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Glycogen Storage Disease Type III

Synonyms: Cori Disease, Debrancher Deficiency, Forbes Disease, GSDIII

, MD, , MD, and , MD, MMSc.

Author Information
, MD
Glycogen Storage Disease Program
University of Florida College of Medicine
Gainesville, Florida
, MD
Department of Metabolic Diseases
Beatrix Children's Hospital
University Medical Center Groningen
Groningen, The Netherlands
, MD, MMSc
Glycogen Storage Disease Program
University of Florida College of Medicine
Gainesville, Florida

Initial Posting: ; Last Update: September 6, 2012.

Summary

Disease characteristics. Glycogen storage disease type III (GSD III) is characterized by variable liver, cardiac muscle, and skeletal muscle involvement.

GSD IIIa, the most common subtype present in about 85% of affected individuals, manifests with liver and muscle involvement; GSD IIIb, with liver involvement only, comprises about 15% of all GSD III. In infancy and early childhood, liver involvement presents as ketotic hypoglycemia, hepatomegaly, hyperlipidemia, and elevated hepatic transaminases. In adolescence and adulthood, liver disease becomes less prominent. Hypertrophic cardiomyopathy develops in the majority of those with GSD IIIa, usually during childhood. Its clinical significance ranges from asymptomatic in the majority to severe cardiac dysfunction, congestive heart failure, and rarely sudden death. Skeletal myopathy manifesting as weakness is not usually evident in childhood, but slowly progresses, typically becoming prominent in the third to fourth decade.

Diagnosis/testing. Hepatomegaly, ketotic hypoglycemia with fasting, and elevated serum concentrations of transaminases and CK are the hallmarks of GSD III. The serum CK may not be elevated at the time of the diagnostic work-up, but the absence of lactic acidosis and markedly elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations may provide clues to the diagnosis. Measurement of fasting serum concentration of glucose after glucagon administration can be used to support the diagnosis; glucagon administration should not cause the glucose concentration to rise following a prolonged fast, but should do so after a fast of two hours or less. Molecular genetic testing of AGL, the only gene in which mutations are known to cause GSD III, allows confirmation of the diagnosis.

Management. Treatment of manifestations: A high-protein diet and frequent feeds (every three to four hours) to maintain euglycemia is the mainstay of management in infancy. Fructose and galactose can be used; special formulas are not required. Toward the end of the first year of life, one to three daily doses of 1g/kg cornstarch can be used to avoid hypoglycemia. A protein intake of 3g/kg is recommended. Liver transplantation is reserved for those with severe hepatic cirrhosis, liver dysfunction, and/or hepatocellular carcinoma. Liver transplantation may exacerbate myopathy and cardiomyopathy.

Prevention of primary manifestations: See Treatment of manifestations.

Prevention of secondary complications: Special precautions for persons undergoing surgery to avoid hypoglycemia.

Surveillance: To identify periods of suboptimal control, blood or urine ketones upon awakening and blood glucose concentrations at 2 to 4 AM should be measured at least several times per month. Annual: measurement of height and weight; liver ultrasound examinations; laboratory studies (LFTs, CK, lipid profile); and echocardiogram. A bone density determination is recommended after growth is complete.

Agents/circumstances to avoid: High simple sugar intake; steroid-based drugs; growth hormone replacement. Use with caution: hormonal contraceptives and statins for control of hyperlipidemia.

Evaluation of relatives at risk: Diagnosis of at-risk sibs at birth allows for early dietary intervention to prevent hypoglycemia.

Pregnancy management: Increased monitoring and support during pregnancy of women with GSD III because of increasing glucose needs during the course of pregnancy.

Genetic counseling. GSD III is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations have been identified in the family.

Diagnosis

Clinical Diagnosis

Glycogen storage disease type III (GSD III) is characterized by variable liver, cardiac muscle, and skeletal muscle involvement.

