Andersen Disease (GSD IV)
NORD is very grateful to Deborah Marsden, MD, Chief of Endocrinology and Metabolism at Children's Hospital of Boston, for assistance in the preparation of this report.
Synonyms of Andersen Disease (GSD IV)
- Andersen glycogenosis
- brancher deficiency
- branching enzyme deficiency
- glycogenosis type IV
- glycogen storage disease IV
- No subdivisions found.
Andersen disease belongs to a group of rare genetic disorders of glycogen metabolism, known as glycogen storage diseases. Glycogen is a complex carbohydrate that is converted into the simple sugar glucose for the body's use as energy. Glycogen storage diseases are characterized by deficiencies of certain enzymes involved in the metabolism of glycogen, leading to an accumulation of abnormal forms or amounts of glycogen in various parts of the body, particularly the liver and muscle.
Andersen disease is also known as glycogen storage disease (GSD) type IV. It is caused by deficient activity of the glycogen-branching enzyme, resulting in accumulation of abnormal glycogen in the liver, muscle, and/or other tissues. In most affected individuals, symptoms and findings become evident in the first months of life. Such features typically include failure to grow and gain weight at the expected rate (failure to thrive) and abnormal enlargement of the liver and spleen (hepatosplenomegaly). In such cases, the disease course is typically characterized by progressive liver (hepatic) scarring (cirrhosis) and liver failure, leading to potentially life-threatening complications. In rare cases, however, progressive liver disease may not develop. In addition, several neuromuscular variants of Andersen disease have been described that may be evident at birth, in late childhood, or adulthood. The disease is inherited as an autosomal recessive trait.
Andersen disease is named for the investigator (DH Andersen) who initially described the disease in 1956.
Andersen disease is a multisystem disorder that may affect the liver, voluntary (skeletal) muscles, the heart, the nervous system, and other bodily tissues. Disease nature and course may vary in several aspects, including age at onset, associated symptoms and signs, degree of abnormal glycogen accumulation in various tissues, and specific organs affected.
However, the most common, classic form of the disease is typically characterized by progressive internal scarring (fibrosis) and destruction of liver tissue (cirrhosis), leaving areas of nonfunctioning scar tissue and gradually impaired liver function. In such cases, the disease typically becomes evident during infancy or up to about 18 months of age. Initial symptoms and signs commonly include failure to grow and gain weight at the expected rate (failure to thrive) and abnormal enlargement of the liver and spleen (hepatosplenomegaly). The cirrhosis typically progresses to cause high blood pressure in veins from the spleen and intestines to the liver (portal hypertension); abnormal fluid accumulation in the abdomen (ascites); enlargement of veins in the wall of the esophagus (esophageal varices), which may rupture, resulting in coughing up or vomiting of blood; and liver failure. In some cases, initial symptoms and findings associated with cirrhosis may include yellowish discoloration of the skin, mucous membranes, and whites of the eyes (jaundice); mental confusion; and/or other abnormalities. Rarely, liver cirrhosis associated with Andersen disease may also lead to abnormally reduced blood glucose levels (hypoglycemia). In most individuals with classic Andersen disease, progressive liver disease may lead to liver transplantation or potentially life-threatening complications by approximately age five years. However, some rare cases have also been reported in which affected individuals have nonprogressive liver disease. In some of these cases, mildly affected individuals may not have apparent symptoms (asymptomatic).
Several neuromuscular variants of Andersen disease have also been described in the medical literature. Most commonly, there may be primary or isolated muscle involvement beginning in late childhood, with disease of skeletal and/or heart muscle (myopathy and/or cardiomyopathy). Accumulation of abnormal glycogen in skeletal muscle may lead to muscle weakness and fatigue, exercise intolerance, muscle wasting (atrophy), and/or other symptoms and findings. In those with cardiomyopathy, weakening of heart muscle may lead to stretching and enlargement (dilation) of the heart's lower chambers (ventricles). Dilated cardiomyopathy may gradually lead to weakening of the heart's pumping action, causing an impaired ability to circulate enough blood to meet the body's requirements for oxygen (heart failure). Associated symptoms and findings may include fatigue; irritability; feeding difficulties; lack of appetite; failure to thrive; shortness of breath with exertion and eventually at rest; an abnormal accumulation of fluid in body tissues (edema); abnormalities of heart rhythm (arrhythmias); and potentially life-threatening complications in some cases.
