrosis, cirrhosis and its complications, such as portal hypertension, ascites and esophageal varices, with death occurring before the age of five owing to liver failure [ 24 , 25 ].
Liver transplantation remains the only effective treatment for patients with the progressive hepatic subtype of GSD type IV who develop liver failure. However, some patients treated by liver transplantation displayed over time extrahepatic manifestations, such as cardiomyopathy and myopathy [ 26 , 27 , 28 , 29 ].
The non-progressive hepatic disease exhibits different grades of severity, with the milder phenotype showing hepatomegaly and inconstant elevation of transaminases. McConkie-Rosell et al.
Conversely, Dhawan et al. The severity of the phenotype might depend both on the involvement of different tissue isozymes [ 1 ] and the residual activity of branching enzyme [ 21 ]. GSD type IV patients exhibit a continuum of different phenotypes, with extremely variable clinical features.
Hypoglycemia has traditionally been considered a late manifestation, related to hepatocellular dysfunction; notably, a recent report documented fasting intolerance in patients without any sign of liver involvement [ 26 ]. The neuromuscular variants of GSD type IV are very rare; nevertheless, the perinatal variant should be considered one of the differential diagnoses in neonates with severe hypotonia and in pregnancies complicated by polyhydramnios, fetal hydrops, reduced fetal movements, arthrogryposis, hypoplastic lungs of unknown etiology [ 19 , 20 , 21 , 32 ].
The congenital neuromuscular subtype begins in the newborn period with profound hypotonia, respiratory distress, and dilated cardiomyopathy and, as well as the previous one, results in death in the neonatal period. The childhood neuromuscular subtype, which is the rarest one, has most variable course.
Its onset ranges from the second life decade with a mild disease course to a more severe, progressive course resulting in death in the third decade [ 21 ]. Neurological adult form can present as isolated myopathy or as widespread upper and lower motor neuron lesions adult polyglucosan body disease , which presents usually after the age of 50 years.
Its hallmarks are progressive spastic paraparesis, neurogenic bladder, and axonal neuropathy [ 29 , 33 ]. PYGL gene chromosome 14qq22 mutations are associated to GSD type VI, also known as Hers disease [ 34 ]. Affected individuals lack the glycogen phosphorylase activity, which breaks up glycogen into glucose units as a response to hypoglycemia.
This is a rate limiting step in glycogen degradation, hence the untreated child shows moderate fasting hypoglycemia with mild ketosis, hyperlipidemia, elevated liver enzymes, abdominal distension, hepatomegaly and growth failure.
Pre-albumin is also reduced [ 34 , 35 ]. Symptoms begin at the pre-school age; hypoglycemia may originate during prolonged fasting, illnesses or stressful conditions, thus a strict surveillance must be realized in these cases [ 34 , 36 ].
Ketotic hypoglycemia without hepatomegaly has also been recently described in GSD type VI as the only sign of disease [ 6 ]. GSD type VI was previously considered as a mild disease. However, recent reports highlighted the possibility of a progression to fibrosis and cirrhosis, and a degeneration to hepatocellular carcinoma, so a rigorous long-term monitoring of hepatic function is needed [ 4 , 37 , 38 ].
PhK is composed of four different subunits: α, β, γ and δ. Subunits α and β have regulatory functions, the γ-subunit has catalytic function and δ-subunit is a calmodulin protein. The subunits possess tissue-specific isoforms; the liver-specific isoforms of the α-, β- and γ-subunits are encoded by PHKA2 , PHKB and PHKG2 respectively, and are causative of GSD IX subtypes IXa, IXb and IXc [ 39 ].
However, PHKB is expressed in both liver and muscle. Furthermore, the α- and γ-subunits have a muscle-specific isoform, encoded by PHKA1 and PHKG1 respectively. The α-subunit isoforms are inherited in an X-linked fashion, while the other isoforms have an autosomal recessive inheritance [ 40 ].
Furthermore, the subtype IXa is distinguished in types XLG I and XLG II, two clinically similar entities basically differing for the possibility to discover the enzyme deficiency on erythrocytes [ 41 ].
GSD type IX represents the most frequent type of glycogen storage disease, with a prevalence of , births [ 42 ]. Renal tubulopathy is an inconstant finding [ 37 ].
