Glycogen Storage Disease Type IXa GSD-IXa is the most common subtype of GSD IX, and is caused by the deficiency of phosphorylase kinase in the liver. Affected individuals often develop an enlarged liver hepatomegaly , low blood glucose levels hypoglycemia and high levels of blood ketones during fasting, and growth delays.

Some children have delays in motor development. Hypoglycemia can develop after fasting overnight, after shorter periods of fasting, or if food intake is reduced during illness. Symptoms of hypoglycemia include shakiness, irritability, unexplained fatigue, headache, pale skin, and rapid heartbeat.

Hypoglycemia can result in the body burning fat for energy in which causes high levels of ketones in the body hyperketosis. Hyperketotic hypoglycemia can be associated with nausea and vomiting. Hypoglycemia can also be very severe and may recur.

Growth delays can be pronounced during childhood, but most children show catch-up growth and ultimately reach a normal adult height.

Diminished muscle tone hypotonia and muscle weakness may also be seen during early childhood. Puberty may be delayed. Increased levels of different lipids such as cholesterol hypercholesterolemia and triglycerides hypertriglyceridemia may be seen in blood of some affected individuals.

Although GSD-IXa has, historically, been considered a benign mild disorder, this notion is being currently dispelled with reports of patients with severe symptoms. It is being increasingly recognized that there is a broad range in the severity of symptoms. Some people have few or no problems with hypoglycemia while others have severe and recurrent hypoglycemia.

There have been reports in the medical literature of cases in which scar tissue has developed within the liver fibrosis and, in some children may develop irreversible scarring of the liver cirrhosis.

Glycogen Storage Disease Type IXb This subtype of the disorder is characterized by phosphorylase kinase deficiency of the liver and the muscle. It is also known as PHKB-related phosphorylase kinase deficiency. The symptoms are similar to those in people with GSD-IXa.

Children with GSD-IXb can develop an enlarged liver hepatomegaly , hypoglycemia, diminished muscle tone hypotonia , muscle weakness, and growth delays that can result in childhood short stature.

Despite the deficiency of PhK in muscle as well as liver, muscle weakness is not always reported in people with this subtype. Glycogen Storage Disease Type IXc This subtype of GSD-IX is characterized by phosphorylase kinase deficiency of the liver.

It is also known as PHKG2-related phosphorylase kinase deficiency. The symptoms are similar to those in people with GSD-IXa and GSD-IXb, but tend to be severe. Like GSD IXa and GSD-IXb, this form of the disorder is characterized by an enlarged liver, hypoglycemia, hypotonia and delays in motor development in some children, and growth delays in childhood.

Most individuals attain a normal adult height.. Some children may develop recurrent episodes of low blood glucose levels hypoglycemia. This can result in the body burning fat for energy resulting in high levels of ketones in the body hyperketosis. Hyperketotic hypoglycemia may only occur after prolonged fasting, such as overnight or during an illness if food intake is reduced, and can be associated with nausea and vomiting.

Benign tumors of the liver, also known as hepatic adenomas may be seen in some individuals. Affected individuals may present with a wide range of disease symptoms. Understanding of this disease continues to evolve as more cases come to light.

In some cases of GSD-IXc, more serious complications can occur such as the development scar tissue fibrosis within the liver as well as degeneration, inflammation and scarring of the liver cirrhosis. The risk of these complications appears to be greater in GSD-IXc than in other forms of the disorder.

Liver transplantation may be needed for survival in some patients who have severe liver damage. Glycogen Storage Disease Type IXd This extremely rare form of the disorder is characterized by phosphorylase kinase deficiency of the muscle. The liver is not affected. Affected individuals may develop progressive muscle weakness, muscle degeneration atrophy , muscle cramps, abnormal muscle pain myalgia that occurs following exercise exercise-induced muscle pain , abnormal muscle stiffness following exercise and rust colored urine due to excretion of myoglobin, a muscle protein myoglobinuria.

In general, affected individuals cannot exercise at normally accepted levels exercise intolerance. The onset of symptoms can occur in childhood or adulthood; most patients have adult onset.

