Andersen's disease
Andersen's disease, also known as glycogen storage disease type IV (GSD IV), is a rare genetic disorder that leads to the accumulation of structurally abnormal glycogen in the body due to a deficiency in the glycogen branching enzyme (GBE). This disease presents in various forms, including hepatic, neuromuscular, and multisystem subtypes, each characterized by specific symptoms and age of onset. Unlike other glycogen storage diseases, hypoglycemia is not typically a feature of GSD IV. The condition is inherited in an autosomal recessive pattern, with a notable prevalence in individuals of Ashkenazi Jewish descent.
Patients with the classic hepatic form may experience severe liver dysfunction, often requiring liver transplantation, while those with the adult-onset neuromuscular form may face cognitive challenges and mobility issues. Diagnosis of GSD IV involves clinical evaluations and laboratory tests to assess GBE activity levels, which are critical for understanding the severity of the disease. Unfortunately, prognosis varies; while classic forms can lead to early mortality without intervention, some later-onset forms allow for a longer life with progressive disability. Supportive care and genetic counseling options are available for affected individuals and their families.
Andersen's disease
ALSO KNOWN AS: Glycogen storage disease type IV; GSD IV; brancher enzyme deficiency; glycogen branching enzyme deficiency; GBE1 deficiency; glycogenosis IV; amylopectinosis; adult polyglucosan body disease; APBD
DEFINITION Andersen’s disease, also known as glycogen storage disease type IV (GSD IV), is a clinically heterogeneous disorder resulting from the accumulation of structurally abnormal glycogen in the body. Hepatic, neuromuscular, and multisystem subtypes are characterized by the tissue(s) affected, clinical presentation, and age of onset. Hypoglycemia is not a common feature of GSD IV, as in other GSDs.
Risk Factors
Since GSD IV is inherited as an autosomal recessive trait, the parents of a child with GSD IV have a 25 percent recurrence risk for an affected child with each pregnancy. The adult-onset neuromuscular form, called adult polyglucosan body disease (APBD), is more common in individuals of Ashkenazi Jewish ancestry.
Etiology and Genetics
Glycogen storage diseases are a group of disorders characterized by the deficiency of specific enzymes involved in the formation or breakdown of glycogen. Glycogen is a complex carbohydrate that is stored in various tissues in the body and converted into glucose for energy. GSD IV is an uncommon form of GSD, accounting for only 0.3 percent of all cases. Patients with GSD IV form an abnormal glycogen molecule with fewer branch points and longer outer branches resembling amylopectin, the major storage polysaccharide in legumes (beans, peas).
An essential step in the synthesis of glycogen is the formation of branch points at regular intervals along the glycogen molecule. Normally, glycogen branching (GBE) catalyzes the transfer of at least six glucose units from the outer end of a glycogen chain to produce a branch point on the same or a neighboring chain. This branched structure of glycogen allows it to form a compact, soluble molecule in the cytoplasm.
Patients with GSD IV have decreased or absent GBE activity in one or more tissues. The particular subtype of GSD IV reflects the distribution of GBE activity and the accumulation of abnormal glycogen. Although the glycogen concentration in affected tissues is not increased, the reduced number of branch points leads to decreased solubility and aggregation of this abnormal glycogen in the cytoplasm of affected cells. Thus, decreased GBE activity and abnormal glycogen accumulation occur primarily in liver cells of patients with classic GSD IV and in nerve cells of patients with APBD. The presence of this insoluble glycogen induces a foreign-body reaction that triggers the immune system and leads to cellular injury and organ dysfunction. This immune-mediated reaction is responsible for the severe scarring (cirrhosis) of the liver seen in patients with classic GSD IV.
GSD IV results from mutations in the GBE1 gene, which encodes for the glycogen branching enzyme. The GBE1 gene is located on chromosome band 3p12. GSD IV is different from other GSDs in the spectrum of subtypes and clinical presentations (hepatic, neuromuscular, multisystem) that result from different mutations in the same gene. Correlations between (clinical presentation) and (mutation type) are not well defined. In general, subtypes with severe symptoms and earlier onset have been associated with GBE1 mutations resulting in absent or low (0 to 10 percent) levels of GBE activity. A GBE1 mutation (Tyr329Ser) is found in all APBD patients of Ashkenazi Jewish descent.
Symptoms
Hepatic subtypes of GSD IV include the classic form, characterized by progressive liver during early childhood, and a milder, nonprogressive hepatic form. Neuromuscular subtypes of GSD IV range from a perinatal form with severe hypotonia and cardiomyopathy to an adult-onset form with dementia, urinary incontinence, and walking difficulties.
Screening and Diagnosis
The diagnosis of a hepatic or neuromuscular form of GSD IV is initially based upon the constellation of abnormal clinical findings and laboratory evidence of organ dysfunction. Characteristic microscopic findings of affected tissues include PAS-positive, diastase-resistant cytoplasmic material and polyglucosan bodies by electron microscopy. Definitive diagnosis of GSD IV relies on the demonstration of decreased or absent GBE activity in affected tissues. Sequence analysis of the GBE1 gene has identified different mutations associated with the subtypes of GSD IV.
Treatment and Therapy
Patients with classic GSD IV initially require medical treatment for progressive liver dysfunction and associated complications, such as portal hypertension. Liver transplantation is the definitive treatment for these patients. Long-term success, however, is limited by complications from transplantation and the possibility of disease progression in other organs. Heart transplantation may be warranted for those with cardiomyopathy. Treatment for APBD patients includes medications and catheterization for spastic bladder, walking devices, and cognitive aids. Supportive care is necessary for patients with GSD IV subtypes with severe multisystem involvement.
Prevention and Outcomes
Classic GSD IV leads to end-stage liver failure and death in affected children by age five, unless liver transplantation is performed. The perinatal and infantile subtypes are fatal. Patients with cardiomyopathy develop progressive heart failure. Patients with later-onset neuromuscular subtypes have a better long-term prognosis, although they may have progressive disability.
Genetic counseling, prenatal diagnosis, and preimplantation genetic diagnosis (PGD) are available to affected or at-risk family members for the prevention of GSD IV.
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