Hypoglycemia is not always pronounced because gluconeogenesis and fatty acid oxidation are intact, and normal blood glucose concentrations are often maintained [ 43 , 44 ]. When hypoglycemia is present, ketosis is associated in fasting conditions [ 45 ]. More recently, isolated ketotic hypoglycemia without hepatomegaly has been related to PhK deficiency, mostly due to PHKA2 mutations [ 6 ].
PhK deficiency was generally considered a benign condition, with symptoms of hypoglycemia, hepatomegaly and growth retardation improving after the early introduction of a strict dietary treatment [ 43 ].
Nevertheless, recent studies have focused on the existence of complications and different prognosis depending on the causative mutation. For instance, an evolution to liver fibrosis and chronic liver disease associated to PHKA2 mutations has been reported [ 46 , 47 ].
Furthermore, Burwinkel et al. The phenotype associated to PHKB mutations is similar to what observed in the milder PHKA2 mutations; symptoms related to muscular involvement may be present [ 48 ].
PHKG2 associated phenotypes show a more severe presentation [ 49 ]. The clinical spectrum includes fasting hypoglycemia, hepatomegaly, elevated transaminases, liver fibrosis, cirrhosis, muscle weakness, hypotonia, motor developmental delay, growth retardation and fatigue [ 50 , 51 ].
More recently, the presence of variable degree of liver fibrosis and cirrhosis still in early childhood has been reported in the three subtypes [ 4 ]. GSD type XI is caused by defective glucose and galactose transporter GLUT2 SLC2A2 gene, chromosome 3q This condition causes impaired influx and efflux of glucose from the aforementioned cell types, and it may have a role in insulin secretion [ 53 ].
This is a severe disease with a peculiar clinical presentation. Both transport and metabolism of glucose and galactose are defective, with subsequent increased hepatorenal glycogen storage leading to hepatomegaly. At early stages, a slight elevation of transaminases is recorded.
Neonatal screening may show hypergalactosemia but cataract is not present in this condition [ 54 ]. Impaired renal glucose reabsorption, as well as the accumulation of glucose in the liver, which reduces glycogen breakdown, causes fasting ketotic hypoglycemia. Conversely, in the fed state hyperglycemia is observed.
This may be due to the impairment of glucose transportation from the enterocytes and decreased glucose uptake by the liver, consequent to impaired insulin secretion [ 53 ]. Signs and symptoms usually begin between 3 and 10 months of life with poor feeding, failure to thrive and laboratory findings as glycosuria [ 54 ].
The proximal renal tubular dysfunction implicates glycosuria, proteinuria, phosphaturia, aminoaciduria and bicarbonate wasting, resulting in a metabolic hyperchloremic acidosis with normal anion gap [ 52 ]. Hypercalciuria is a constant finding.
In older children, pubertal delay and hypophosphatemic rickets are described [ 55 , 56 ]. Tendency to hyponatremia and hypokalemia is frequent owing to renal losses.
Polyuria may be present as a consequence of high osmotic load. Patients may exhibit chronic diarrhea secondary to intestinal malabsorption. Hyperlipidemia is recorded, leading to moon-shaped face and fat deposition on shoulders and abdomen, which are typical features [ 1 , 54 ].
Notably, a GLUT2 deleted mouse model exhibited an increased expression of ChREBP Carbohydrate Response Element Binding Protein which in turn activates the lipogenic target genes transcription [ 57 ].
Patients with Fanconi-Bickel syndrome manifest a dysregulation of glucose homeostasis, with presentation of fasting hypoglycemia, post-prandial hyperglycemia, glucose intolerance, transient neonatal diabetes, gestational diabetes and frank diabetes mellitus.
Impaired glucose control along with low birth weight suggest that GLUT2 might have a role in insulin physiology from fetal to adult age [ 53 ]. A few cases of patients with a similar phenotype but without any mutation of SLC2A2 were reported, suggesting other genes involved in the pathogenesis of this condition, remaining unknown so far [ 58 ].
Remarkably, the mutations p. These HNF4α mutations might decrease the SLC2A2 expression in both liver and kidney, resulting in nonfunctional GLUT2 and are responsive to therapy with diazoxide [ 59 , 60 ].
Fasting ketotic hypoglycemia is a hallmark of hepatic GSDs [ 26 , 61 ]. Patients with GSD type 0 and XI show also a typical post-prandial hyperglycemia [ 12 , 16 , 53 ]. In GSD type IV, hypoglycemia can appear late in the clinical course, but it can be also found in patients without signs of liver disease [ 26 ].