A neuromuscular variant has also been reported that is evident at birth. This form may be characterized by generalized edema (hydrops), severely diminished skeletal muscle tone (hypotonia), muscle weakness and atrophy, bending or extension of multiple joints in various fixed postures (contractures), and neurologic involvement, leading to potentially life-threatening complications early in life.
In addition, a rare neuromuscular variant has also been described in adults. This form of the disease, so-called adult polyglucosan body disease, may be characterized by dysfunction of the central and peripheral nervous systems. The central nervous system (CNS) refers to the brain and spinal cord. The peripheral nerves extend from the CNS to muscles, glands, skin, sensory organs, and internal organs. Peripheral nerves include motor nerves; sensory nerves; and nerves of the autonomic nervous system, which are involved in involuntary functions, including regulating blood pressure, temperature, and heart rate. In individuals with adult polyglucosan body disease, associated symptoms and findings may include sensory loss in the legs; progressive muscle weakness of the arms and legs; walking (gait) disturbances; urination difficulties; mild cognitive impairment or dementia; and/or other abnormalities.
As noted above, Andersen disease is a disorder of glycogen metabolism. Metabolism refers to all the chemical processes in the body, including the breakdown of complex substances into simpler ones and processes in which complex substances are built up from simpler ones. Metabolic disorders result from abnormal functioning of a specific protein or enzyme that accelerates particular chemical activities in the body.
Glycogen is the major carbohydrate stored in cells of the body. It is a complex carbohydrate (polysaccharide) made up of several sugar molecules that are linked together, forming a long chain. Glycogen, which is stored primarily in the liver and muscles, is converted into the simple sugar (monosaccharide) glucose and released into the bloodstream as needed. When blood sugar levels are increased, the excess is converted into glycogen for storage. Glucose is the body's primary source of energy for cell metabolism.
Andersen disease is characterized by deficient activity of the glycogen-branching enzyme or GBE (which normally serves to increase the number of branch points during the formation of glycogen). In most cases, deficient GBE activity leads to a generalized accumulation of structurally abnormal glycogen (i.e., with long, unbranched outer chains) in various body tissues. Such tissue deposition has been demonstrated within the liver, muscle, nerve cells, heart, intestines, skin, etc. Andersen disease is sometimes called amylopectinosis since the abnormal glycogen is similar in structure to another complex carbohydrate known as amylopectin.
Various specific mutations of the GBE gene have been identified in people with Andersen disease, including individuals with the classic hepatic form, those with nonprogressive liver disease, and newborns with the severe neuromuscular form. Further research is needed to determine whether certain mutations may be associated with particular variants of the disease.
Andersen disease is inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one 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 defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% 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%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
As noted above, the classic hepatic form of Andersen disease typically becomes apparent during the first months of life. However, other forms of the disease have also been described that may be evident at birth, during late childhood, or in adulthood. Males and females appear to be affected in relatively equal numbers.
The frequency of all glycogen storage diseases is estimated to be one in approximately 20,000 to 25,000 live births. However, some investigators suggest that the true frequency may be higher, since some individuals with certain forms of glycogen storage disease may have minimal symptoms that remain undiagnosed.
Symptoms of the following disorders may be similar to those of Andersen disease. Comparisons may be useful for a differential diagnosis:
There are a number of other diseases and conditions that may be characterized by certain symptoms and signs similar to those potentially associated with Andersen disease. These include additional disorders of glycogen metabolism (i.e., glycogen storage diseases). As noted above, these diseases are due to deficiency of one or more enzymes involved in the formation or breakdown of glycogen, resulting in the accumulation of abnormal amounts or forms of glycogen within certain body tissues, particularly the liver, skeletal muscle, and/or heart muscle. Most of these diseases are inherited as an autosomal recessive trait. (For further information, please choose the exact disease name in question or "glycogen storage disease" as your search term in the Rare Disease Database.)