Notably, some individuals with phosphorylase kinase deficiency in muscle do not have any obvious symptoms. This form is also known as PHKA1-related phosphorylase kinase deficiency.

Glycogen storage disease type IX is caused by mutations in the PHKA1 , the PHKA2 , the PHKB , or the PHKG2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation is present in a gene, the protein product may be faulty, inefficient, or absent.

Depending upon the functions of the particular protein, this can affect many organ systems of the body. For GSD-IX, these mutations can be inherited in either an autosomal recessive or X-linked manner.

Genetic diseases are determined by the combination of genes for a particular trait. Genes are packaged in the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits an altered gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms.

The chance is the same for males and females. X-linked recessive genetic disorders are conditions caused by an altered gene on the X chromosome.

In some cells of the body, one of the X chromosomes is inactivated, while in the remaining cells, the other X chromosome is inactivated.

Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder but may have symptoms if the X chromosome with the altered gene is the one that is active in a larger proportion of cells.

Females who are carriers and have symptoms of an X-linked disorder are known as manifesting heterozygotes. A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters.

The daughters will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.

Investigators have determined that glycogen storage disease type GSD-IXa is caused by mutations in the PHKA2 gene, which is located on the short arm p of the X chromosome Xp This form of the disorder is inherited in an X-linked manner.

Some individuals have a mutation in this gene that causes detectable phosphorylase kinase deficiency in laboratory tests sometimes called X-linked glycogenesis type 1 or XLG1. Other individuals have a different mutation in this gene that presumably disrupts the function of phosphorylase kinase in the body, but results in normal activity of the enzyme in laboratory tests sometimes called X-linked glycogenesis type 2 or XLG2.

Investigators have determined that glycogen storage disease type IXb is caused by mutations in the PHKB gene, which is located on the long arm q of chromosome 16 16q This form of the disorder is inherited in an autosomal recessive manner.

Investigators have determined that glycogen storage disease type IXc is caused by mutations in the PHKG2 gene, which is located on the short arm p of chromosome 16 16p Investigators have determined that glycogen storage disease type IXd is caused by mutations in the PHKA1 gene, which is located on the long arm q of the X chromosome Xq The enzyme phosphorylase kinase consists of four separate pieces called subunits.

Each of the genes associated with GSD-IX contain instructions for creating encoding one of these subunits. A mutation in one of these genes results in a deficiency of functional levels of the associated protein product. An abnormality in any of these subunits results in phosphorylase kinase deficiency, although the specific symptoms may vary.

For example, mutations in the PHKA1 gene result in a deficiency of the alpha subunit of phosphorylase kinase in muscle. This causes a deficiency of the enzyme in muscle, but not the liver. The autosomal recessive forms of glycogen storage disease IX affect males and females in equal numbers.

The X-linked forms primarily affect males, although females can have symptoms, such as enlargement of the liver and, more rarely, females can have symptoms similar to those seen in males.

GSD-IX types A, B and C are estimated to affect 1 in , individuals in the general population. Because some affected individuals go undiagnosed or misdiagnosed, it is difficult to determine the true frequency of GSD-IX in the general population.

GSD-IXd is extremely rare and its prevalence is unknown. Symptoms of the following disorders can be similar to those of glycogen storage disease type IX. Comparisons may be useful for a differential diagnosis. Hers disease, also known as glycogen storage disease type VI GSD-VI , is a rare genetic disorder characterized by deficiency of the liver glycogen phosphorylase enzyme.

This enzyme is activated by the liver enzyme, phosphorylase kinase that is deficient in GSD-IX. These disorders cannot be distinguished from associated symptoms, which are extremely similar.

Enzymatic assay or molecular genetic testing can distinguish GSD-VI from GSD-IX. GSD-VI is caused by mutations in the PYGL gene and is inherited in an autosomal recessive manner.

Other glycogen storage diseases, such as GSD-III, can have symptoms and physical findings that are similar to those seen in individuals with the liver form of GSD-IX.

In addition, certain mitochondrial myopathies and other metabolic diseases may have symptoms that are similar to the muscle form of GSD-IX. Such disorders include carnitine palmitoyltransferase II deficiency, very long chain Acyl CoA dehydrogenase VCLAD deficiency, and phosphoglycerate kinase deficiency.

