Glycogen Storage Disease (GSD) belongs to a group of rare genetic hereditary metabolic disorders of glycogen metabolism, known as glycogen storage diseases is characterized by a triad of episodic flaccid muscle weakness (i.e., periodic paralysis); ventricular arrhythmias and prolonged QT interval; and anomalies including low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. 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. Affected children appear normal at birth but fail to thrive and later lose muscle tone, becoming lethargic. The liver and spleen become enlarged, and progressive liver failure occurs prior to death, usually before age three, caused by heart failure or bleeding from the esophagus
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 the 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 in 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.
Types
- The fatal perinatal neuromuscular type – It is the most severe form of GSD IV, with signs developing before birth. Excess fluid may build up around the fetus (polyhydramnios) and in the fetus’ body. Affected fetuses have a condition called fetal akinesia deformation sequence, which causes a decrease in fetal movement and can lead to joint stiffness (arthrogryposis) after birth. Infants with the fatal perinatal neuromuscular type of GSD IV have very low muscle tone (severe hypotonia) and muscle wasting (atrophy). These infants usually do not survive past the newborn period due to weakened heart and breathing muscles.
- The congenital muscular type of GSD IV – It is usually not evident before birth but develops in early infancy. Affected infants have severe hypotonia, which affects the muscles needed for breathing. These babies often have dilated cardiomyopathy, which enlarges and weakens the heart (cardiac) muscle, preventing the heart from pumping blood efficiently. Infants with the congenital muscular type of GSD IV typically survive only a few months.
- The progressive hepatic type – It is the most common form of GSD IV. Within the first months of life, affected infants have difficulty gaining weight and growing at the expected rate (failure to thrive) and develop an enlarged liver (hepatomegaly). Children with this type develop a form of liver disease called cirrhosis that often is irreversible. High blood pressure in the vein that supplies blood to the liver (portal hypertension) and an abnormal buildup of fluid in the abdominal cavity (ascites) can also occur. By age 1 or 2, affected children develop hypotonia. Children with the progressive hepatic type of GSD IV often die of liver failure in early childhood.
- The non-progressive hepatic type of GSD IV – has many of the same features as the progressive hepatic type, but the liver disease is not as severe. In the non-progressive hepatic type, hepatomegaly and liver disease are usually evident in early childhood, but affected individuals typically do not develop cirrhosis. People with this type of disorder can also have hypotonia and muscle weakness (myopathy). Most individuals with this type survive into adulthood, although life expectancy varies depending on the severity of the signs and symptoms.
- The childhood neuromuscular type of GSD IV – develops in late childhood and is characterized by myopathy and dilated cardiomyopathy. The severity of this type of GSD IV varies greatly; some people have only mild muscle weakness while others have severe cardiomyopathy and die in early adulthood.
Variant types
Fatal perinatal neuromuscular type
- Excess fluid builds up around and in the body of the fetus
- Fetuses exhibit fetal akinesia deformation sequence
- Causes decrease in fetal movement and stiffness of joints after birth
- Infants have low muscle tone and muscle wasting
- Do not survive past the newborn stage due to weakened heart and lungs
Congenital muscular type
- Develops in early infancy
- Babies have dilated cardiomyopathy, preventing the heart from pumping efficiently
- Only survive a few months
Progressive hepatic type
- Infants have difficulty gaining weight
- Develop enlarged liver and cirrhosis that is irreversible
- High BP in hepatic portal vein and buildup of fluid in the abdominal cavity
- Die of liver failure in early childhood
Non-progressive hepatic type
- Same as progressive, but the liver disease is not so severe
- Do not usually develop cirrhosis
- Usually, show muscle weakness and hypotonia
- Survive into adulthood
- Life expectancy varies on symptom severity
Childhood neuromuscular type
- Develops in late childhood
- Has myopathy and dilated cardiomyopathy
- Varies greatly
- Some have mild muscle weakness
- Some have severe cardiomyopathy and die in early adulthood
Symptoms
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 the approximate age of 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 the 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 the 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.
Causes
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 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 of 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.
Mutations in the GBE1 gene cause GSD IV. The GBE1 gene provides instructions for making the glycogen branching enzyme. This enzyme is involved in the production of glycogen, which is a major source of stored energy in the body. GBE1 gene mutations that cause GSD IV to lead to a shortage (deficiency) of the glycogen branching enzyme. As a result, glycogen is not formed properly. Abnormal glycogen molecules called polyglucosan bodies to accumulate in cells, leading to damage and cell death. Polyglucosan bodies accumulate in cells throughout the body, but liver cells and muscle cells are most severely affected in GSD IV. Glycogen accumulation in the liver leads to hepatomegaly and interferes with liver functioning. The inability of muscle cells to break down glycogen for energy leads to muscle weakness and wasting.
Diagnosis
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 issues. 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.
Andersen-Tawil syndrome (ATS) should be suspected in individuals with either A or B:
A. Presence of two of the following three criteria:
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Periodic paralysis
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Symptomatic cardiac arrhythmias or electrocardiographic evidence of enlarged U-waves, ventricular ectopy, or a prolonged QTc or QUc interval
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Characteristic facies, dental anomalies, small hands and feet, AND at least two of the following:
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Low-set ears
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Widely spaced eyes
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Small mandible
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Fifth-digit clinodactyly
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Syndactyly of toes 2 and 3
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B. One of the above three criteria AND at least one other family member who meets two of the three criteria [Statland et al 2018]
Individuals with either episodic weakness or cardiac symptoms require careful evaluation by a neurologist and/or cardiologist as well as measurement of serum potassium concentration (baseline and during attacks of flaccid paralysis), a 12-lead EKG, a 24-hour Holter monitor, and possibly the long exercise protocol.
