Glycogen Storage Disease Type Iii

Clinical characteristics.

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

GSD IIIa is the most common subtype, present in about 85% of affected individuals; it 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. The diagnosis is established by identification of biallelic pathogenic variants in AGL.

Management.

Treatment of manifestations: A high-protein diet and frequent feeds (every 3-4 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 1 g/kg cornstarch can be used to avoid hypoglycemia. A protein intake of 3 g/kg is recommended. For those who cannot make it through the night on cornstarch and protein, Glycosade^® extended-release cornstarch can be used. 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 metabolic control, blood glucose should be measured between 2 AM and 4 AM or urine ketones should be measured upon awakening at least several times per month. Annual: measurement of height and weight; liver ultrasound examination; 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 and preimplantation genetic testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in the family.

Suggestive Findings

GSD III should be suspected in individuals with the following cardinal clinical features of GSD IIIa and GSD IIIb and preliminary laboratory findings.

Preliminary Laboratory Findings

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

• 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 2001].
• 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 than 500 U/L and often higher than 1000 U/L.
• Uric acid and lactic acid are usually normal [Chen 2001, Wolfsdorf & Weinstein 2003].

Establishing the Diagnosis

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

Identification of biallelic AGL pathogenic variants on molecular genetic testing is the next step in confirming the diagnosis:

• Single-gene testing is performed first (see Table 1).
• A multigene panel that includes AGL and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

If molecular genetic testing cannot establish a diagnosis, analysis of debranching enzyme activity in either liver or muscle can be considered (see Analysis of debranching enzyme activity).

Analysis of debranching enzyme activity. 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). Because liver or muscle biopsy is not required to make the diagnosis of GSD III, they are rarely performed. However, if molecular genetic testing is inconclusive, debranching enzyme activity can be measured in either liver or muscle biopsy specimens and compared to controls.

Note: (1) Analysis of debranching enzyme activity in white blood cells is not available in the United States. (2) To distinguish GSD IIIa (liver and muscle involvement; 85% of affected individuals) from GSD IIIb (liver only; 15% of affected individuals), muscle biopsy may be considered to measure debranching enzyme activity and glycogen content since normal serum CK concentrations do not preclude muscle involvement, and information on genotype-phenotype correlations is insufficient for clinical subtyping.

Clinical Description

Glycogen storage disease type III (GSD III) is characterized by variable liver, skeletal muscle, and cardiac muscle involvement. GSD IIIa (~85% of all GSD III), characterized by liver and muscle involvement, and GSD IIIb (~15% of all GSD III), characterized by only liver involvement, typically present in childhood with hepatomegaly and ketotic hypoglycemia with markedly elevated liver transaminases and hypertriglyceridemia.

Liver disease. The spectrum of presentation may include severe hypoglycemia as seen in GSD I or asymptomatic hepatomegaly. Liver disease is progressive, resulting in 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].

Liver histology shows prominent distension of hepatocytes by glycogen; fibrous septa and periportal fibrosis are frequently present. Fibrosis increases during the course of the disease, and is typically greater in GSD III than in the other forms of GSD (Differential Diagnosis).

Elevated prothrombin time and low serum concentration of albumin are noted in those with GSD III who develop cirrhosis [Demo et al 2007].

Hepatic adenomas have been observed in small cohorts in as many as 25% of individuals with GSD III. However, the true prevalence is thought to be less; more recently Sentner et al [2016] showed a prevalence of 6.9%. The relationship between metabolic control and formation of adenomas has not been elucidated.

In GSD III, hepatic cirrhosis – not adenomas − leads to hepatocellular carcinoma [Demo et al 2007]. In contrast, in GSD I hepatocellular carcinoma develops in existing adenomas.

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 (including the calves, peroneal muscles [Lucchiari et al 2007], and hands) is also seen.

Altered perfusion [Wary et al 2010] and nerve dysfunction may contribute to exercise intolerance and muscle weakness [Hobson-Webb et al 2010], respectively.

Cardiomyopathy with an echocardiographic appearance of hypertrophic cardiomyopathy occurs in the majority of individuals with GSD IIIa. Most recently cardiac involvement was reported in 58% of persons with GSD IIIa included in the worldwide type III database [Sentner et al 2016].

Cardiomyopathy usually appears during childhood; however, rarely it 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.

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. Melis et al [2016] also hypothesized a multifactorial causation due to metabolic imbalance stemming from chronic hyperlipidemia and reduced serum levels of IGF-1, insulin, and osteocalcin.

Polycystic ovary disease may be seen in GSD III; fertility does not appear to be affected [Chen 2001].

Genotype-Phenotype Correlations

There is a clear genotype-phenotype correlation with at least two pathogenic variants in exon 3 (c.17_18delAG and c.16C>T) associated with GSD IIIb. It is unclear, however, what mechanism enables individuals with pathogenic variants 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 pathogenic variant is bypassed using a downstream start codon, thus creating a fully functioning isoform without the exon 3 pathogenic variants.

No genotype-phenotype correlations between other AGL pathogenic variants 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 have high prevalence as the result of a founder effect, including:

• The Inuit population in Nunavik (Canada) (~1:2500) [Rousseau-Nepton et al 2015];
• The Faroese (~1:3100) [Santer et al 2001];
• North African Jews from Israel (~1:5400) [Parvari et al 1997].

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
• Consultation with a biochemical geneticist

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 prevent 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. For those who cannot make it through the night on cornstarch and protein, Glycosade^® extended-release cornstarch can be used [Ross et al 2015].

A high-protein diet prevents breakdown of endogenous muscle protein in times of glucose need and preserves skeletal and cardiac muscles.

Periods of suboptimal metabolic control can be identified by measuring blood glucose and blood ketone several times per month.

• Although hypoglycemia upon awakening is uncommon in older children and adults since counter-regulation can raise blood glucose concentrations, monitoring blood glucose concentrations between 2 to 4 AM can reveal periods of suboptimal control.
• 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). Additionally, morning urine ketone measurements can be monitored with regular urine dipsticks to give an overview of overnight metabolic 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. Liver transplantation will prevent hypoglycemia in both GSD IIIa and GSD IIIb; the muscular defect, however, will remain present in individuals with GSD IIIa.

Because liver transplantation does not cure the heart and muscle problems and because transplantation has been associated with worsening myopathy and cardiomyopathy, 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. New evidence suggests that skeletal muscle metabolism is impaired during exercise in GSD III. Consumption of fructose or sucrose prior to exercise may improve exercise tolerance, but does not completely prevent exercise-induced damage [Preisler et al 2015].

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 hyperinsulinemic 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

To identify periods of suboptimal metabolic control, blood glucose should be measured between 2 AM and 4 AM or urine ketones should be measured upon awakening at least several times per month.

• 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.
• 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.

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 therapy 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 AGL pathogenic variants in the family are known, molecular genetic testing is the best way to determine the genetic status of an at-risk sib.
• If the AGL pathogenic variants 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

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 in the US and EU Clinical Trials Register in Europe 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.