For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database. Isolated cases of cardiac phosphorylase kinase deficiency, which present as heart failure in infancy, have been reported.

However it has come to light that this is primarily caused by a mutation in the PRKAG2 gene. The deficiency of phosphorylase kinase in this disorder seems to be a secondary effect Affected individuals develop disease or weakening of the heart muscle cardiomyopathy very early in life.

A diagnosis of glycogen storage disease type IX is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Clinical Testing and Workup The diagnosis of the liver form of GSD-IX is often first suspected from symptoms, such as hepatomegaly and growth delay, and abnormalities on routine laboratory tests including elevated liver transaminases, and elevations of cholesterol and triglyceride levels.

Some children may present with seizures caused by low glucose levels. However, these findings are nonspecific and more specialized enzyme and genetic tests are needed to diagnose GSD-IX.

These tests include an enzyme assay that measures the activity of phosphorylase kinase in red blood cells erythrocytes or in liver tissue. However, normal phosphorylase kinase activity does not exclude a diagnosis samples from some affected individuals have had normal activity when tested.

Individuals with symptoms of muscle PhK activity can have elevated creatine kinase level in blood but the presentation is similar to many other muscle disorders, and measurement of phosphorylase kinase activity in a muscle sample is needed to further investigate the diagnosis.

Molecular genetic testing can confirm a diagnosis of GSD-IX. Molecular genetic testing can detect mutations in specific genes known to cause GSD-IX but, like the enzyme test, is available only as a diagnostic service at specialized laboratories.

Prenatal diagnosis for at-risk pregnancies allows prior identification of risk in families with affected individuals. Evaluation of family members at risk may be done by carrier testing.

The treatment of GSD-IX is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists.

Genetic counseling may be of benefit for affected individuals and their families. There are no dietary restrictions associated with GSD-IX, although ingestion of simple sugars should be limited. A high-protein, complex carbohydrate diet is recommended.

Prolonged fasting should be avoided. Frequent, small meals that can be supplemented with uncooked cornstarch are recommended to avoid hypoglycemia. Some individuals may need to have a bedtime snack or cornstarch to prevent nighttime development of hypoglycemia.

Some individuals will only require cornstarch supplementation before bedtime. If hypoglycemia or ketosis develops, affected individuals can be treated with Polycose® glucose polymer powder or fruit juice.

Some individuals may be unable to tolerate oral therapy with Polycose® or fruit juice and may require glucose to be delivered through an IV line. If the muscles are affected, physical therapy may be recommended. Vigorous exercise should be avoided and drugs that can damage muscle tissue such as statins should be taken after consultation with a physician.

Monitoring of blood glucose and ketone levels periodically as well as during periods of stress is necessary. Prognosis is considered generally good for the X-linked and certain autosomal forms of the disease.

However, at this time, more severe presentations such as liver fibrosis and cirrhosis are being reported, even in the X-linked form. Further research is needed to completely understand long-term complications of the disease progression into adulthood.

If affected individuals require general anesthesia, precautions against malignant hyperthermia should be taken.

Malignant hyperthermia is a disorder characterized by an abnormal and potentially life-threatening response to muscle relaxants and general anesthesia drugs. 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. Diseases disrupting the neuromuscular junction can cause abnormal muscle fatigue, such as myasthenia gravis , an auto-immune disease.

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. Contents move to sidebar hide. Article Talk.

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Alternative titles; symbols. Glycogen storage disease XV AR 3 GYG1 7p13 Glycogen storage disease X AR 3 PGAM2 7q Glycogen storage disease type I, also known as von Gierke disease, typically manifests during the first year of life with severe hypoglycemia and hepatomegaly caused by the accumulation of glycogen.

Affected individuals exhibit growth retardation, delayed puberty, lactic acidemia, hyperlipidemia, hyperuricemia, and in adults a high incidence of hepatic adenomas summary by Lei et al.

Burchell et al. The patient with complete type Ia had had unexplained hepatomegaly and a bleeding diathesis since the age of 7 years and gout since age He had spider angiomas, xanthomas, gouty tophi, severe hypoglycemia, and compensated metabolic acidosis.