Ketotic hypoglycemia without hepatomegaly has also been recently described in GSD type VI and IX [ 6 ]. Futhermore, isolated ketonemia with normoglycemia has been described in patients with GSD types VI and IX [ 62 ].
GSD type XI exhibits a wide range of alterations in glucose homeostasis, including fasting hypoglycemia, hyperglycemia in the fed state, glucose intolerance up to diabetes mellitus in rare cases [ 53 ].
Elevated triglyceridemia and cholesterolemia are common findings in GSDs with liver involvement. In these conditions, the dysregulation of glucose metabolism leads to fasting intolerance, enhancing secondary lipolysis and increased mitochondrial fatty acid oxidation [ 1 ].
In GDS type XI, the administration of statins may be required [ 63 ]. In the other forms, the dyslipidemia is generally moderate and an appropriate nutritional therapy is effective to reduce plasma lipid values [ 64 ]. As previously mentioned, the distinctive element of the glycogen synthase deficiency is the absence of hepatomegaly, since hepatic glycogen storage is impaired [ 9 , 12 ], although enlarged liver has been reported in some cases of GSD type 0 [ 13 , 16 ].
By contrast, hepatomegaly is the hallmark of the GSD type IV, VI, IX and XI with various degrees of severity, which may show an improvement after puberty in treated GSD type IX patients [ 64 , 65 ].
However, a progression of the liver disease may occur despite a reduction of the liver size [ 44 ]. In GSD type IV the accumulation of abnormal glycogen, less soluble than normal glycogen, causes a foreign body reaction with consequent osmotic swelling and cell death [ 50 ], leading to interstitial fibrosis evolving toward cirrhosis [ 24 ].
Liver fibrosis is outlined also in individuals with GSD types VI [ 38 , 66 ] and IX [ 4 , 51 ]. Furthermore, cirrhosis has recently been depicted in GSD type VI [ 38 ]. Among the GSD IX subtypes, the progression to liver cirrhosis had initially been described only in patients affected by PHKG2 mutations [ 49 ].
Nevertheless, Tsilianidis et al. More recently, early appearance of liver cirrhosis in a 2 years old child with homozygous mutations in PHKB has been reported [ 40 ]. Tumor degeneration is described in GSD type IV, VI and IX. Hepatocellular adenoma and carcinoma have been described in GSD type IV [ 67 ].
GSD type VI can be rarely complicated by focal nodular hyperplasia [ 68 ] and one case of hepatocellular carcinoma has been reported to date [ 69 ].
With regards to GSD type IX, hepatocellular adenomas have been reported in IXa and IXb subtypes [ 4 , 44 ]. Furthermore, the development of hepatocellular carcinoma associated to GSD type IXc has recently been described [ 70 ].
In GSD type XI, liver histology shows marked accumulation of glycogen in hepatocytes along with steatosis. The degeneration to hepatic adenomas or carcinomas is rare [ 54 ]. The first case of hepatocellular carcinoma in a young boy affected by Fanconi-Bickel syndrome was described in by Pogoriler and colleagues [ 71 ].
Conversely, individuals affected by PHKA2 and PHKG2 mutations can display renal tubular acidosis and tubulopathy with secondary development of rickets in a patient with GSD type IXc. The establishment of an adequate nutritional therapy improves tubular acidosis [ 37 ]. In addition, renal involvement represents a hallmark of GSD type XI, in which the renal epithelial cells are damaged by the accumulation of glycogen and monosaccharides; this alteration leads to proximal tubular dysfunction, documented by glycosuria and aminoaciduria.
Although this condition is related to a severe phenotype, rare cases of patients with mild renal dysfunction have been described [ 8 ]. Normal length and weight at birth are usually observed, suggesting that the metabolic disorders do not interfere with fetal growth [ 11 , 19 , 72 ], except for newborns with GSD type XI, which are typically low birth weight [ 53 ].
Patients diagnosed with GSD type 0 may show either normal or poor growth with a delayed bone age in early childhood [ 15 , 17 ]. A catch-up growth has been described after the introduction of adequate dietary therapy, comprising uncooked cornstarch [ 9 ].
