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.
  
  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 hallmark 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 and 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 myopathy or muscle weakness has been reported [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.

  • Liver transaminases in GSD III are highest among all the glycogen storage diseases; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are usually over 500 U/L and often over 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. This testing is not performed clinically in the US.

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. Steatosis is less than that seen in GSD I.

Molecular Genetic Testing

Gene. AGL is the only gene known to be associated with glycogen storage disease type III.

Clinical testing

• Sequence analysis. Most AGL mutations are private and only four alleles (p.Arg864X, p.Arg1228X, c.3964delT, and c.4349-12A>G) have been found in more than 5% of unselected GSD III cases [Shaiu et al 2000]. Three mutations (p.Arg864X, p.Arg1228X, and p.Trp680X) account for approximately 28% of the known mutations in individuals of European origin [Demo et al 2007]. See Table 2.
  
  Mutations that result from a founder effect in populations include c.1222C>T (p.Arg408X) in the Faroese people [Santer et al 2001] and c.4455delT in North African Jewish individuals [Parvari et al 1997].

• Deletion/duplication analysis is available to identify mutations not detected by sequence analysis, such as exon deletion(s) or some complex rearrangements which are uncommon [Endo et al 2009].

Research testing.

• Targeted mutation analysis for mutations in exon 3 (e.g., c.17_18delAG, c.16C>T) have been associated with the GSD IIIb phenotype [Shen et al 1996].

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

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
AGL	Targeted mutation analysis	c.17_18delAG 2 and c.16C>T 2,3	100% for the targeted variants	Research only
	Sequence analysis	Sequence variants 4	~95%	Clinical
	Deletion/duplication analysis 5	Exonic or whole-gene deletions	Unknown

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

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

3. Targeted mutations detected may vary by laboratory.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

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

Testing Strategy

To 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.

• As serum concentration of CK may not always be elevated at the time of diagnostic work-up, a fasting study may be performed to differentiate between different glycogen storage diseases. In GSD III, serum concentrations of glucose do not increase following glucagon administration after a six hour fast, but can increase following glucagon administration after a two-hour fast [Wolfsdorf et al 1999].

• 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. It should be used when molecular genetic testing is not able to establish the diagnosis. (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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in AGL.

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, in GSD III both existing adenomas and hepatic cirrhosis may contribute to hepatocellular carcinoma formation [Demo et al 2007]. Although hepatic adenomas have been observed in as many as 25% of individuals with GSD III, the true prevalence is thought to be less than that in this initial report. The relationship between metabolic control and formation of lesions has not been elucidated.

Cardiomyopathy with an echocardiographic appearance of idiopathic 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.

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.

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, but 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.

There is no genotype-phenotype correlation with other AGL mutations and disease severity. 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 such as 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].

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 size of the liver and to identify adenomas if present

• Baseline echocardiogram

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.

Note: 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.

• 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].

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.

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. Additionally supplementation with vitamin D and calcium is 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.

• 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 determinations are recommended after growth is complete.

Pregnancy. Increased monitoring and support are required in pregnancy of women with GSD III as glucose needs will increase. 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.

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 which can induce hypoglycemia

Testing 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.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 available once the mutations have been identified in the family.

Biochemical genetic testing is not available.

Related Genetic Counseling Issues

See Management, Testing Relatives at Risk for information on testing 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. See for a list of laboratories offering DNA banking.

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.

Biochemical genetic testing is not available.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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6. Dagli AI, Zori RT, McCune H, Ivsic T, Maisenbacher MK, Weinstein DA. Reversal of glycogen storage disease type IIIa-related cardiomyopathy with modification of diet. J Inherit Metab Dis. 2009 [PubMed: 19322675]
7. Demo E, Frush D, Gottfried M, Koepke J, Boney A, Bali D, Chen YT, Kishnani PS. Glycogen storage disease type III-hepatocellular carcinoma a long-term complication? J Hepatol. 2007;46:492–8. [PMC free article: PMC2683272] [PubMed: 17196294]
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10. Endo Y, Horinishi A, Vorgerd M, Aoyama Y, Ebara T, Murase T, Odawara M, Podskarbi T, Shin YS, Okubo M. Molecular analysis of the AGL gene: heterogeneity of mutations in patients with glycogen storage disease type III from Germany, Canada, Afghanistan, Iran, and Turkey. J Hum Genet. 2006;51:958–63. [PubMed: 17047887]
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12. Lee PJ, Deanfield JE, Burch M, Baig K, McKenna WJ, Leonard JV. Comparison of the functional significance of left ventricular hypertrophy in hypertrophic cardiomyopathy and glycogenosis type III. Am J Cardiol. 1997;79:834–8. [PubMed: 9070576]
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15. Parvari R, Moses S, Shen J, Hershkovitz E, Lerner A, Chen YT. A single-base deletion in the 3'-coding region of glycogen-debranching enzyme is prevalent in glycogen storage disease type IIIA in a population of North African Jewish patients. Eur J Hum Genet. 1997;5:266–70. [PubMed: 9412782]
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17. Shaiu WL, Kishnani PS, Shen J, Liu HM, Chen YT. Genotype-phenotype correlation in two frequent mutations and mutation update in type III glycogen storage disease. Mol Genet Metab. 2000;69:16–23. [PubMed: 10655153]
18. Shen J, Bao Y, Liu HM, Lee P, Leonard JV, Chen YT. Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle. J Clin Invest. 1996;98:352–7. [PMC free article: PMC507437] [PubMed: 8755644]
19. Siciliano M, De Candia E, Ballarin S, Vecchio FM, Servidei S, Annese R, Landolfi R, Rossi L. Hepatocellular carcinoma complicating liver cirrhosis in type IIIa glycogen storage disease. J Clin Gastroenterol. 2000;31:80–2. [PubMed: 10914784]
20. Seigel J, Weinstein DA, Hillman R, Colbert B, Matthews B, Bachrach B. Glycogen storage disease type IIIa presenting as non-ketotic hypoglycemia: use of a newly approved commercially available mutation analysis to non-invasively confirm the diagnosis. J Pediatr Endocrinol Metab. 2008;21:587–90. [PubMed: 18717245]
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Revision History

• 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