The diagnosis was not made until he presented with hepatocellular carcinoma. The 2 patients with partial type Ia had low or absent blood-glucose response to glucagon. Their hypoglycemic symptoms occurred with exercise, suggesting that they were unable to respond by increasing their hepatic glucose production above a certain level.

In both cases, symptoms resolved after the introduction of frequent meals high in cornstarch, a treatment proposed by Chen et al.

Of 2 sisters with type Ia GSD, both of whom had multiple hepatic adenomas, malignancy developed in 1 at the age of 20 years. AFP levels were normal throughout the entire course of this patient, whereas the younger sister had elevated levels despite the absence of malignant lesions.

Chen et al. Fourteen of the 20 older patients aged 13 to 47 years had disturbed renal function manifested by persistent proteinuria; many also had hypertension, hematuria, or altered creatinine clearance.

Progressive renal insufficiency developed in 6 of these 14 patients, leading to death from renal failure in 3. At the onset of proteinuria, creatinine clearance was increased in 7 patients.

Renal biopsies performed after an average of 10 years of proteinuria demonstrated focal segmental glomerulosclerosis. In studies of 11 patients, Restaino et al. All 9 who were tested had evidence of impaired acid excretion.

Restaino et al. Obara et al. Smit studied retrospectively 41 patients over 10 years of age from 5 different European centers. Height was below the third percentile in Hypoglycemia was still reported in 6. Hepatomegaly was present in 39 of the 40 and was marked in at least 11 of these.

Adenomas were detected in 11 of 39 patients. Blood cholesterol concentration was elevated in 31 of 38 patients; blood triglycerides were elevated in 29 of 34 patients.

Blood uric acid concentration was elevated in 19 of 35 patients, of whom 12 were being treated with allopurinol. Ullrich and Smit reviewed the clinical aspects of type I GSD as discussed in a symposium. Pancreatitis in association with hypertriglyceridemia or severe metabolic acidosis was reported in isolated cases.

No progression of hepatic adenoma after pregnancy was observed. A huge adenoma was successfully removed surgically in a female patient. The mechanism of renal hyperfiltration manifested by elevated glomerular filtration rate remained unclear.

It had been found in children below the age of 1 year. Liver adenomas are often present in GSD I Howell et al. Stevenson et al. He was relatively asymptomatic in childhood and adolescence. His growth lagged behind that of his peers and puberty was delayed to age He was active in competitive sports in high school, however, and was inducted into military service at age Ito et al.

Bianchi found 50 published cases of hepatocellular adenoma in GSD I and 10 cases of hepatocellular carcinoma.

Reitsma-Bierens pointed out that adult patients may have chronic renal disease. Gout, nephropathy, and renal stones are not the only complications; after a period of 'silent' hyperfiltration, renal damage develops with proteinuria, hypertension and renal dysfunction.

Biopsies of such patients show focal glomerulosclerosis. In a multicenter study in the United States and Canada, Talente et al. Talente et al. Pizzo and Furukawa et al. In both patients there was no evidence of portal hypertension; both patients developed pulmonary hypertension in their second decade.

Furukawa et al. Michels and Beaudet and Kikuchi et al. Ryan et al. The diagnosis had been made in childhood. At the age of 10 years, she was seen with hepatomegaly, renomegaly, anemia, fasting hypoglycemia, hyperuricemia, hypertriglyceridemia, frequent epistaxis, and prolonged bleeding time.

She was started on a regimen of frequent day feedings, which maintained adequate nutritional support for growth and development. However, puberty was delayed, with menarche at age When she was 23 years old, 2 liver masses consistent with hepatic adenomas were noted. This resulted in a reduction in total liver size but not in the size of the adenomas.

The patient's first pregnancy, at age 29, ended in an unexpected fetal death at 33 weeks 5 days of gestation.

At autopsy the fetus had no gross abnormalities that could explain the cause of death. An unrecognized hypoglycemic episode in the mother was suggested as a possibility. Two subsequent pregnancies were monitored in hospital after the thirty-third and thirty-fourth weeks, respectively.