Four subtypes of GSD type III, based on differences in tissue expression of the deficient enzyme [Endo et al 2006], are recognized:

  • GSD IIIa (~85% of all GSD III). Liver and muscle involvement, presumably resulting from enzyme deficiency in both liver and muscle
  • GSD IIIb (~15% of all GSD III). Only liver involvement, presumably resulting from enzyme deficiency in liver only
  • GSDIIIc (extremely rare). Presumably the result of deficiency of only glucosidase debranching activity
  • GSDIIId (extremely rare). Presumably the result of deficiency of only transferase debranching activity

The cardinal features of GSD IIIa and GSD IIIb:

  • In infancy and early childhood, cardinal features are related to liver involvement: ketotic hypoglycemia, hepatomegaly, hyperlipidemia, and elevated hepatic transaminases. Hepatomegaly becomes evident early in infancy and may be the presenting feature. The liver is firm and may be markedly enlarged on clinical examination.

    In GSD IIIa cardiomyopathy usually appears during childhood, rarely as early as the first year of life; skeletal myopathy is absent or minimal.
  • In adolescence and adulthood, the liver manifestations become less prominent, possibly due to progressing hepatic fibrosis and decreased glucose demands. However, hepatic cirrhosis and adenomas are seen in a small percentage of affected individuals.
  • Hypertrophic cardiomyopathy develops in the majority of people with GSD IIIa. Its clinical significance varies as most affected individuals are asymptomatic [Lee et al 1997]; however, severe cardiac dysfunction, congestive heart failure, and (rarely) sudden death have been reported. The myopathy, presenting as weakness, progresses slowly, becoming prominent in the third to fourth decade of life [Lucchiari et al 2007].

Testing

Hepatomegaly and ketotic hypoglycemia in the setting of elevated serum concentrations of transaminases and CK are the hallmarks of GSD III.

Ketotic hypoglycemia with fasting is a prominent feature of GSD III. However, non-ketotic hypoglycemia has been reported [Seigel et al 2008]. Ketone concentrations of 0.5-1.5 mmol/L after an overnight fast can be seen in the untreated state; they resolve when hypoglycemia is prevented.

Serum concentrations of:

  • Creatine kinase (CK) is elevated once toddlers become active; however, a normal CK in the first few years of life does not exclude muscle involvement. Likewise isolated CK elevation without clinical evidence of myopathy or muscle weakness is common in the first two decades of life. [Chen 2000].
  • Triglycerides, cholesterol, and liver transaminases are elevated in the untreated state:
    • Serum concentrations of triglycerides of 200-500 mg/dL and occasionally up to 4000 mg/dL have been noted. With treatment, the triglycerides normalize, but they may also be elevated in the treated state when metabolic control is suboptimal.
    • Liver transaminases in GSD III are highest among all the glycogen storage diseases; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are usually higher than500 U/L and often higher than 1000 U/L.
  • Uric acid and lactic acid are usually normal [Chen 2000, Wolfsdorf & Weinstein 2003].

The debranching enzyme is a single polypeptide with two catalytic sites, amylo-1,6-glucosidase (EC 3.2.1.33) and 4-alpha-glucanotransferase (EC 2.4.1.25). Normal enzyme activity in the liver is 0.31 ± 0.10 units. Debranching enzyme activity can be measured in muscle and liver biopsy specimens and compared to controls.

In Europe many centers measure debranching enzyme in white blood cells as an initial screen for GSD type III. Such testing is not performed clinically in the United States.

Liver biopsy shows prominent distension of hepatocytes by glycogen; fibrous septa and periportal fibrosis are frequently present. The extent of fibrosis in GSD III is typically greater than in the other forms of GSD, and will increase during the course of the disease. Fibrosis is not a feature of GSD I, and steatosis is less than that seen in GSD I. Fibrosis can also be seen in GSD IV and less prominent fibrosis occurs in GSD IX.

Molecular Genetic Testing

Gene. AGL is the only gene in which mutations are known to cause glycogen storage disease type III.

