Forbes disease
Forbes disease, also known as Cori disease or glycogen storage disease type III, is a rare genetic disorder characterized by an inability to properly break down glycogen in the liver, muscles, and heart due to a mutation in the glycogen debranching enzyme gene. This enzyme's deficiency leads to an accumulation of glycogen, resulting in the enlargement of affected tissues and impairing their function. The disease is inherited in an autosomal recessive manner and is particularly noted in certain populations, such as North African non-Ashkenazi Jews and residents of the Faroe Islands. Symptoms often begin with liver enlargement, followed by potential muscle weakness and heart issues, with the severity and age of onset varying significantly among individuals.
Diagnosis typically involves a liver or muscle biopsy to identify abnormal glycogen structures, alongside genetic testing for known mutations. While treatment focuses on managing symptoms—such as frequent high-protein meals to maintain blood glucose levels—no therapies currently exist to directly address muscle and heart complications. Liver transplants may be necessary for those with severe liver dysfunction. Despite the potential for serious health impacts, the prognosis can be more favorable in cases limited to liver involvement, highlighting the importance of early diagnosis and management.
Forbes disease
ALSO KNOWN AS: Cori disease; glycogen storage disease Type III; GSDIII; glycogen debrancher deficiency; amylo-alpha-1,6-glucosidase deficiency; limit dextrinosis
DEFINITION Forbes disease, one of a dozen glycogen storage diseases, is a rare genetic defect that prevents the normal breakdown of glycogen in liver, muscles, and heart. Glycogen is largely unavailable for use in the body and builds up in these tissues, leading to their enlargement and impairing their function.
Risk Factors
The disease exhibits a familial association and is due to a deleterious mutation in the gene for glycogen debranching enzyme, also called amylo-alpha-1,6-glucosidase (AGL; formerly amylo-1,6-glucosidase). The condition is rare (1 in 400,000 live births), but it is frequent among non-Ashkenazi Jews in North Africa (1 in 5,400) and among inhabitants of the Faroe Islands (1 in 3,600). According to the US National Library of Medicine's Medline Plus, the incidence of the disease in the United States is 1 in 100,000 individuals. It is widely distributed geographically and ethnically; it affects boys and girls equally.
Etiology and Genetics
It is named for Gilbert B. Forbes, who first characterized it in 1953. Forbes disease is an autosomal recessive condition involving a mutation in the AGL gene, which is located on chromosome 1 in the region 1p21. Over a dozen separate mutations that lead to an inactive or unstable enzyme have been identified.
Glycogen, the storage form of carbohydrate in the body, is a highly branched polymer of glucose molecules. Glycogen phosphorylase, the enzyme that breaks down glycogen, removes glucose molecules one at a time from the end of a glycogen strand but is unable to do so at a branch point. AGL removes a strand of glucose molecules at a branch point, reattaching it to the end of a strand, and permits glycogen phosphorylase to continue working. If the debranching enzyme is lacking, then only the glucose molecules from the outermost ends can be released, leaving a glycogen structure referred to as limit dextrin. Most of the glycogen remains unavailable to the body. In addition, when more dietary glucose is available, more glucose is attached to the end of the strands and more branching is added, leading to larger and larger amounts of glycogen in the tissues, which cannot be effectively used when needed. Because glycogen is normally stored in the liver, muscles, and heart, these tissues are affected in this disease, leading to their enlargement and impairing their function.
Glycogen in the liver is used primarily between meals as a source of glucose for the body. At these times, patients with Forbes disease are not able to make full use of such glycogen and are dependent on gluconeogenesis, making glucose from noncarbohydrate sources. Over time, the buildup of glycogen may lead to cirrhosis and liver failure. Glycogen in muscles is used as a source of energy when needed for heavy exercise, and patients with Forbes disease have difficulty under that condition; they can have muscle weakness that may worsen with age. Glycogen in the heart is not an important source of energy, but excessive heart glycogen impairs its function.
Forbes disease exhibits considerable variability. Type IIIa, which accounts for approximately 85 percent of Forbes disease cases according to a 2012 report in GeneReviews, affects the liver, muscles, and heart. Type IIIb, accounting for about 15 percent of cases, involves only the liver. Some patients have no measurable AGL, whereas others may have 15 percent of normal. Some are affected shortly after birth, while others manifest the condition later in life. Some improve around puberty, but others get worse with age.
Symptoms
The first symptom is usually an enlarged liver, which may be so severe as to distend the belly. Low blood glucose after an overnight fast is sometimes seen, but is less severe than in von Gierke disease. Growth may be delayed during childhood, but adult height is usually reached. Muscle weakness is often seen and can get progressively worse. Involvement of the heart will result in an abnormal electrocardiogram.
Screening and Diagnosis
Definitive diagnosis requires a biopsy of the liver and/or muscle and the demonstration of abnormal glycogen (limit dextrin, with short outer branches) and a deficiency of AGL. The latter can also be measured in skin cells or white blood cells. DNA tests are available for many known mutations in the AGL gene; these tests are particularly effective with the Type IIIb disorder.
Treatment and Therapy
Treatment of Forbes disease is less demanding than for von Gierke disease. Any low blood glucose can be rectified by frequent high protein meals and overnight infusion of protein supplements, as these provide substrates for glucose synthesis via gluconeogenesis, while minimizing more glycogen deposition. No current treatment is available to treat the muscle and heart problems associated with this disease. Liver transplants have been performed in patients with highly compromised liver function.
Prevention and Outcomes
Prenatal diagnosis of the disease is possible, especially when a familial association has been shown. Early neonatal diagnosis is desirable to minimize preventable side effects. Type IIIb, which only involves the liver, generally has a benign prognosis. When muscles are involved, it is considered a muscular dystrophy and patients may qualify for services provided by the Muscular Dystrophy Association.
Bibliography
Badash, Michelle. "Glycogen Storage Diseases." Health Library. EBSCO, 5 May 2014. Web. 23 July 2014.
Dagli, Aditi, Christiaan P. Sentner, and David A. Weinstein. "Glycogen Storage Disease Type III." GeneReviews. Ed. Roberta A. Pagon, et al. Seattle: U of Washington, Seattle, 1993–2014. NCBI Bookshelf. Natl. Center for Biotechnology Information, 6 Sept. 2012. Web. 23 July 2014.
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"Glycogen Storage Disease Type III." US National Library of Medicine Medline Plus, 1 Dec. 2014, medlineplus.gov/genetics/condition/glycogen-storage-disease-type-iii/. Accessed 6 Sept. 2024.
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Schreuder, Andrea B., Alessandro Rossi, Sarah C. Grunert, and Terry G. J. Derks. "Glycogen Storage Disease Type III." US National Library of Medicine National Center for Biotechnology Information, 6 Jan. 2022, www.ncbi.nlm.nih.gov/books/NBK26372/. Accessed 6 Sept. 2024.
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