In the second pregnancy, cesarean section was performed at 35 weeks 4 days with delivery of a girl. A repeat cesarean section at 35 weeks 2 days was performed for the third pregnancy with delivery of a boy.

Both infants were healthy and appeared to be unaffected by von Gierke disease. Hepatic adenomas did not enlarge during the pregnancies. Wang et al. In GSDIa, 68 of patients were anemic at their last follow-up.

Preadolescent patients tended to have milder anemia secondary to iron deficiency, but anemia of chronic disease predominated in adults. The anemia improved or resolved in all 10 subjects who underwent resection of liver lesions.

Severe anemia in GSDIa is likely due to hepatic adenomas, whereas anemia in GSDIb is likely due to enterocolitis. Minarich et al. In patients with GSDIb, 8 of 12 In patients with glycogen storage disease type Ia, serum triglyceride concentrations are markedly raised, whereas phospholipids and cholesterol levels are only moderately raised.

In addition, both VLDL and LDL lipoprotein fractions are raised. Despite these abnormalities, endothelial vascular dysfunction and atherosclerosis seem to be rare in such patients. Trioche et al. The distribution of each allele at the apoE locus was similar to that reported in the general population, whereas serum apoE concentrations were raised in the GSD Ia patients.

Mean apoE concentrations were They identified 5 novel mutations in the G6PC gene. The authors suggested that molecular genetic analysis is a reliable and convenient alternative to enzyme assay in fresh liver biopsy specimens for the diagnosis of GSD Ia.

Marcolongo et al. They found that G6P, glucose, and phosphate could all cross the microsomal membrane in 4 cases of GSD type Ia. In contrast, liver microsomal transport of G6P and phosphate was deficient in the GSD Ib and Ic patients, respectively. Since the results obtained with the light-scattering method were in accordance with conventional kinetic analysis of the microsomal glucosephosphatase system, Marcolongo et al.

Qu et al. Molecular analysis showed that the fetus was not affected. Emmett and Narins found no improvement with renal transplantation. However, Selby et al. In infants with low levels of pancreatic activity, the therapy was ineffective. The indexes used were urinary excretion of amino acids, phosphate, and betamicroglobulin In 14 children with GSD Ia and GSD Ib who ranged in age from 4 to 16 years, Lee et al.

The use of diazoxide in patients with GSD type Ia was first described by Rennert and Mukhopadhyay for improvement of glucose homeostasis. The treatment was abandoned because of skin rashes and later forgotten.

Unaware of this early observation, Nuoffer et al. Both showed an impressive catch-up growth. This appeared to be due to prolongation of normoglycemia after meals and reduction of fasting lactic acidosis by the drug. Nuoffer et al. The resulting hyperpolarization of membranes decreases insulin release.

The drug was given at the beginning of meals and before going to bed. Faivre et al. Renal function was normal in all patients. During the 6 to 8 years following transplantation, the quality of life was initially greatly improved, with none of the previous dietary restraints and a spectacular increase in height.

However, long-term complications included chronic hepatitis C in 1 patient, gouty attacks in another, and focal segmental glomerulosclerosis with progressive renal insufficiency in the third.

The experience was taken to indicate that liver transplantation does not prevent focal segmental glomerulosclerosis associated with GSD Ia. Weinstein et al. Urinary citrate excretion was unrelated to markers of metabolic control. Hypercalciuria occurred in 9 of 15 patients and was also inversely correlated with age.

The combination of low citrate excretion and hypercalciuria appears to be important in the pathogenesis of nephrocalcinosis and nephrolithiasis.

Wierzbicki et al. Their study demonstrated normal hepatic secretion of VLDL, but hypocatabolism of VLDL, probably due to lack of lipoprotein lipase activity. The production rate of intermediate density lipoprotein IDL was slightly increased, but the turnover rate of LDL was normal.

Rousseau-Nepton et al. They also found that sleep quality, as assessed by the Pittsburgh Sleep Quality Index PSQI questionnaire, was significantly improved, whereas no change was detected on sleep diary, actigraphy, or quality of life assessments.

