Cori Disease: Type 3 Glycogen Storage Disease

GeneReviews Link for Cori Disease

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Introduction to Cori Disease

Glycogen storage disease type 3 (GSD3) is also known as Cori disease, Forbes disease and limit dextrinosis. Cori disease is inherited as an autosomal recessive disorder. The symptoms associated with Cori diseaseI were first described in 1952 by Illingworth and Cori and was studies clinically by Forbes hence the associated names for this disorder. The disorder is associated with the accumulation of an abnormally structured glycogen having very short outer chains. This structure is similar to what would be seen in a phosphorylase-limit dextrin. The disorder was predicted, and later shown, to be the result of a deficiency of amylo-α-1,6-glucosidase, 4-α-glucanotransferase (AGL), also known more simply as the glycogen debrancher enzyme (GDE).

The AGL gene is located on chromosome 1p21 spanning 85 kb and is composed of 36 exons that generate six alternatively spliced mRNAs. Four of these mRNAs encode the same 1532 amino acid protein identified as AGL isoform 1. AGL isoform 2 is 1515 amino acids and AGL isoform 3 is 1516 amino acids. The AGL encoded protein has a predicted molecular mass of 173 kDa. The enzyme has two distinct catalytic activities, amylo-α-1,6-glucosidase and 4-α-glucanotransferase. The two activities encompass distinct catalytic sites on the enzyme and can function independent of each other. However, both activities, as well as the binding of glycogen, are required for complete function. AGL isoform 1 represents the major form of the enzyme and it results from mRNAs that begin transcription at exon 1 and initiate translation in exon 3. There are at least 3 muscle-specific isoforms which begin transcription at exon 2. There are two promoters for the AGL gene which direct the tissue-specific expression pattern of the various isoforms of AGL mRNA.

Reaction catalyzed by glycogen debranching enzyme

Reaction catalyzed by glycogen debranching enzyme

Clinical Features of Cori Disease

Deficiency in glycogen debranching activity causes hepatomegaly, ketotic hypoglycemia, hyperlipidemia, variable skeletal myopathy, cardiomyopathy and results in short stature. Patients with both liver and muscle involvement have GSD3a and those with only liver involvement (~15% of GSD3 patients) are classified as GSD3b. Because hepatomegaly, hypoglycemia, hyperlipidemia and growth retardation are common symptoms in both von Gierke disease (GSD1) and Cori disease (GSD3), it is difficult to initially determine from which disease an infant is suffering. Definitive diagnosis is only made by examining the structure of the glycogen in patients as well as assaying for the level of activity of the debranching enzyme. This diagnosis is best accomplished from liver and/or muscle biopsy. The hepatic symptoms of Cori disease usually resolve after puberty. However, liver failure due to cirrhosis may occur. During periods of hypoglycemia, Cori disease is treated with frequent high carbohydrate meals with cornstarch supplements. A high protein diet is also an effective treatment as this drives gluconeogenesis. There is currently no effective treatment for the progressive cardiomyopathy.












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Last modified: August 12, 2017