There are numerous forms of glycogen storage diseases, but the common end-result is inability to store glycogen in either the liver and/or muscles due to enzyme deficiencies that are transmitted by an autosomal recessive pattern of inheritance. Symptoms are diverse, but hepatosplenomegaly, failure to thrive and hypoglycemia are the most common. The diagnosis is confirmed by genetic testing, while treatment depends on the subtype.
Clinical presentation somewhat depends on the type of GSD and a broad classification into liver and muscle glycogenoses aids the physician in differentiating between various forms . Symptoms may appear at any age, but peak in childhood, adulthood and mid-adolescence. Liver disease is present in patients with type I, III, IV, VI, IX, XI, and 0, hepatomegaly being the most prominent symptom . Hypoglycemia, hyperlipidemia and growth retardation are commonly observed, but some symptoms are specific for certain subtypes, such as elevated blood lactate (type I), profound neutropenia (type Ib), ketosis (types VI and 0) and cardiomyopathy (type II). On the other hand, skeletal glycogenoses (types V, VII) are characterized by muscle cramping, fatigue, myoglobinuria during strenuous exercise and anemia. Pompe disease (type II) has a distinct clinical presentation, encompassing both muscular and hepatic manifestations, together with rapidly progressive cardiac and respiratory failure .
Entire Body System
GSD-I children, not significant), concurring with moderate muscle weakness (GSD-I adults vs. healthy matched pairs, p < 0.05). [ncbi.nlm.nih.gov]
For types II, V, and VII, the main symptom is usually weakness (myopathy). [msdmanuals.com]
[…] or fatigue during 2nd decade Fatigue: Young adults Weakness: Older adults; Legs & Trunk; Running & Sports Muscle discomfort: Cramps May present with high CK but normal strength Weakness Symmetric Respiratory failure Presenting feature in 5% to 30%: Often [neuromuscular.wustl.edu]
We report a new muscle GSD0 patient, a Japanese girl, who had been suffering from recurrent attacks of exertional syncope accompanied by muscle weakness and pain since age 5 years until she died of cardiac arrest at age 12. [ncbi.nlm.nih.gov]
Muscle cramps on exercise, pain, weakness & stiffness of muscles. No lactate is formed. Muscle may get damaged. 10. Enzyme deficiency: Liver glycogen phosphorylase. Glycogen deposited is normal in structure. Organs mainly affected liver [slideshare.net]
Reduced energy production in muscle cells leads to muscle weakness, pain, and cramping. GSD IX can have different inheritance patterns depending on the genetic cause of the condition. [ghr.nlm.nih.gov]
These episodes can result in painful cramping injuries that require medical attention. McArdle’s disease is an inherited condition, and is caused by a missing or non-functioning enzyme needed to make glucose for energy. [mcardlesdisease.org]
- Recurrent Infection
Type Ib GSD is due to a defect of a transmembrane protein which results, similar to type Ia GSD, in hypoglycemia, a markedly enlarged liver and, additionally, in neutropenia, recurrent infections, and inflammatory bowel disease. [ncbi.nlm.nih.gov]
Symptoms include enlarged spleen, gastrointestinal problems, recurrent infection, and pancreatitis. Managed by dietary restrictions. [jewishgeneticdiseases.org]
[…] adenomas, renomegaly with progressive renal insufficiency and hypertension, short stature, hypertriglyceridemia, hyperuricemia, platelet dysfunction with epistaxis, and anemia In type Ib, less severe but includes neutropenia, neutrophil dysfunction with recurrent [merckmanuals.com]
- Delayed Growth and Development
growth and development GSD V (McArdle disease) Muscle Muscle cramps or weakness during physical activity GSD VI (Hers disease) Liver Enlarged liver Episodes of low blood sugar during fasting Often no symptoms GSD VII (Tarui disease) Skeletal muscle and [msdmanuals.com]
The continued presence of low blood sugar can eventually leads to delayed growth and development as well as abnormal levels of some metabolites (substances) in the blood and urine. [web.archive.org]