Glycogen storage disease Ia is an autosomal recessive disorder Lei et al. Lei et al. Ekstein et al. In 2 patients with glycogen storage disease Ia, Lei et al. They uncovered 16 mutations that were shown by expression to abolish or greatly reduce G6Pase activity and that, therefore, were responsible for the clinical disorder.

R83C The QX mutation was identified only in Caucasians, and the X mutation was identified only in Hispanic patients.

A form of GDS Ia, designated GSD IaSP and described in 1 patient by Burchell and Waddell , was proposed to be caused by a defect in a kD stabilizing protein, SP, purified on the basis of its ability to stabilize the G6Pase catalytic unit in vitro.

The R83C mutation Kajihara et al. Chevalier-Porst et al. 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.

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Rake JP, Visser G, Labrune, et al. Guidelines for management of glycogen storage disease type I-European study on glycogen storage disease type I ESGSD I. Eur J Pediatr. Rake JP Visser G, Labrune P, et al.

Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European study on glycogen storage disease type I EGGSD I.

Eur J Pediat. Chou JY, Matern D, Mansfield, et al. Type I glycogen Storage diseases: disorders of the glucosePhosphatase complex. Signs and symptoms of this condition typically appear around the age of 3 or 4 months, when babies start to sleep through the night and do not eat as frequently as newborns.

Affected infants may have low blood sugar hypoglycemia , which can lead to seizures. They can also have a buildup of lactic acid in the body lactic acidosis , high blood levels of a waste product called uric acid hyperuricemia , and excess amounts of fats in the blood hyperlipidemia.

As they get older, children with GSDI have thin arms and legs and short stature. An enlarged liver may give the appearance of a protruding abdomen. The kidneys may also be enlarged. Affected individuals may also have diarrhea and deposits of cholesterol in the skin xanthomas.

People with GSDI may experience delayed puberty. Beginning in young to mid-adulthood, affected individuals may have thinning of the bones osteoporosis , a form of arthritis resulting from uric acid crystals in the joints gout , kidney disease, and high blood pressure in the blood vessels that supply the lungs pulmonary hypertension.

Females with this condition may also have abnormal development of the ovaries polycystic ovaries. In affected teens and adults, tumors called adenomas may form in the liver.

Adenomas are usually noncancerous benign , but occasionally these tumors can become cancerous malignant. Researchers have described two types of GSDI, which differ in their signs and symptoms and genetic cause.

These types are known as glycogen storage disease type Ia GSDIa and glycogen storage disease type Ib GSDIb. Two other forms of GSDI have been described, and they were originally named types Ic and Id.

However, these types are now known to be variations of GSDIb; for this reason, GSDIb is sometimes called GSD type I non-a. Many people with GSDIb have a shortage of white blood cells neutropenia , which can make them prone to recurrent bacterial infections.

Neutropenia is usually apparent by age 1. Many affected individuals also have inflammation of the intestinal walls inflammatory bowel disease. People with GSDIb may have oral problems including cavities, inflammation of the gums gingivitis , chronic gum periodontal disease, abnormal tooth development, and open sores ulcers in the mouth.

The neutropenia and oral problems are specific to people with GSDIb and are typically not seen in people with GSDIa. The overall incidence of GSDI is 1 in , individuals.

GSDIa is more common than GSDIb, accounting for 80 percent of all GSDI cases. Mutations in two genes, G6PC and SLC37A4 , cause GSDI. G6PC gene mutations cause GSDIa, and SLC37A4 gene mutations cause GSDIb.

The symptoms of both Pompe and Danon diseases are very similar due to a defect in lysosomes. However, in Danon disease, some show abnormal glycogen accumulation, but not all.

myogenic hyperuricemia [18]. Exercise-induced muscle cramps, stiffness, pain. Myopathy including exercise-related fatigue, exercise intolerance , muscle weakness. Muscle biopsy shows glycogen accumulation.

Second Wind phenomenon in some [32] but not all [3]. 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.

Glycogen storage diseases that involve skeletal muscle typically have exercise-induced dynamic symptoms, such as muscle fatigue , rather than fixed weakness static symptoms. Problems originating within the circulatory system, rather than the muscle itself, can produce exercise-induced muscle fatigue, pain and cramping that alleviates with rest, resulting from inadequate blood flow ischemia to the muscles.