Andersen disease is usually diagnosed or confirmed after birth (postnatally) during infancy or childhood (or, in some cases, adulthood), based upon a thorough clinical evaluation; identification of characteristic physical findings; a complete patient and family history; and the results of various specialized tests. Removal (biopsy) and microscopic examination of small samples of certain tissues (e.g., liver, skeletal muscle, heart, skin, peripheral nerve) may demonstrate abnormal deposition of amylopectin-like materials. However, testing to confirm a diagnosis of Andersen disease requires detection of deficient GBE activity (indirect enzyme assay), such as in liver tissue, muscle, certain skin cells (cultured fibroblasts), white blood cells (leukocytes), red blood cells (erythrocytes), nerve cells, or other tissues. Reports indicate that, for individuals with adult polyglucosan body disease, peripheral nerve biopsy or evaluation of leukocytes is required for diagnosis, since deficient GBE activity is limited to such tissues. In addition, partial GBE deficiency may be detected (e.g., in erythrocytes, leukocytes, fibroblasts) in individuals who carry one copy of a mutated gene for Andersen disease (heterozygous carriers).
Diagnostic evaluation typically includes various studies to help detect and characterize certain abnormalities that may be associated with the disorder. Such testing may include various laboratory studies (e.g., complete blood count; liver function tests; blood glucose studies; etc.); specialized imaging techniques (e.g., abdominal ultrasound, CT scanning, and/or MRI); testing that records electrical activity in skeletal muscle at rest and during muscle contraction (electromyography [EMG]); studies to help assess cardiac structure and function, such as ultrasound studies of the heart (echocardiography); and/or other tests.
In some cases, a diagnosis of Andersen disease may be suggested before birth (prenatally) by specialized tests. These include studies that may detect decreased GBE activity in certain fetal cells obtained via amniocentesis or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. In addition, if available, DNA mutation analysis may be used in selected cases.
The treatment of Andersen disease is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians or internists; physicians who diagnose and treat disorders of the digestive tract; neurologists; cardiologists; dietitians; and/or other health care professionals.
Specific therapies are symptomatic and supportive and may include long-term management of cirrhosis and impaired liver function; neuromuscular disease; and/or heart dysfunction. Treatment may commonly require dietary measures to maintain normal levels of glucose in the blood (normoglycemia) and provide sufficient nutritional intake in order to improve liver function and muscular strength. For cases in which there is cardiomyopathy, recommended disease management may include the use of certain medications, such as to treat heart failure and improve cardiac output; surgical intervention; and/or other measures.
In individuals with progressive liver failure, liver transplantation has been conducted and may be effective in some cases. According to reports in the medical literature, following transplantation, some patients may develop progressive accumulation of abnormal glycogen in other organs, such as the heart, leading to potentially life-threatening complications. However, reports indicate that most patients have not had neuromuscular or heart complications (i.e., during follow-up periods of up to 13 years); in addition, in some of these patients, accumulations of glycogen in the heart and skeletal muscle have appeared to diminish following transplantation. However, experts advise that the long-term effectiveness (efficacy) of liver transplantation and its effect on other organ systems remains uncertain in those with Andersen disease. Thus, further investigation is needed to determine the long-term safety and efficacy of liver transplantation and its effect on disease progression in classic Andersen disease.
Genetic counseling will be of benefit for affected individuals and family members. Other treatment for this disorder is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about Andersen disease:
Deborah Marsden, MD
Metabolism Program, Division of Genetics
Children's Hospital Boston
300 Longwood Ave, Boston MA 02115
Organizations related to Andersen Disease (GSD IV)
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