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 affected individuals. In infancy and early childhood, liver involvement presents as hepatomegaly and failure to thrive, with fasting ketotic hypoglycemia, hyperlipidemia, and elevated hepatic transaminases. In adolescence and adulthood, liver disease becomes less prominent. Most individuals develop cardiac involvement with cardiac hypertrophy and/or cardiomyopathy. Skeletal myopathy manifesting as weakness may be evident in childhood and slowly progresses, typically becoming prominent in the third to fourth decade. The overall prognosis is favorable but cannot be predicted on an individual basis. Long-term complications such as muscular and cardiac symptoms as well as liver fibrosis/cirrhosis and hepatocellular carcinoma may have a severe impact on prognosis and quality of life. To date, it is unknown if long-term complications can be alleviated and/or avoided by dietary interventions.

Diagnosis/testing.

The diagnosis of GSD III is established in a proband by identification of biallelic pathogenic variants in AGL. If molecular genetic testing is inconclusive, debranching enzyme activity can be measured in either blood cells (leukocytes or erythrocytes), skin fibroblasts, or liver or muscle biopsy.

Management.

Treatment of manifestations: Dietary management tailored to the individual patient remains the primary therapy. Frequent feeds (every 3-4 hours) are needed to maintain euglycemia in infancy. Toward the end of the first year of life, several doses per day (~1 g/kg) of cornstarch may be required to avoid hypoglycemia. Protein intake of 3 g/kg is recommended; extra protein supplementation may be needed. For those with night-time hypoglycemia, Glycosade^® extended-release cornstarch or continuous nocturnal drip-feeding can be used. Titration of dietary protein and cornstarch is based on self-monitored capillary blood glucose and ketone concentrations, to maintain euglycemia and to prevent ketosis, hypercholesterolemia, and hypertriglyceridemia. Maltodextrin or rapidly absorbable carbohydrates prior to exercise to prevent hypoglycemia during physical activity; oral fructose and sucrose ingestion to improve exercise tolerance. High-fat diet to reduce cardiomyopathy can be considered. Up-to-date individualized emergency letters; perioperative glucose infusion for surgeries to prevent hypoglycemia. Liver transplantation is reserved for those with severe hepatic cirrhosis, liver dysfunction, and/or hepatocellular carcinoma. Liver transplantation may exacerbate myopathy and cardiomyopathy. Vitamin D and calcium supplementation to prevent osteoporosis.

Surveillance: Aspartate aminotransferase, alanine transaminase, liver function as needed (e.g., albumin, bilirubin, ammonia, and clotting studies), creatine kinase (CK), lipid profile every six to 12 months, liver ultrasound every six to 12 months in children and every 12 to 24 months in adults, liver MRI as needed. To identify periods of suboptimal metabolic control, measured preprandial blood glucose and blood ketones or urine ketones on waking. Neurologic, physical therapy, and musculoskeletal assessments; NT-proBNP, CK-MB, electrocardiogram, and echocardiogram every 12 to 24 months in those with GSD IIIa, and every five years in those with GSD IIIb; measurement of height, weight, body mass index, head circumference, and assessment of diet and exercise as needed based on age; serum calcium and 25(OH)-vitamin D annually; regular bone density measurement is recommended.

Agents/circumstances to avoid: High carbohydrate intake, steroid-based drugs, growth hormone replacement therapy, medications that can cause rhabdomyolysis. Use with caution: hormonal contraceptives, statins for control of hyperlipidemia, and beta blockers.

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 increased glucose needs during pregnancy. Although gestational diabetes can occur, oral glucose tests are not indicated. Glucose infusion and regular monitoring of blood glucose, ketones, blood gases, and CK is necessary during labor and perinatally to prevent ketonuria and risk of hyperketosis, metabolic acidosis, and acute rhabdomyolysis. Glucose management requires balancing undertreatment against the risks assocated with overtreatment (e.g., fetal hyperinsulinemic hypoglycemia).

Genetic counseling.

GSD III is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an AGL pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected with GSD III, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial AGL pathogenic variants. Once the AGL pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal and preimplantation genetic testing for a pregnancy at increased risk are possible.

Suggestive Findings

Glycogen storage disease type III (GSD III) should be suspected in individuals with any of the following clinical and laboratory findings.

Clinical findings

• Hepatomegaly (presenting feature in ~98%, typically in infancy or early childhood)
• Failure to thrive / short stature (presenting feature in ~49%)
• Hepatic cirrhosis and hepatic adenomas (in adolescence and adulthood)
• Weakness / myopathy
• Exercise intolerance
• Hypertrophic cardiomyopathy

Laboratory findings

• Ketotic hypoglycemia or ketotic normoglycemia with fasting; elevated ketone concentrations after an overnight fast in untreated individuals
• Elevated creatine kinase (once toddlers become active)
• Hyperlipidemia, elevated serum triglycerides, and/or cholesterol postprandially initially increases and subsequently decreases, reaching lowest concentrations preprandially.
• Elevated transaminase levels
• Uric acid and lactate are usually normal [Chen 2001, Wolfsdorf & Weinstein 2003], although lactate can be increased postprandially.