Ischemia that often produces symptoms in the leg muscles includes intermittent claudication , popliteal artery entrapment syndrome , and chronic venous insufficiency.

Diseases disrupting the neuromuscular junction can cause abnormal muscle fatigue, such as myasthenia gravis , an auto-immune disease. 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. Contents move to sidebar hide. Article Talk. Read Edit View history. Tools Tools. What links here Related changes Upload file Special pages Permanent link Page information Cite this page Get shortened URL Download QR code Wikidata item.

Download as PDF Printable version. In other projects. Wikimedia Commons. Medical condition. Journal of Neonatal-Perinatal Medicine. doi : PMID S2CID Veterinary Pathology. New England Journal of Medicine. ISSN Retrieved 5 July Cleveland Clinic. Retrieved MedLine Plus. Association for Glycogen Storage Diseases AGSD.

October Archived from the original on 11 April Vazquez Cantu, D. Ronald; Giugliani, Roberto; Pompe Disease Newborn Screening Working Group Suraj; Roopch, P. Sreedharan; Kabeer, K. Abdulkhayar; Shaji, C. Velayudhan July Archives of Medicine and Health Sciences. OMIM — Online Medelian Inheritance in Man.

Peter A. July Genetics in Medicine. Medscape Reference. Retrieved October 24, Myogenic hyperuricemia. A common pathophysiologic feature of glycogenosis types III, V, and VII. N Engl J Med. doi: McArdle Disease. Treasure Island, Florida FL : StatPearls Publishing.

Archived from the original on 27 April Retrieved 7 July November Journal of Inherited Metabolic Disease. eMedicine Medscape Reference. Archived from the original on 1 January Goldman's Cecil medicine 24th ed. ISBN Genetics Home Reference. PMC Molecular Genetics and Metabolism.

Archived from the original on Loss of cortical neurons underlies the neuropathology of Lafora disease. Polyglucosan storage myopathies.

Mol Aspects Med. Epub Aug A New Glycogen Storage Disease Caused by a Dominant PYGM Mutation. Ann Neurol. Epub Jun 3. Neuromuscular Disorders. A case of myopathy associated with a dystrophin gene deletion and abnormal glycogen storage.

Muscle Nerve. February Pediatric Neurology. Acta Myologica. Annals of Indian Academy of Neurology. Practical Neurology. Retrieved May 24, MedLink Neurology. Biochemical Journal. April Clinical Physiology.

Journal of Thyroid Research. Living With McArdle Disease PDF. IamGSD Internation Association for Muscle Glycogen Storage Disease. Orphanet Journal of Rare Diseases. Other authors report massive parallel sequencing to have changed a diagnosis of congenital disorder of glycosylation on the discovery of mutations in the GSD-associated gene PGM1 MIM The present work returned unexpected findings for five patients.

In two patients with liver dysfunction, one carried in homozygosity the most common mutation seen in ALDOB MIM and the other carried mutations associated with LIPA. Three patients with the muscular or cardiac phenotype had mutations in CPT2 , NKX , or ANO5.

All had an atypical presentation of the disease, and the overlapping clinical and biochemical phenotypes may have led to clinical misdiagnoses. For example, LAL deficiency was ruled out by the clinicians of the patient with two mutations in LIPA given the very slight dyslipidemia seen.

Similarly, the absence of plasma acylcarnitines meant no carnitine defect was suspected in P In both cases, the presence of specific mutations, c. AlaLeu, were probably responsible for this atypical phenotype. Re-evaluation of the clinical findings in close collaboration with clinicians allowed accurate diagnoses to be made.

Patient P23, who had a congenital heart defect, had an unexpected mutation in homozygosis: the mutation p. Arg25Cys already described for NKX MIM To the best of our knowledge, p. Arg25Cys has always been detected in heterozygosity in congenital heart defects.

All the clinical cardiac hallmarks associated with this defect were present in this patient. The patient also had other clinical features described here for the first time Table 3. These are probably the result of other malfunctions of this transcriptional factor in processes other than fetal heart development.