The continued presence of low blood sugar can eventually lead to delayed growth and development as well as abnormal levels of some metabolites (substances) in the blood and urine. [agsdus.org]
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. [rarediseases.org]
- Congestive Heart Failure
heart failure Cardiomyopathy: Vacuolar; Cardiomegaly, Biventricular hypertrophy Glycogen: Increased in myocardium Phosphorylase kinase activity: Absent in myocardium Respiratory Failure Pulmonary edema Macroglossia : Some patients Death: 3 weeks to 5 [neuromuscular.wustl.edu]
Another case report in 1984 described a young woman with GSD III who developed symptomatic congestive heart failure during pregnancy and also had cardiac hypertrophy with glycogen deposition documented by heart biopsy. 71 Thus, cardiac involvement in [nature.com]
Although none of seven surviving female family members (14 to 46 years of age) with LAMP2 mutations had cardiac symptoms or abnormal cardiac studies, one woman (Family Member CZ I-2) died from congestive heart failure at the age of 44. [nejm.org]
- Failure to Thrive
BACKGROUND: Glycogen storage disease type VI (GSD-VI) presents with failure to thrive and also fibrosis in some cases, without cirrhosis. [ncbi.nlm.nih.gov]
[…] to thrive, hypotonia, hepatomegaly, lactic acidosis, hypoglycemia Treatment: Avoidance of fasting, uncooked cornstarch * For complete gene, molecular, and chromosomal location information, see the Online Mendelian Inheritance in Man® (OMIM®) database [merckmanuals.com]
Enlargement of heart (cardiomegaly). Nervous system is also affected. No hypoglycemia Death occurs due to heart failure. 7. Enzyme deficiency: Amylo a-1,6-glucosidase (debranching enzyme) Organs affected - Liver (Hepatomegaly), muscle, Heart [slideshare.net]
Infantile GSDII presents during the first weeks or months of life with poor feeding, failure to thrive, macroglossia, severe hypotonia, cardiomegaly, mild hepatomegaly, and respiratory insufficiency. [genedx.com]
Glycogenosis Any of a group of 12 inherited AR defects in the ability to store and/or retrieve glucose from intracellular depots, resulting in accumulation of glycogen in liver, muscle, heart, kidney, and other tissues enzyme defects, and hepatosplenomegaly, cardiomegaly [medical-dictionary.thefreedictionary.com]
[…] disease von Gierke's disease ICD-9-CM Volume 2 Index entries containing back-references to 271.0 : Aglycogenosis 271.0 Amylopectinosis (brancher enzyme deficiency) 271.0 Andersen's glycogen storage disease 271.0 Cardiomegalia glycogenica diffusa 271.0 Cardiomegaly [icd9data.com]
[…] modification Some mutations prevent protein secretion Clinical features General Several syndromes: Vary with age of onset Intrafamilial features: Homogeneous Infant onset: Multisystem; Severe Onset Age: < 6 months Hypotonia Systemic Cardiac (> 90%) Cardiomegaly [neuromuscular.wustl.edu]
- Heart Disease
The presence of premature atherosclerotic heart disease in patients with GSD III has not been reported in the literature. [ncbi.nlm.nih.gov]
A liver transplant can be proposed in severe forms without associated heart disease. Prognosis Prognosis is unfavorable for patients with perinatal onset and classic forms who do not undergo liver transplantation. [orpha.net]
Most of us will someday have conditions that are common — cancer, diabetes, heart disease — diseases with familiar symptoms as recognizable as a horse. But my 3½-year-old son, Bodhi, is a zebra. [startribune.com]
heart disease, hydrocephalus, and hearing loss. [ceaccp.oxfordjournals.org]
One proband had a family history of heart disease. None had mental retardation or overt neurologic or musculoskeletal deficits. [nejm.org]
Jaw & Teeth
Macroglossia is a feature of Pompe disease and can cause airway difficulties. [ceaccp.oxfordjournals.org]
Infantile GSDII presents during the first weeks or months of life with poor feeding, failure to thrive, macroglossia, severe hypotonia, cardiomegaly, mild hepatomegaly, and respiratory insufficiency. [genedx.com]
Glucose-6-phosphate translocase T3 GSD II (Pompe disease; 232300*) Onset: Infancy, childhood, or adulthood; residual enzyme activity in child and adult forms Clinical features: In infantile form, cardiomyopathy with heart failure, severe hypotonia, macroglossia [merckmanuals.com]