Osteopenia is a possible complication [ 5 ]. Growth impairment is not a hallmark of GDS type IV and it may be present or not, depending on the causing mutation and the clinical subtype [ 24 ].
In contrast, short stature is a common feature in GSD types VI and IX, with a variability in the degree of improvement of parameters in treated patients reaching the adult age [ 36 ]. Most individuals affected by PhK deficiency achieve standard adult stature parameters, but they show a peculiar growth pattern, with an initial growth retardation in the first 2—3 years of age, followed by a gradual normalization of the linear growth [ 65 ].
Abnormal bone mineralization with and without osteopenia has been reported in GSDs types VI and IX [ 37 , 73 ]. Dietary deficiencies and chronic ketosis are speculated to be contributory factors [ 37 ]. Rickets has been reported in a case of GSD type IXc, due to renal tubulopathy with an inappropriate parathyroid response [ 37 ].
Severe growth impairment is described in Fanconi-Bickel syndrome. Patients affected by proximal renal tubular dysfunction of variable genetic causes show growth retardation ascribed to renal losses but the short stature observed in Fanconi-Bickel syndrome is more pronounced, suggesting other mechanisms not clearly understood [ 74 ].
Newborns are generally low birth weight, likely effect of the insulin deregulation starting in utero [ 53 ]. Furthermore, dwarfism is a striking feature in adult patients [ 1 ], with scarce response to nutritional therapy.
Remarkably, Pennisi and colleagues [ 63 ] reported a substantial improvement of height and weight by the administration of nocturnal enteral nutrition from the age of 1 year, in five patients. Four patients were supplemented with uncooked cornstarch in the enteral nutrition.
Notably, untreated patients reached an adult height ranging from Among all GSDs, bone is mostly affected in GSD type XI, where hypophosphatemic rickets, frequent fractures and bone deformities are described as a result of the renal tubular dysfunction [ 76 ].
Limbs deformities and lumbar hyperlordosis may appear in patients with delayed diagnosis, as observed in developing countries [ 74 ]. Skeletal muscle and myocardial involvement is not observed in GSD type 0a [ 9 ].
Heart failure after orthotropic liver transplantation has been described in patients with the progressive liver form of GSD type IV with no previous history of cardiac involvement [ 27 , 28 ].
This could be due to a progression of disease, despite liver transplantation. Indeed, in patients dead after liver transplantation, amylopectin deposits have been observed in different organs and tissues myocardial fibers, skeletal muscle fibers, central and peripheral nervous system cells, macrophages at autopsy [ 77 ].
A good clinical response to liver transplantation may be explained by a mechanism of microchimerism, through which the donor cells transfer the deficient enzyme to the host cells, thus reducing amylopectin deposits [ 78 ]. Mild to severe myopathy and dilated cardiomyopathy are also described in the neuromuscular forms of GSD type IV [ 24 , 79 ].
Remarkably, cardiomyopathy has been reported as the sole presenting symptom of branching enzyme deficiency in one case [ 21 ]. Muscular cramps or fatigue after physical exercise have been recorded in a minority of reports of GSD type VI, usually related to undertreatment and protein deficiency [ 36 ].
Muscle weakness may or may not be observed in PhK deficiency with any genotype [ 48 , 49 ]. In a recent case series, asymptomatic left ventricular and septal hypertrophy was reported in a patient with GSD type VI, and interventricular septal hypertrophy was found in a patient with GSD type IXb.
The authors recommended echocardiogram every 1—2 years for patients with GSD type VI and IX after 5 years of age [ 44 ]. A systematic review of the literature did not reveal other individuals with GSD type VI or IX and cardiac problems [ 3 ].
Muscular involvement can be seen in the context of dyselectrolytemia in GSD type XI [ 52 ], revealed by exercise intolerance and rhabdomyolysis [ 33 ]. In these patients, hypoglycemia is often non symptomatic, as the loss of neuroglycopenic signs in recurrent hypoglycemia is notable [ 14 ].
The phenomenon, noted as hypoglycemia-associated autonomic failure, is due to a defective glucose counter-regulation with an attenuated sympathoadrenal and neural response leading to reduced neurogenic and cerebral symptoms [ 80 ].
Seizures are uncommon [ 5 ]. Mild developmental delay was also reported in GSD types VI, IX and XI [ 36 , 76 ]. With regards to GSD type IX, a recently published literature review with data analysis of patients outlined that a mild developmental delay was present in type IXc, with a frequency two times higher than other subtypes [ 4 ].