A prompt and accurate diagnosis is important if treatment that can avoid irreversible damage is to be provided. Reaching a diagnosis, however, can be a difficult task when dealing with heterogeneous pathologies involving defects in multiple genes. Some of the diagnoses made in this work allowed new treatments to be prescribed.

Similarly, the patient with ALDOB deficiency P19 , once thought to have a form of GSD, has now been prescribed a fructose-free diet and has improved considerably. A correct genetic diagnosis is, of course, essential if proper genetic counseling is to be given, for a management plan to be designed, and for an outcome to be predicted.

In summary, the present work shows the usefulness of massive parallel sequencing in diagnosing GSD, and in differentiating it from diseases with overlapping phenotypes. It is cost-effective and time-efficient, and it could prevent patients from receiving the wrong treatment for years on end.

When required, CES can be used to broaden the number of analyzable genes beyond that used in TES, allowing the detection of mutations in non-GSD-associated genes causing symptoms that might overlap with those of clinical GSD. Ozen H.

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Application of whole exome sequencing to a rare inherited metabolic disease with neurological and gastrointestinal manifestations: a congenital disorder of glycosylation mimicking glycogen storage disease.

Clin Chim Acta ; — Download references. Ana I Vega, Celia Medrano, Celia Pérez-Cerdá and Belen Pérez: The first two authors and the last two authors contributed equally to this work.

Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras CIBERER , Madrid, Spain.

Instituto de Investigación La Paz IdiPAZ , Madrid, Spain. Unidad de Nutrición y Metabolopatías, Hospital La Fe, Valencia, Spain. You can also search for this author in PubMed Google Scholar. Correspondence to Belen Pérez PhD.

Reprints and permissions. Vega, A. et al. Molecular diagnosis of glycogen storage disease and disorders with overlapping clinical symptoms by massive parallel sequencing. Genet Med 18 , — Download citation.

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Download PDF. Subjects Genetic testing Medical genetics Metabolic disorders Next-generation sequencing. Abstract Purpose: Glycogen storage disease GSD is an umbrella term for a group of genetic disorders that involve the abnormal metabolism of glycogen; to date, 23 types of GSD have been identified.

Methods: This work reports the use of massive parallel sequencing to diagnose patients at our laboratory in Spain using either a customized gene panel targeted exome sequencing or the Illumina Clinical-Exome TruSight One Gene Panel clinical exome sequencing CES. Results: Pathogenic mutations were detected in 23 patients.

Conclusions: These results show that next-generation sequencing, in combination with the detection of biochemical and clinical hallmarks, provides an accurate, high-throughput means of making genetic diagnoses of GSD and related diseases.

Genet Med 18 10, — Clinical and genetic spectrum of glycogen storage disease in Iranian population using targeted gene sequencing Article Open access 29 March An integrated multiomic approach as an excellent tool for the diagnosis of metabolic diseases: our first patients Article Open access 25 May Successful application of genome sequencing in a diagnostic setting: index cases from a clinically heterogeneous cohort Article Open access 28 August Materials and Methods Blood samples from 47 patients suspected of having GSD were sent to the genetics laboratory at the Centro de Diagnóstico de Enfermedades Moleculares in Madrid, Spain, for genetic analysis.

Table 1 Horizontal and vertical coverage of GSD-associated genes in TruSight One and HaloPlex Custom gene panel Full size table. Results When TES was used to determine the diagnosis rate using a reduced number of genes to restrict incidental findings , three patients were detected bearing biallelic mutations in GAA P1 , AGL P2 , or PYGL P18 Table 2.

Table 2 Mutations detected by massive parallel sequencing in GSD-associated genes Full size table. Table 3 Patient clinically diagnosed as a possible GSD carrying mutations in other genes Full size table.

Discussion The present work reports the first extensive mutation spectrum for GSD in Spain. Disclosure The authors declare no conflict of interest. Similar content being viewed by others. References Ozen H. Article CAS Google Scholar Hicks J, Wartchow E, Mierau G.

Article Google Scholar Laforêt P, Weinstein DA, Smit, PA.