Table 1. Summary of Molecular Genetic Testing Used in Glycogen Storage Disease Type III

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
AGLSequence analysisSequence variants 2~95% 3, 4
Deletion/duplication analysis 5Exonic or whole-gene deletionsUnknown 6

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. Most AGL mutations are private and only four alleles (p.Arg864*, p.Arg1228*, c.3964delT, and c.4349-12A>G) have been found in more than 5% of unselected persons with GSD III [Shaiu et al 2000]. Three mutations (p.Arg864*, p.Arg1228*, and p.Trp680*) account for approximately 28% of the known mutations in individuals of European origin [Demo et al 2007]. See Table 2.

4. Some mutations result from founder effects (see Molecular Genetics).

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. Exon deletion(s) or complex rearrangements [Endo et al 2009]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband

  • A triad of hepatomegaly, ketotic hypoglycemia, and elevated serum concentration of transaminases and CK is pathognomonic of GSD III.
  • Molecular genetic testing is the next step in confirming the diagnosis.

Note: (1) Although debranching enzyme activity can be measured in liver biopsy specimens, this is now not necessary for diagnosis. Genetic testing is the recommended test if GSD III is suspected. If genetic testing cannot establish a diagnosis, testing of debranching enzyme activity in leukocytes is the preferred second line test, if available. (2) Since normal serum CK concentrations do not preclude the muscle phenotype, a muscle biopsy was required in the past to assess debranching enzyme activity and glycogen content in order to distinguish the GSD IIIa phenotype from the GSD IIIb phenotype. Evolving understanding of genotype-phenotype correlations may obviate this need. See Genotype-Phenotype Correlations.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Both GSD IIIa and GSD IIIb typically present in childhood with hepatomegaly and ketotic hypoglycemia with markedly elevated liver transaminases and hypertriglyceridemia. The spectrum of presentation may include severe hypoglycemia as seen in GSD I or asymptomatic hepatomegaly.

It was previously believed that hepatomegaly and elevated transaminases improve or normalize by adolescence with or without treatment; however, it has been noted more recently that progressive liver disease occurs throughout life with the development of liver fibrosis and, in some cases, cirrhosis and hepatocellular carcinoma [Siciliano et al 2000, Cosme et al 2005, Demo et al 2007, Lucchiari et al 2007].

Elevated prothrombin time and low serum concentration of albumin are noted in those with GSD III who develop cirrhosis [Demo et al 2007]. Unlike GSD I in which hepatocellular carcinoma develops in existing adenomas, hepatic cirrhosis contributes mainly to hepatocellular carcinoma formation in GSD III [Demo et al 2007]. Although hepatic adenomas have been observed in as many as 25% of individuals with GSD III in small cohorts, the true prevalence is thought to be less. The relationship between metabolic control and formation of lesions has not been elucidated.

Cardiomyopathy with an echocardiographic appearance of hypertrophic cardiomyopathy occurs in the majority of individuals with GSD IIIa. Cardiomyopathy usually appears during childhood, but rarely has been documented in the first year of life. Its clinical significance is uncertain as most affected individuals are asymptomatic; however, severe cardiac dysfunction, congestive heart failure, and sudden death have occasionally been reported. Recently, three separate groups reported affected individuals in whom a diet high in protein and limited in carbohydrates reduced or even normalized severe cardiac hypertrophy on ultrasound and ECG [Dagli et al 2009, Valayannopoulos et al 2011, Sentner et al 2012].

Myopathy is absent or minimal in childhood and progresses slowly, becoming prominent in the third to fourth decade of life. Proximal muscles are primarily affected but involvement of distal muscles involving the calves, peroneal muscles [Lucchiari et al 2007], and hands is also seen.

Recent studies suggest that altered perfusion [Wary et al 2010] and nerve dysfunction may contribute to exercise intolerance and muscle weakness [Hobson-Webb et al 2010], respectively.