In the progressive hepatic GSD type IV the muscle tone is often normal at the time of diagnosis, but progression to generalized hypotonia may develop within the two years of life [ 20 ]. GSD type IV shows a complex involvement of neuromuscular system.
The perinatal and congenital neuromuscular subtypes show severe congenital hypotonia and respiratory distress, which impose the differential diagnosis with spinal muscular atrophy and the inherited storage disorders with neuromuscular involvement eg Pompe disease, Zellweger disease [ 19 , 20 ].
Patients affected by the childhood neuromuscular subtype show skeletal myopathy and hypotonia and may experience motor developmental delay with possible death in early adulthood [ 24 ]. Furthermore, progressive spastic paraparesis, neurogenic bladder, and axonal neuropathy have been described in the adult polyglucosan body disease [ 33 ].
This is a rare condition due to the accumulation of polyglucosan bodies into the neuronal axons and processes of astrocytes and oligodendrocytes. This process leads to a sensorimotor neuropathy, with involvement of both upper and lower motor neuron and onset around the fifth decade.
The clinical presentation is very variable, characterized by symptoms of neurogenic bladder, legs weakness, gait disturbances, spasticity, cognitive dementia with different grades of severity.
Among the neurologic signs, spasticity, reduced ankle reflexes, extensor plantar response and sensory deficits of lower extremities are seen [ 81 ]. Mild hypotonia was reported in a few GSD type VI patients [ 36 ]. Hypotonia and motor delay can be rarely associated to PHKB and PHKG2 mutations [ 48 , 51 ].
With regards to PHKA2 mutations, Lau et al. Hypotonia and motor impairment were also recorded in GSD type XI [ 1 , 3 ]. A summary of the main clinical features of the GSDs is provided in Table 1.
A careful clinical history and examination together with laboratory findings may suggest the diagnosis. An OGTT can be realized when GSD types 0, VI and IX are suspected; in all forms elevated lactate will be recorded at min. Patients with GSD type 0 will show hyperglycemia within the first two hours, then hypoglycemia might be observed at a prolonged OGTT, likely due to hyperglycemia-induced hyperinsulinemia [ 12 ].
In the past, enzymatic activity in peripheral blood cells and cultured skin fibroblasts was performed. The reduced activity of branching enzyme in leucocytes, erythrocytes and fibroblasts confirmed the diagnosis of GSD type IV, however normal activity in leukocytes could not exclude the neuromuscular forms [ 24 ].
In GSD type VI a reduced phosphorylase activity could be detected in erythrocytes and leukocytes [ 35 ]. The deficiency of phosphorylase kinase activity could be outlined in leucocytes, erythrocytes and fibroblasts, except for the forms associated to certain missense mutations of PHKA2 and PHKB [ 41 , 47 ].
In the case of normal enzymatic activity in peripheral blood cells, a liver biopsy for enzymatic assay in hepatocytes was assessed [ 47 ]. More recently, molecular analysis became the method of choice to confirm the diagnosis for each GSD type.
However, these forms may have similar clinical and biochemical presentation. Thus, performing single gene analysis would result time consuming and expensive. In the last decade, next generation sequencing technology as gene panel or clinical exome found a wide application for the diagnosis of inborn errors of metabolism for the genetic heterogeneity of these conditions, allowing to carry out large molecular characterization of patients within an useful timeframe and at a reasonable cost [ 18 ].
In these cases, histology and enzyme testing on a liver biopsy specimen may be required to confirm the diagnosis [ 37 ]. A strict dietary regimen high in proteins and low in simple carbohydrates, which includes frequent intake of complex carbohydrates such as maltodextrin and uncooked cornstarch, is fundamental to prevent hypoglycemia in ketotic GSDs [ 6 ].
Indeed, a metabolic imbalance results in overnight hypoglycemia and ketosis, that are associated to short stature, osteopenia, and neurologic complications [ 43 ].
GSDs types 0, VI and particularly type IX would benefit from a strict glycemia monitoring. A minority of patients with mutations of PHKA2 and PHKG2 associated to a severe phenotype often require overnight feeding to maintain euglycemia [ 85 ].