Neonatal Cardiac PR interval: Short Congestive heart failure Cardiomyopathy: Vacuolar; Cardiomegaly, Biventricular hypertrophy Glycogen: Increased in myocardium Phosphorylase kinase activity: Absent in myocardium Respiratory Failure Pulmonary edema Macroglossia [neuromuscular.wustl.edu]
Liver, Gall & Pancreas
[…] abnormal. Moderate hypoglycemia. 8. Enzyme deficiency: Glucosyl 4-6 transferase (branching enzyme) Glycogen deposited is abnormal. Glycogen with only few branches accumulate. Organs mainly affected - liver (Hepatomegaly), heart, muscle & [slideshare.net]
Disorder of glycogen breakdown and gluconeogenesis, typically presenting in infancy with hypoglycaemia, hyperlacticacidaemia, hypertriglyceridaemia, and hepatomegaly. [bestpractice.bmj.com]
GSD should be suspected in a child with unexplained hepatomegaly and investigated accordingly. [ncbi.nlm.nih.gov]
CASE REPORTS: We report four patients with confirmed GSD-II who were at first diagnosed with hypothyroid myopathy, connective tissue disorder, an underlying liver disease and muscular dystrophy, respectively. [ncbi.nlm.nih.gov]
Muscular GSDs are characterized by exercise intolerance, myopathies and/or myalgias due to muscle tissue breakdown secondary to compromised energy production. [invitae.com]
The presence of systemic complications such as growth retardation, ovarian polycystosis, diabetes mellitus and osteopenia/osteoporosis has been reported. The pathogenesis of osteopenia/osteoporosis is still unclear. [ncbi.nlm.nih.gov]
Osteoporosis may require bisphosphonates. [orpha.net]
Long-term complications include gout, hepatic adenomas, osteoporosis and renal disease. GSD1a is caused by a deficiency of the enzyme glucose-6-phosphatase (G6Pase), which has an important role in glycogen metabolism and blood glucose homeostasis. [labs.gosh.nhs.uk]
Excess of acetyl CoA resulting in increased cholesterol levels, produce xanthomas. There is a blockade in gluconeogenesis. 5. Hyperuricemia: Glucose 6-phosphate that accumulates is diverted to HMP Shunt, leading to increased synthesis of ribose [slideshare.net]
At age 18 years of age, she had marked hypertriglyceridemia (3860 mg/dL) and eruptive xanthomas and was treated with fenofibrate, atorvastatin, and fish oil. [ncbi.nlm.nih.gov]
Affected individuals may also have diarrhea and deposits of cholesterol in the skin (xanthomas). People with GSDI may experience delayed puberty. [ghr.nlm.nih.gov]
High lipid levels can lead to the formation of fatty skin growths called xanthomas. [rarediseases.org]
- Kidney Failure
Early treatment also decreases the rate of severe problems such as: Gout Kidney failure Life-threatening low blood sugar Liver tumors Possible Complications These complications can occur: Frequent infection Gout Kidney failure Liver tumors Osteoporosis [mountsinai.org]
Myoglobinuria occurs when muscle tissue breaks down abnormally and releases a protein called myoglobin, which is processed by the kidneys and released in the urine. If untreated, myoglobinuria can lead to kidney failure. [ghr.nlm.nih.gov]
In type I glycogen storage disease, kidney failure is common at age 11 to 20 years or later. [msdmanuals.com]
OMIM Number) Defective Proteins or Enzymes Comments GSD I (von Gierke disease) Most common type of GSD I: Ia (> 80%) Onset: Before 1 year Clinical features: Before 1 year, severe hypoglycemia, lactic acidosis, and hepatomegaly; later, hepatic adenomas, renomegaly [merckmanuals.com]
Making the diagnosis of GSD may be difficult, but patients with progressive liver disease and/or muscle cramping, fatigue and poor general condition without an identifiable cause, a high suspicion to one of the GSDs should be present. Initial laboratory findings may reveal elevated liver transaminases and impaired synthetic function, anemia, as well as hypoglycemia, elevated triglycerides, cholesterol, and lactate. The gold standard, however, is either biopsy or detection of reduced enzymatic activity in the target tissue, while magnetic resonance imaging (MRI) can provide important clues as well .