Growth may be compromised by poor metabolic control. Catch-up growth may be observed with the establishment of good metabolic control.

Osteoporosis and osteopenia have been noted in GSD III as in other glycogen storage diseases. Mundy et al [2008] suggested that the cause of the osteoporosis is probably multifactorial with muscle weakness, abnormal metabolic environment, and suboptimal nutrition playing roles in pathogenesis.

Polycystic ovary disease may be seen in GSD III; fertility does not appear to be affected [Chen 2000].

Genotype-Phenotype Correlations

There is a clear genotype-phenotype correlation with at least two mutations in exon 3 (c.17_18delAG and c.16C>T) associated with GSD IIIb. It is unclear, however, what mechanism enables individuals with mutations in exon 3 to retain debranching enzyme activity in muscle tissue. A possible explanation was proposed by Goldstein et al [2010] in which the exon 3 mutation is bypassed using a downstream start codon, thus creating a fully functioning isoform without the exon 3 mutations.

No genotype-phenotype correlations between other AGL mutations and disease severity have been reported. Heterogeneity even within a given family has been noted [Lucchiari et al 2007].

Nomenclature

Abnormal glycogen with short outer chains was first recognized by Illingworth & Cori [1952] in a patient of Dr. GB Forbes. Hence, GSD III is also known as limit dextrinosis, Cori disease, and Forbes disease.

Prevalence

GSD III is rare with an incidence of 1:100,000.

Certain populations including North African Jews from Israel (~1:5400) and the Faroese (~1:3100) show a higher than usual incidence as a result of a founder effect [Santer et al 2001].

Differential Diagnosis

Findings in GSD III that may help distinguish it from other forms of GSD include the following:

  • A history of hypoglycemia and hepatomegaly in childhood.
  • Elevated serum CK concentrations in the setting of a hepatic glycogen storage disease in a young child.
  • Remarkably elevated serum transaminases often in the 1000 range prior to commencement of treatment. No other GSD is associated with such marked elevation of AST and ALT [Chen 2000, Wolfsdorf & Weinstein 2003].

Glycogen storage disease type I. GSD III may be indistinguishable from GSD I in infancy. However, some important differences may help distinguish the two.

  • GSD III does not usually have the elevations in uric acid and lactic acid seen in GSD I.
  • In contrast to GSD I, ketotic hypoglycemia is seen in GSD III, and ketones are grossly elevated in morning urine samples of untreated individuals.
  • Hypoglycemia and hypertriglyceridemia are more severe in GSD I than in GSD III.

Glycogen storage disease type VI and type IX are caused by a deficiency of hepatic glycogen phosphorylase and phosphorylase kinase, respectively. Phosphorylase kinase is responsible for activation of hepatic glycogen phosphorylase that cleaves the terminal glucose moieties from the glycogen chain. The phenotypes of GSD VI and GSD IX are clinically indistinguishable. Affected individuals present with ketotic hypoglycemia and hepatomegaly. They do not have elevated serum concentrations of CK, and AST and ALT are usually not as high as in GSD III.

Other muscle forms of GSDs including GSD V and VII present with muscle weakness and rhabdomyolysis in adulthood.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with glycogen storage disease type III (GSD III), the following are recommended:

  • Liver ultrasound examination to determine the size of the liver and to identify adenomas if present
  • Baseline electrocardiogram and echocardiogram
  • Medical genetics consultation

Treatment of Manifestations

The mainstay of management of GSD III is a high-protein diet with cornstarch supplementation to maintain euglycemia.

In infancy, feeds every three to four hours are recommended. Unlike the diet used to treat infants with GSD I, the diet used to treat infants with GSD III can include fructose and galactose, as individuals with GSD III can utilize these sugars; special formulas are not required.

Toward the end of the first year of life, cornstarch is tolerated and can be used to avoid hypoglycemia. Initially one to three doses per day may be required with typical starting dose of 1 g/kg every six hours. The doses can be titrated based on the results of glucose and ketone monitoring.

