NORD gratefully acknowledges Priya S. Kishnani, MD, and Mrudu Herbert, MD, Division of Medical Genetics, Department of Pediatrics, Duke University Health System, for assistance in the preparation of this report.
Glycogen storage disease type IX (GSD-IX) is a group of at least four disorders characterized by a deficiency of the enzyme phosphorylase kinase. This enzyme is necessary to break down (metabolize) a type of complex sugar known as glycogen. Normally, glycogen is metabolized into a simple sugar known as glucose. Glucose is one of the main sources of energy for the body. When there is excess glycogen, it is stored in the body, primarily in the liver and muscles and, when the body needs more energy, is eventually converted into glucose. Because individuals with GSD-IX cannot properly break down glycogen, excess amounts accumulate in the liver, muscles, or both. GSD-IX is sometimes categorized into a liver form (caused by phosphorylase kinase deficiency in the liver, or liver and muscle) and muscle form, which is rare and is caused by phosphorylase kinase deficiency in the muscle only.
Common symptoms of the liver form include abnormal enlargement of the liver (hepatomegaly), unusually low levels of blood glucose (hypoglycemia), increase in blood ketones, which are byproducts generated when the body burns fats for energy (hyperketosis) during fasting, and growth delays. The specific symptoms that develop and the overall severity of GSD-IX can vary greatly from one individual to another, even among individuals with the same subtype. The liver form of GSD-IX is inherited in either an X-linked or autosomal recessive manner and can be caused by a mutation in one of three different genes. Mutations in only one gene have been found in individuals with the muscle form. This form is rare and is inherited in an X-linked manner.
GSD-IX is part of a larger group of disorders in which the body cannot metabolize glycogen into glucose (glycogen storage diseases). The underlying cause is different for each glycogen storage disease. GSD-IX was first described in the medical literature in 1966 by Dr. Hug, et al. They reported on a young girl with phosphorylase kinase deficiency of the liver that was consistent with autosomal recessive inheritance. Later on, similar individuals were described in the medical literature whose cases were more consistent with X-linked inheritance. This second group of individuals was originally classified as having glycogen storage disease type VIII. However, the X-linked form is now classified as a subtype of GSD-IX since the disorder involves the same enzyme complex as the autosomal recessive forms. The classification of GSD-VIII is no longer used (obsolete).
GSD-IX is caused by deficiency of the enzyme phosphorylase kinase. The specific symptoms present, severity and prognosis can vary depending upon the subtype and the areas of the body affected. The symptoms and severity can vary even among individuals with the same mutation. In addition, some subtypes have only been reported in a handful of individuals, which prevents physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Individuals with the liver form of GSD-IX have a wide range of clinical symptoms ranging from less severe to more severe hepatic manifestations of the disease. Natural history studies are necessary to understand completely the long-term course and prognosis of GSD IX.
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. It accounts for approximately 75% of affected individuals and is also known as X-linked liver glycogenesis or PHKA2-related phosphorylase kinase deficiency. 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. Although hypoglycemia can be considered mild symptoms could be masked because of the body’s ability to lower levels of blood glucose than in unaffected individuals. 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 risk for two carrier parents to both pass the altered gene and, therefore, have an affected child is 25% (1 in 4) with each pregnancy. The risk to have a child who is a carrier like the parents is 50% (1 in 2) with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25% (1 in 4). 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. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. This process, called “X-inactivation”, is random. 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. Female carriers of an X-linked disorder have a 25% (1 in 4) chance with each pregnancy to have a carrier daughter like themselves, a 25% (1 in 4) chance to have a non-carrier daughter, a 25% (1 in 4) chance to have a son affected with the disease, and a 25% (1 in 4) chance to have an unaffected son. In other words, if a female carrier is pregnant with a male child, there is a 50% (1 in 2) chance that the baby will have inherited the altered gene and will have GSD IX, and if the baby is female, there is a 50% (1 in 2) chance that she will be a carrier.
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 (Xp22.13). 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 (16q12.1). 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 (16p11.2). This form of the disorder is inherited in an autosomal recessive manner.
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 (Xq13.1-13.2). This form of the disorder is inherited in an X-linked manner.
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 100,000 individuals in the general population. These disorders account for approximately 25% of all glycogen storage disorders making GSD-IX one of the most common forms of these disorders. 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.
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. Pediatricians, liver specialists (hepatologists), pediatric gastroenterologists, nutritionists, physical therapists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. 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. Follow-up of liver involvement may be done by checking liver enzyme levels such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and gamma glutaryl transferase (GGT) and abdominal ultrasound/MRI every 6-12 months or as clinically relevant.
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. (For more information on this disorder, choose “malignant hyperthermia” as your search term in the Rare Disease Database.)
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