Hyperuricemia can reach levels that require use of xanthine oxidase inhibitors to prevent nephrolithiasis. Nephrolithiasis secondary to increased uric acid is a constant threat to patients with poorly controlled disease. [emedicine.medscape.com]
Because of the hyperuricemia, uric acid nephrolithiasis and gout nephropathy can develop. [cjasn.asnjournals.org]
Restaino I, Kaplan BS, Stanley C, Baker L (1993) Nephrolithiasis, hypercitraturia, and a distal renal tubular acidification defect in type I glycogen storage disease. J Pediatr 122: 392–396 PubMed CrossRef Google Scholar 12. [link.springer.com]
Nephrolithiasis, hypocitraturia, and a distal renal tubular acidification defect in type 1 glycogen storage disease. J Pediatr 1993; 122:392–396. 17. Cabrera-Abreu J, Crabtree NJ, Elias E, et al. [journals.lww.com]
He was incidentally found to have profound hypoglycaemia, high-anion-gap lactic acidosis, ketonuria, hyperlipidemia, hepatomegaly, growth failure and neutropenia. [ncbi.nlm.nih.gov]
Death from cardio respiratory failure by 2 yr in severe infantile form Type III (Cori disease) Autosomal recessive, 1:100 000–150 000 Liver, muscles Hypoglycaemia, ketonuria, hepatomegaly, muscle fatigue. [ceaccp.oxfordjournals.org]
Emergency labs revealed a fasting blood glucose of 276 mg/dl, but with no ketonuria and arterial blood gases were essentially normal. Her liver transaminases were mildly elevated at the time. [casesjournal.biomedcentral.com]
- Enlargement of the Liver
The symptoms of disease in the liver group are similar, ranging from symptomatic hypoglycemia and ketoacidosis to largely asymptomatic enlargement of the liver (hepatomegaly). [britannica.com]
Symptoms and signs depend upon the exact type but can include enlargement of the liver (hepatomegaly), hypoglycemia, and muscle weakness or cramps eventually accompanied by muscle wasting. [medicinenet.com]
But the inability of the liver to produce glucose results in an over-accumulation of glycogen and fat in the liver, which contributes to an enlarged and fatty liver. [sciencedaily.com]
Fasting hypoglycemia: Hypoglycemia, decreases insulin secretion, which in turn inhibits protein synthesis causes stunted growth (dwarfism). Lactic acidemia: Glucose is not synthesized from lactate produced in muscle & liver. 4. Lactate level [slideshare.net]
INTRODUCTION: Ketone formation is a normal response when hypoglycemia occurs. [ncbi.nlm.nih.gov]
[…] of galactose and fructose during the day and to prevent hypoglycemia during the night. [journals.lww.com]
There were no major complications related to neutropenia except for oral ulcers. The infants did well, except for respiratory distress in two of them at birth. [ncbi.nlm.nih.gov]
Neutropenia is characteristically seen in GSD type Ib. All content herein referring to type I GSD includes type Ia and type Ib unless stated otherwise. [bestpractice.bmj.com]
- Fasting Hypoglycemia
The management of glycemic control remains a clinical challenge, requiring management of both fasting hypoglycemia from glycogen storage disease, as well as post-prandial hyperglycemia from diabetes mellitus. [ncbi.nlm.nih.gov]
Most affected individuals exhibit resolution of hepatomegaly, hypotonia, muscle weakness, risk of fasting hypoglycemia, and abnormal biochemical parameters before or at puberty. [emedicine.medscape.com]
[…] be produced by glomerular hyperfiltration, TGF-beta expression which is induced by renin-angiotensin-aldosterone system (RAS) and uric acid, and the increase in both small dense LDL and modified LDL which is characteristic of GSD Iota(a) as well as hypertriglyceridemia [ncbi.nlm.nih.gov]
[…] into alternative pathways resulting in 3 major metabolic consequences:  Hyperlacticacidemia, which develops as a byproduct of enhanced glycolysis Hyperuricemia, which arises due to shunting of glucose-6-phosphate into the pentose phosphate pathway Hypertriglyceridemia [online.epocrates.com]
Biological findings include hypoglycemia without acidosis, hypertriglyceridemia, and hypertransaminasemia during childhood. [orpha.net]