A protein intake of 3 g/kg is recommended as gluconeogenesis is intact and protein can be used as a source of glucose. A high-protein diet prevents breakdown of endogenous muscle protein in times of glucose need and preserves skeletal and cardiac muscles.

Metabolic control can be monitored using home blood glucose and blood ketone monitoring. Elevated ketones reflect poor metabolic control as ketones are produced when glucose is unavailable and instead fatty acid oxidation is used as a source of energy. Additionally, morning urine ketone measurements can be monitored with regular urine dipsticks to give an overview of overnight metabolic control.

  • Monitoring blood ketones upon awakening at least several times per month using a portable blood ketone meter is recommended. The goal is to maintain blood beta-OH-butyrate concentrations in the normal range (<0.3 mmol/L).
  • Hypoglycemia upon awakening is uncommon in older children and adults since counter-regulation can raise blood glucose concentrations; however, monitoring blood glucose concentrations at 2 to 4 AM can reveal periods of suboptimal control.

Existing skeletal and cardiac myopathies can be improved with high-protein diet and avoidance of excessive carbohydrate intake [Slonim et al 1982, Slonim et al 1984, Dagli et al 2009, Valayannopoulos et al 2011, Sentner et al 2012].

Titration of protein and cornstarch in the diet is the primary treatment for elevated cholesterol and triglyceride concentrations, which usually result from suboptimal metabolic control.

Emergency protocol. An emergency protocol to avoid dangerous hypoglycemia should be established. An intravenous (IV) infusion of 10% dextrose with 0.5 normal saline administered at 1.5 times the maintenance rate should be given immediately on admission to the emergency room. Serum concentrations of electrolytes, glucose, and ketones should be monitored. Efforts should be made to correct ketosis as it can induce vomiting and worsen the catabolic state.

Liver transplantation. In GSD III hepatic complications are not the main cause of morbidity. Also, modern treatment strategies and good metabolic control can prevent major complications. Liver transplantation should therefore be viewed as a treatment of last resort for individuals with GSD III. A liver transplantation will prevent hypoglycemia in both subtypes; the muscular defect, however, will remain present in individuals with GSD IIIa. Liver transplantation does not cure the heart and muscle problems, and transplantation has been associated with worsening myopathy and cardiomyopathy.Therefore, liver transplantation is only indicated in affected individuals with severe hepatic cirrhosis, liver dysfunction, and/or hepatocellular carcinoma [Davis & Weinstein 2008].

Prevention of Primary Manifestations

Most of the primary manifestations of GSD III can be diminished or avoided with good metabolic (dietary) control.

When euglycemia is maintained and ketosis is avoided, hepatomegaly regresses and other abnormal laboratory values (e.g., elevated AST and ALT, increased serum concentration of triglycerides) normalize or come close to baseline [Bernier et al 2008].

Myopathy and cardiomyopathy may be partially avoided by good dietary control.

Prevention of Secondary Complications

Surgery. Persons with GSD III undergoing surgery should be admitted the night before the procedure and an IV infusion containing 10% dextrose started within two hours of the last cornstarch dose or the last meal. Glucose and ketone monitoring should continue overnight and during the procedure. IV dextrose infusion should not be stopped abruptly as dangerous hypoglycemia can occur from a hyper-insulinemic state. IV fluids need to be tapered slowly once optimal oral intake has been established and tolerated.

Osteoporosis may occur in adults with GSD III. Good metabolic control leads to improved muscle strength and decreased ketosis. Bone mineralization is adversely affected in acidic environments. In contrast, improved muscle condition and strength increase bone mineralization. Supplementation with vitamin D and calcium is also recommended to augment bone mineralization.