Since gluconeogenesis is preserved, protein supplementation provides gluconeogenic precursors that can be used for repletion of Krebs cycle intermediates and endogenous glucose production in GSD types 0, IV, VI and IX. By improving glucose homeostasis, hepatic glycogen accumulation and secondary complications might be restrained.
High protein intake is especially needed in GSD type VI to improve muscle function [ 44 ]. In Ross and co-workers [ 85 ] described the efficacy of an extended-release cornstarch Glycosade in GSD types 0, III, VI and IX to achieve a longer time of euglycemia during the night, with stable values of other markers of metabolic control and hepatic function.
In the United States, the extended-release cornstarch preparation has been approved for nocturnal use in GSD patients above 5 years of age.
However, the administration of Glycosade in patient between 2 and 5 years of age resulted safe and effective as well [ 86 ]. Adverse effects such as abdominal distension, diarrhea and flatulence have been reported, but to date they were not recorded in patients with GSD types 0, VI and IX [ 61 ].
Patients with GSD type 0 are treated with frequent feeds of hyperglucidic diet plus cornstarch and protein supplementation. Patients with GSD type IV are managed with hyperglucidic diet plus cornstarch, nocturnal enteral feeding, protein enrichment with the aim to limit the accumulation of glycogen, to prevent catabolism and to improve growth and fasting tolerance.
The more severe forms are treated with liver transplantation [ 26 ]. For GSD type XI, Pennisi and co-workers [ 63 ] proposed the nocturnal enteral nutrition in younger children and in patients with a severe growth delay in order to prevent fasting hypoglycemia.
Frequent, small meals, restricted in glucose and galactose, and raw cornstarch administration at night are used to prevent metabolic acidosis, which may occur at times of surgery or other stresses.
Hypercholesterolemia may require a medical treatment with statins after five years of age; bicarbonate supplementation may be required to balance the urinary bicarbonate loss [ 63 ]. According to the available data, universally accepted guidelines for the management of these types of GSDs have not been defined.
Nevertheless, an appropriate follow-up should be provided, in order to establish a good metabolic control and monitor the possible complications. Medical and nutritional evaluations and blood assessment, including complete liver and renal function, lipid profile, calcium-phosphate metabolism, serum electrolytes, blood gas analysis and urinalysis, should be fulfilled every 6 months on average; a higher frequency is recommended in younger patients and in those who have not achieved a metabolic balance.
A continuous glucose monitoring may be helpful to survey the glycemic fluctuations, especially in younger patients.
Alpha-fetoprotein levels along with abdomen ultrasound can be used to screen for hepatocellular carcinoma, even though there are no validated surveillance protocols to date [ 37 ].
GSD type IV patients require a complete cardiac function evaluation, including electrocardiogram and echocardiography. For patients with GSD types VI and IX after 5 years of age a cardiac evaluation is recommended every 1—2 years [ 44 ]. Regarding the bone metabolism, a careful assessment of calcium and vitamin D intake and monitoring of OH vitamin D level is recommended.
Calcium, phosphate and vitamin D supplementations, along with annual DXA scan evaluation, are required to prevent osteopenia and fractures, particularly in GSD type XI, along with a surveillance of renal function [ 61 ].
Skeletal X-Rays are required in GSD type XI to evaluate rickets evolution [ 55 , 56 ]. GSDs type 0, IV, VI, IX and XI with liver involvement may have a similar clinical presentation.
However, these diseases exhibit a phenotypic continuum, and even in the mildest forms, regular monitoring and dietary adjustments are necessary to restrain disease progression and complications.
Some cases may exhibit a clinical burden with severe organ complications. Building a proper knowledge among physicians about these rare conditions is crucial to improve prognosis and quality of life of patients, especially those affected by the most severe forms. Further studies are needed to outline the genotype—phenotype correlation and define personalized therapies and management.
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It is an inherited Livsr that affects the metabolism — the way the storave breaks food Liger into energy. After we eat, Eisease glucose is stored in the liver sforage glycogen Herbal immune support for allergies maintain normal glucose levels in our body. In GSD I, the enzyme needed to release glucose from glycogen is missing. When this occurs, a person cannot maintain his or her blood glucose levels and will develop hypoglycemia low blood sugar within a few hours after eating. The low levels of glucose in the blood of these individuals often result in chronic hunger, fatigue, and irritability. These symptoms are especially noticeable in infants.
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