The lipid abnormalities, which include hypercholesterolemia (decreased high-density lipoprotein [HDL] cholesterol and increased low-density lipoprotein [LDL] cholesterol), together with the characteristic hypertriglyceridemia do not cause premature atherosclerotic [emedicine.medscape.com]
Diagnostic methods Diagnosis is based on clinical presentation, and glycemia and lactacidemia levels, after a meal (hyperglycemia and hypolactacidemia), and after three to four hour fasting (hypoglycemia and hyperlactacidemia). [orpha.net]
Phenotype and clinics Patients have poor tolerance to fasting (with hypoglycemia and hyperlactacidemia after 3 to 4 hours of fasting), marked hepatomegaly, full-cheeked round face, growth retardation (small stature and delayed puberty), generally improved [atlasgeneticsoncology.org]
The enzyme defect results in severe fasting hypoglycemia, hyperlactacidemia, hyperuricemia, and hyperlipidemia. [cjasn.asnjournals.org]
Treatment principles almost strictly depend on the type of GSD:
- Management of type I depends on symptomatic therapy and dietary changes that comprise introduction of raw, uncooked cornstarch, which is profoundly effective in correcting hypoglycemia.
- Type II (Pompe disease), although being one of the most severe forms, is one of the first GSDs to be successfully treated using recombinant human enzymes . It is given every two weeks and its introduction into medical practice has significantly increased survival rates of patients with respiratory and cardiac symptoms .
- Adequate dietary management of hypoglycemia is sufficient for the majority of patients suffering from type III GSD .
- Treatment of type IV (Andersen disease) GSD relies on palliative care, since a rapidly progressive course is seen in many patients and terminal liver failure is often seen. In fact, liver transplantation is frequently necessary.
- Prevention of strenuous exercise while maintaining an adequate level of physical activity is key in managing type V GSD in order to reduce the incidence of rhabdomyolysis but preserve physiological muscle tone. Numerous substances have been tested, including creatine, sucrose, ramipril and various dietary regimens, but a significant correlation with improvement has not been established .
Management of hypoglycemia through dietary changes and additional symptoms is imperative for other GSDs, but in general, this approach is favored across all subtypes so that the metabolic needs for glycogen and energy are fulfilled.
The prognosis of patients with GSDs significantly depend on the subtype. Type Ib patients may develop recurrent infections that can be fatal due to persistent neutropenia, while Pompe disease is often fatal during childhood due to respiratory and cardiac failure  . Rapid liver failure that necessitates transplantation is seen in type IV patients, whereas a mild and relatively benign clinical course may be observed in type III and type VI . Some types (I and VI) have been associated with hepatocellular carcinoma . In all other forms, disease manifestations may range from benign and mild to severe and severely debilitating. For these reasons, it is important to identify the exact subtype in order to instate appropriate therapy and prevent further complications.
Enzyme deficiency that impairs normal glycogen degradation is the principal cause of all GSDs (except in type 0, where glycogen synthase deficiency results in impaired glycogen storage in the liver) . Enzyme deficiencies are acquired through autosomal recessive pattern of inheritance in virtually all types, but rare cases (type IX) have shown to occur as a result of X-linked transmission . For all diseases, the exact enzyme deficiencies have been identified. Glucose-6-phosphatase (type I), acid alpha-glucosidase (type II), glycogen debranching enzyme (type III), glycogen branching enzyme (type IV), glycogen phosphorylase (type V), liver phosphorylase (type IV), phosphofructokinase (type VII), liver phosphorylase kinase (type IX) GLUT2 (type XI), glycogen synthase (type 0) and several other enzyme deficiencies have been established.