Surveillance

Monitoring of blood glucose concentration and blood ketones to assess control is recommended routinely and around periods of increased activity and illness:

  • Monitoring of blood ketones upon awakening at least several times per month using a portable blood ketone meter is recommended. The goal is to maintain blood beta-OH-butyrate concentrations less than 0.3 mmol/L. Alternatively, morning urine ketone measurements may be assessed with regular urine dipsticks to give an overview of overnight metabolic control.
  • Hypoglycemia is uncommon in older children and adults upon awakening since counter-regulation can raise blood glucose concentrations; however, monitoring blood glucose concentrations at 2 to 4 AM can reveal periods of suboptimal control.

The following are appropriate annually:

  • Measurement of height and weight to monitor growth
  • Liver ultrasound examination to screen for adenomas and evidence of liver scarring. MRI scans are limited to those individuals with abnormalities on the primary ultrasound screen.
  • Laboratory studies: LFTs, CK, lipid profile
  • Echocardiogram to monitor for cardiomyopathy; ECG

Bone density measurements are recommended after growth is complete.

Agents/Circumstances to Avoid

Avoid the following:

  • High sugar intake as excess sugar is stored as glycogen, which cannot be broken down
  • Steroid-based drugs as they interfere with glucose metabolism and utilization. Long-term steroid usage itself can cause muscle weakness.
  • Growth hormone replacement as it interferes with glucose metabolism, worsens ketosis, and may theoretically cause liver adenomas to grow

Use the following with caution:

  • Hormonal contraceptives in women as they can cause hepatic adenoma formation
  • Statins for control of hyperlipidemia. Use of statins requires CK monitoring because of the potential of exacerbating the muscle disease of GSD IIIa.
  • Beta blockers as they can induce hypoglycemia

Evaluation of Relatives at Risk

Diagnosis of at-risk sibs at birth allows for early dietary intervention to prevent development of hypoglycemia associated with GSD III. If the disease-causing mutations in the family are known, molecular genetic testing is the best way to determine the genetic status of an at-risk sib. If the disease-causing mutations in the family are not known, diagnosis can be established by presence of fasting ketotic hypoglycemia.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Affected mother. Increased monitoring and support are required in pregnancy of women with GSD III as glucose needs will increase. The metabolic requirements will gradually increase throughout the second and third trimesters, and close monitoring of both glucose and ketones is critical to ensure optimal metabolic control. In the third trimester and close to term, it is imperative to maintain ketones within normal levels as ketosis can precipitate uterine contractions and preterm labor. During labor and in the postnatal period, intravenous glucose supplementation must be available at all times to prevent hypoglycemic episodes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Glycogen storage disease type III is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • The offspring of an individual with glycogen storage disease type III are obligate heterozygotes (carriers) for a disease-causing mutation in AGL.
  • If the reproductive partner of an affected person is a carrier, the offspring are at 50% risk of being affected.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk family members is possible if the mutations have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association for Glycogen Storage Disease (AGSD)
    PO Box 896
    Durant IA 52747
    Phone: 563-514-4022
    Email: maryc@agsdus.org
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Glycogen Storage Disease Type III: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
AGL1p21​.2Glycogen debranching enzymeAGL homepage - Mendelian genesAGL

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Glycogen Storage Disease Type III (View All in OMIM)

232400GLYCOGEN STORAGE DISEASE III; GSD3
610860AMYLO-1,6-GLUCOSIDASE, 4-ALPHA-GLUCANOTRANSFERASE; AGL

Normal allelic variants. AGL is 85 kb in size with 34 exons (NM_000642.2). Bao et al [1997] recognized the presence of six different isoforms that differ in the 5’ end by using several cryptic splice sites upstream of the translation initiation site. This allows the inclusion or removal of exons. Isoform 1 is the generalized form present in liver, muscle, kidney, and lymphoblastoid cells. Isoforms 2, 3, and 4 are present in the muscle and heart. These isoforms are formed as a result of alternative splicing or of a difference in transcription start points. Isoform 1 contains exons 1 and 3; isoforms 2, 3, and 4 start with exon 2. Isoforms 1 through 4 all contain exon 3 which includes the normal initiation codon for protein translation. Exons 4-35 are present in isoforms [Bao et al 1996, Bao et al 1997]. The glycogen binding site is encoded by exons 31 and 32 and the active site is encoded by exons 6, 13, 14, and 15 [Elpeleg 1999].