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Serum potassium concentration during episodes of weakness may be elevated, normal, or, most commonly, reduced (<3.5 mmol/U) [Sansone & Tawil 2007, Statland et al 2018].
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Routine nerve conduction electrophysiology is normal between episodes. A more sensitive electrophysiologic study, the long exercise protocol, may reveal an immediate post-exercise increment followed by an abnormal decrement in the compound motor action potential amplitude (>40%) [Katz et al 1999] or area (>50%) 20-40 minutes post-exercise [Kuntzer et al 2000, Fournier et al 2004]. In a study of 11 individuals with ATS, 82% met long-exercise amplitude decrement criteria for abnormal testing [Tan et al 2011].
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Electrocardiogram may reveal characteristic abnormalities including prominent U waves, prolonged Q-U intervals, premature ventricular contractions, polymorphic ventricular tachycardia, and bidirectional ventricular tachycardia [Zhang et al 2005, Delannoy et al 2013, Koppikar et al 2015, Statland et al 2018].
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24-hour Holter monitoring is important to document the presence, frequency, and duration of ventricular tachycardia (VT) and the presence or absence of associated symptoms.
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Serial single-gene testing. Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice-site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis of KCNJ2 first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis of KCNJ2 to detect intragenic deletions or duplications. If no KCNJ2 pathogenic variant is found, perform sequence analysis of KCNJ5.
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A multigene panel. that includes KCNJ2, KCNJ5, and other genes of interest (see Differential Diagnosis and Long QT Syndrome) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting the identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note:
Treatment
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.
Initially, infants are fed soy-based, sugar-free formula on demand every 2 to 3 hours. With the increase in the infant’s sleep duration (longer than than 3 to 4 hours), it is important to avoid hypoglycemia during the overnight fast. Awakening the infant every 3 to 4 hours to monitor blood glucose and giving feeds is difficult. Therefore, it is important for the parents to be trained in inserting a nasogastric (NG) tube or a G-tube should be placed surgically. This allows the parents to administer feeds especially when the child is sick or refuses to eat.
In patients with GSD I, cornstarch has been used for the treatment of hypoglycemia as its slow digestion provides a steady release of glucose. This maintains the glucose levels for longer periods of time. In young children, 1.6 gm of cornstarch per kg body weight every 3 to 4 hours is recommended. While older children, adolescents, and adults, are given 1.7 to 2.5 gm of cornstarch per kilogram body weight.
All patients with GSD I should wear a medical alert bracelet. Along with blood glucose monitoring, a lactate meter can be a good tool to alert the parents, especially in times of emergency. Hypoglycemia should be treated immediately with a fast-acting glucose source such as cornstarch or commercially prepared glucose polymers or over-the-counter diabetic glucose tablets.
Patients with GSD Ib have an increased risk of infections at the surgical site for G-tube due to neutropenia. Therefore granulocyte colony-stimulating factor (G-CSF) is administered before placing a G-tube. The patients that receive G-CSF need a complete blood count (CBC) evaluation monthly along with the measurement of their spleen.
To avoid pump failures and occluded or disconnected tubing, bed-wetting devices that detect formula spilling onto the bed, infusion pump alarms, safety adapters, connectors, and tape for tubing is recommended as safety precautions. Limiting foods rich in lactose and sucrose such as fruits, juice, and dairy puts a child at risk for nutritional deficiency. The child should be carefully assessed, and the diet should be supplemented with adequate micronutrients.
Oral citrate or bicarbonate is used to treat patients with persistent lactic acidosis. These agents alkalinize the urine and reduce the risk of urolithiasis and nephrocalcinosis. Allopurinol reduces uric acid levels preventing recurrent attacks of gout. However, during an acute attack, Colchicine is preferred.[rx]
Hyperlipidemia has only shown a partial response to medical intervention with statins, niacin, fibrates, and fish oil along with dietary interventions such as consuming medium-chain triglyceride milk. Its resolution has been reported with liver transplantation.[rx][rx]
Starting from infancy, systemic blood pressure measurement should be checked on every office visit while serum creatinine is evaluated every 3 to 6 months to monitor renal function. Patients with persistent microalbuminuria should be treated with an angiotensin-converting enzyme (ACE) inhibitor to prevent worsening of renal function. [rx] Echocardiography is recommended every 3 years beginning after the first decade of life or earlier in the presence of symptoms to screen for pulmonary hypertension.
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 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.
Hyperuricemia is treated with allopurinol and hyperlipidemia with statins. GSD type 2 can now be treated with enzyme replacement therapy (ERT), using recombinant alglucosidase alfa which degrades lysosomal glycogen [rx]
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 a 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.
As per guidelines for the management of GSD I published by the collaborative European study[rx], the following biomedical targets are recommended:
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Preprandial blood glucose greater than 3.5 to 4.0 mmol/L (63 to 72 mg/dL)
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Urine lactate/creatinine ratio less than 0.06 mmol/mmol
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Serum uric acid concentration in high normal range for age
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Venous blood base excess greater than – 5 mmol/L and venous blood bicarbonate greater than 20 mmol/L (20 meq/L)
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Serum triglyceride concentration less than 6 mmol/L (531 mg/dL)
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Normal fecal alpha-1 anti-trypsin concentration for GSD Ib
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Body mass index (BMI) between 0.0 and +2.0 standard deviations
Genetic counseling will be of benefit to affected individuals and family members. Another treatment for this disorder is symptomatic and supportive.
References