Incidence and prevalence rates significantly depend on the subtype, but overall estimations suggest that 1 per 25,000 individuals develop some form of GSD . Type II (Pompe disease) is estimated to develop in 1 per 40,000 births, whereas type III occurs in approximately 1 per 5,400 births, with a significant predilection toward Sephadric Jews of North Africa  . On the other hand, some subtypes have shown to be extremely rare, like type XI and 0, as only a handful of cases described in literature  . Gender distribution is usually diverse, but in type V, a male predominance is observed .
The pathogenesis across all subtypes invariably includes inability to utilize glycogen as a source of energy due to deficiencies of enzymes that are either a part of its degradation or synthesis (type 0) . Under physiological circumstances, excess glucose ingested by food is up to a certain extent converted to glycogen by the action of glycogen synthase (enzyme deficient in type 0) and stored principally in the liver, while the skeletal muscles are also a site of its storage . Glycogen is further stored until the tissues in which it is stored reach maximal capacity (which is impaired in patients suffering from type IV GSD, as the enzyme responsible for its assembly, branching enzyme is deficient), but its conversion back to glucose in metabolic needs is an important source of fuel and provided rapid energy utilization. Various enzymes are involved in its breakdown and conversion to glucose, including debranching enzyme, liver and muscle phosphorylase kinases, acid maltase, phosphofructokinase, glucose-6-phosphatase and GLUT2 transporter . All of these enzymes are deficient in certain types of GSDs, with the common end-result being inability of the liver and muscles to degrade glycogen and provide the necessary energy for metabolic functions, which manifests in a variety of symptoms, depending on the subtype and the severity of enzyme deficiency.
Although exact enzyme deficiencies have been determined in virtually all subtypes, prevention of GSDs is currently not possible, as the triggers that are responsible for their development are unknown. Genetic counseling may be advisable for families with first-degree relatives that have GSDs, but prevention strategies should be focused on ensuring long-term management through adequate treatment.
Glycogen storage diseases (GSDs) result in impaired utilization of glycogen as a result of various enzyme deficiencies. Glycogen is converted from glucose in liver and skeletal muscles to some extent and these two organs are principally affected . Because of its role in energy production and utilization by many tissues, numerous symptoms may be encountered. Up to today, 23 GSDs have been established , and are classified into [1-15]:
- Type I, also known as Von Gierke disease, occurs either due to glucose-6-phosphatase (type Ia, seen in 90% of cases) or glucose-6-phosphatase translocase deficiency (type Ib), leading to symptoms such as growth retardation, hepatomegaly, hyperlipidemia, hypoglycemia, lactic acidemia and renal enlargement . Additionally, impaired function of neutrophils is reported in patients with type Ib and severe neutropenia may lead to recurrent and potentially severe infections, as well as mucosal ulcerations . Additional subtypes that have been included in this group include pyrophosphate translocase (type Ic) and glucose translocase deficiencies (type Id).
- Type II (Pompe disease) develops as a result of acid alpha-glucosidase deficiency, a glycogen-degrading lysosomal enzyme, for which it is often classified into the group of lysosomal storage diseases (LSDs) . Consequently, intralysosomal accumulation of glycogen occurs and causes a severe clinical presentation consisting of cardiac and respiratory failure that may be fatal within a few years after their onset .
- Type III (known as either Forbes of Cori disease) is characterized by glycogen debranching enzyme deficiency, which is essential for glycogen degradation from the liver and muscles. Type IIIa (seen in 85% of individuals) is distinguished by both hepatic and skeletal system manifestations accompanied by hypoglycemia and progressive cardiac disease, whereas type IIIb includes liver symptoms only .
- Type IV (Andersen disease) stems from glycogen branching enzyme deficiency and the clinical course is rapidly progressive and often fatal in most patients. Liver transplantation is frequently indicated, as severe hepatic disease ensues within a short period of time .