Pathologic allelic variants. Certain populations have common mutations as a result of a founder effect. For example:

Table 2. Selected AGL Pathologic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.16C>T 2p.Gln6*NM_000642​.2
NP_000633​.2
c.17_18delAG 2p.Gln6Hisfs*20 3
(25*)
c.1222C>Tp.Arg408*
c.2039G>Ap.Trp680*
c.2590C>Tp.Arg864*
c.3682C>Tp.Arg1228*
c.3965delTp.Val1322Alafs*27 4
c.4349-12A>G 5
(IVS32-12 A>G)
--
c.4455delT 3p.Ser1486Profs*18

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Associated with the GSD IIIb phenotype [Shen et al 1996]

3. Parvari et al [1997]

4. Mutation causes a premature stop codon, translating a truncated AGL protein of 1321 wild-type amino acids plus 26 novel residues. The protein product lacks 211 amino acid residues, from exon 31, which is one of glycogen binding areas [Shaiu et al 2000].

5. Mutation creates a novel splice site, such that the 11 intronic nucleotides from the immediate 3’ end of intron 32 are adjoined to the 3’ end of exon 32 creating a frameshift [Shaiu et al 2000].

Normal gene product. Glucose molecules forming UDP glucose are added via alpha 1,4 linkages to the matrix for glycogen, called glycogenin. This process is catalyzed by glycogen synthase. When the chain reaches a certain length, “branching enzyme” cleaves off the terminal portion of the chain and attaches it via an alpha 1,6 linkage to the parent chain. This process is repeated over and over again on all the different branches of the chain and the complex glycogen molecules are created.

When digestion of a meal is complete, insulin levels fall and glucagon is secreted. In a process mediated by the enzyme glycogen phosphorylase, these hormones stimulate cleavage of glucose molecules from the terminal strands of glycogen as glucose-1-phosphate. This process continues until four glucose molecules remain before the alpha 1,6 bond. At this point, the human debranching enzyme with its two distinct catalytic activities comes into play. The 1,4-α-D-glucan 4-α-D-glycosyl transferase component transfers the terminal three glucose molecules to the parent chain and the amylo-1,6-glucosidase component cleaves the alpha 1,6 bond to release free glucose.

Abnormal gene product. With debranching enzyme deficiency, glycogen cannot be degraded and an abnormal glycogen with branched outer points called “limit dextrin” accumulates.

Except for the founder mutations described previously and some common mutations, most mutations are unique. Missense and splice site mutations, small deletions and insertions, and large intragenic deletions and insertions have been described, many of which produce truncated proteins.

The c.4455delT mutation in the North African Jewish community generates a truncated protein that is about 97% of its length. This proves that the carboxy terminus, downstream of the glycogen binding site, is essential for normal enzyme function [Parvari et al 1997].

Individuals with GSD IIIb have mutations in exon 3 of one of their AGL alleles. The nonsense mutation p.Gln6* and the frameshift deletion c.17_18delAG both generate truncated proteins with few amino acids. It is thought that alternative exon or translation initiation in muscle isoforms does not require exon 3, thus leading to normal enzyme activity in the muscles of persons with GSD IIIb who have an exon 3 deletion [Shen et al 1996, Elpeleg 1999].

References

Literature Cited

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Chapter Notes

Revision History

  • 6 September 2012 (me) Comprehensive update posted live
  • 15 March 2011 (cd) Revision: targeted mutation analysis no longer listed in the GeneTests Laboratory Directory as clinically available
  • 21 October 2010 (cd) Revision: deletion/duplication analysis available for AGL
  • 3 March 2010 (me) Review posted live
  • 5 November 2009 (daw) Original submission
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