- Type V (McArdle disease) is a GSD in which the skeletal muscles are principally affected, as the enzyme that is supposed to break down glycogen, myophosphorylase (or glycogen phosphorylase), is not present, leading to cramping, myalgia, profound premature fatigue and elevations of creatine kinase (CK) . For unknown reasons, a gender predilection toward males is observed .
- Type VI (Hers disease) manifests similarly to other GSDs, including hyperlipidemia, hypoglycemia and ketosis, but it is often considered a benign form of disease. Deficiency of liver phosphorylase is the underlying cause .
- Type VII (Tarui disease) is most commonly seen in Ashkenazi Jews and the Japanese. Deficiency of phosphofructokinase is the main pathological mechanism .
- Type IX GSD, unlike all other forms, is transmitted both by autosomal recessive and X-linked patterns of inheritance. Type IX stems from deficiency of liver phosphorylase kinase. Clinically, it is almost identical to type VI, but the course of disease ranges from mild to severe and life-threatening.
- Type XI (Fanconi-Bickel syndrome) is an extremely rare GSD that develops due to impaired function of glucose transporters (GLUT2) .
- Type 0 (glycogen synthase deficiency) is distinguished from all other GSDs by absence of liver symptoms, since glycogen synthase is responsible for storage of glycogen in the liver . This GSD is even more rare than type XI and only about 20 cases have been reported in literature .
Although each type is distinguished by deficiency of different enzymes, signs and symptoms that reflect hepatic and skeletal pathology without an evident cause can rise clinical suspicion. The initial diagnosis can be made by clinical criteria, whereas confirmation can be determined by genetic testing that may reveal mutated genes that led to enzyme deficiencies. Treatment depends on the subtype . For some GSDs, moderate exercise, vitamin supplementation and appropriate dietary changes are only options. Maintenance of blood glucose through introduction of corn starch is highly effective for type III and type I, although fructose and galactose intake should be limited for type I patients. On the other hand, enzyme supplementation has been introduced to patients suffering from type II GSD and has markedly improved patient outcomes . In general, the prognosis of GSDs range from mild to severe and rapidly fatal across different subtypes , but early recognition of the disease may prevent complications such as hepatic, respiratory and cardiac failure, which will invariably prolong the patient's life.
Today, more than 20 glycogen storage diseases (GSDs) are described in literature and they all cause the same metabolic disturbance - disruption of normal glycogen storage and inability of the body to utilize this source of energy for its needs. Glycogen is synthesized when excess concentrations of glucose are introduced through food, but the body can store limited amounts of glycogen. The liver and the skeletal muscles are sites where glycogen can be stored, but in the setting of various GSDs, enzymes that are involved in its creation from glucose are deficient. Consequently, impaired glycogen conversion to glucose leads to very low glucose levels (hypoglycemia), one of the most important manifestations of this group of diseases. Enzyme deficiencies occur as a result of genetic mutations that are transferred from parent to their child through an autosomal recessive pattern of inheritance. This means that the disease is present only if both parent transfer have a defective gene copy and transfer it to their child, whereas only one transferred copy implies that the child is a carrier but does not develop any symptoms. GSDs roughly develop in approximately 1 per 25,000 individuals and gender distribution is mostly equal. Based on clinical symptoms, GSDs are roughly divided into those that involve the liver and those in whom symptoms are mostly related to skeletal muscles, but both organs may be affected across various types. Liver enlargement, increased circulating values of lipids, and decreased blood sugar are the most common manifestations of GSDs, while muscle cramping, profound fatigue and weakness are also frequently encountered. Making the diagnosis may be quite difficult, but liver or skeletal muscle symptoms together with hypoglycemia that do not have an identifiable cause should rise suspicion toward GSDs. A definite diagnosis can be made by either biopsy or genetic testing for deficient enzymes. Treatment principles depend on the subtype. Changes in dietary habits through introduction of uncooked cornstarch is a very useful method to recover from persistent low sugar levels, whereas symptomatic therapy and even use of recombinant human enzymes has been accomplished in some subtypes. Many patients, however, suffer a poor prognosis, as several subtypes can be fatal within years due to heart or liver failure, which is why early recognition of this disease is imperative in prolonging survival rates.
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