Note: Blood glucose, ketones, lactate, and lipid levels are affected by diet and timing of blood draw and proximity to the last meal and/or duration of fasting.

Establishing the Diagnosis

The diagnosis of GSD III is established in a proband by identification of biallelic AGL pathogenic variants on molecular genetic testing. If molecular genetic testing cannot establish a diagnosis, analysis for debranching enzyme activity deficiency can be considered in either circulating blood cells (leukocytes or erythrocytes), cultured skin fibroblasts, or liver or muscle tissue after biopsy (see Analysis of Debranching Enzyme Activity).

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) is characterized by liver and muscle involvement, and GSD IIIb (~15% of all GSD III) is characterized by liver involvement only, 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 or asymptomatic hepatomegaly. When euglycemia is maintained and ketosis is avoided, hepatomegaly regresses and other abnormal laboratory values (e.g., elevated aspartate aminotransferase and alanine transaminase, increased serum concentration of triglycerides) normalize or come close to baseline [Bernier et al 2008]. Liver disease can be progressive, resulting in liver fibrosis; in some individuals, cirrhosis and hepatocellular carcinoma occur. It is unknown whether early optimal nutritional management can completely prevent these chronic liver complications.

Liver histology shows prominent distension of hepatocytes by glycogen; fibrous septa and periportal fibrosis are frequently present. Fibrosis increases over time and is typically greater in individuals with GSD III than in the other forms of GSD (Differential Diagnosis). The degree of liver fibrosis may be assessed by a FibroScan^® examination.

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 are reported in 6.9% of individuals [Sentner et al 2016]. It is unknown if optimized dietary treatment reduces the formation of hepatic adenomas.

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. Several individuals requiring liver transplantation due to cirrhosis and/or hepatocellular carcinoma have been reported.

Childhood myopathy can occur, and may progress 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. Foot deformities, genu valgum, kyphosis, and scoliosis have been reported [Ben Chehida et al 2019].

Altered perfusion [Wary et al 2010] with impaired dynamic muscle glycogenolytic capacity [Preisler et al 2015] and nerve dysfunction may contribute to exercise intolerance and muscle weakness [Hobson-Webb et al 2010], respectively.

Myopathy may be partially avoided, and existing skeletal myopathy can be improved with high-protein diet and avoidance of excessive carbohydrate intake [Valayannopoulos et al 2011, Sentner et al 2012, Derks & Smit 2015, Hoogeveen et al 2021].

Cardiac involvement occurs in most individuals with GSD IIIa (reported in 58% of persons with GSD IIIa included in the International Study on Glycogen Storage Disease [Sentner et al 2016]). Most individuals display electrocardiographic and/or echocardiographic signs of left ventricular hypertrophy.

Cardiomyopathy often appears during childhood; 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 [Austin et al 2012, Focardi et al 2020].

Cardiac myopathies can be improved with high-protein diet and avoidance of excessive carbohydrate intake [Valayannopoulos et al 2011, Sentner et al 2012, Derks & Smit 2015]. Possible benefit of high-fat diet on cardiomyopathy has been reported [Rossi et al 2020]. It is not known whether cardiac signs and symptoms can be avoided with optimal treatment.

Growth may be compromised by poor metabolic control. Catch-up growth is usually observed with optimized, individualized dietary management. The risk of overtreatment resulting in obesity should be considered.

Osteoporosis and osteopenia are common findings in individuals with GSD III. 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 etiology, with metabolic imbalance resulting from chronic hyperlipidemia and reduced serum levels of insulin-like growth factor 1, insulin, and osteocalcin.

Polycystic ovary disease may be seen in women with GSD III; fertility does not appear to be affected [Chen 2001, Sentner et al 2016].

Type 2 diabetes mellitus may occur in individuals with GSD III [Sentner et al 2016]. The optimal treatment for type 2 diabetes in individuals with GSD III is as yet undefined [Oki et al 2000, Ismail 2009, Spengos et al 2009].

Prognosis. Long-term complications such as muscular and cardiac symptoms as well as liver fibrosis/cirrhosis, hepatocellular carcinoma, and type 2 diabetes may have a severe impact on the quality of life. It is unknown to what extent early optimal nutritional management can completely prevent these long-term complications.

Genotype-Phenotype Correlations

There is a clear genotype-phenotype correlation with at least two pathogenic variants in exon 3 (c.18_19delGA and c.16C>T) associated with GSD IIIb; 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]. 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 clear genotype-phenotype correlations between other AGL pathogenic variants and disease severity have been reported. An overrepresentation of non-missense AGL variants [Sentner et al 2016] but also heterogeneity even within a given family has been noted [Lucchiari et al 2007]. A possible association of frameshift, nonsense, and splice site variants with a severe phenotype has been proposed [Perveen et al 2020]. Some AGL variants may be associated with a more severe (e.g., c.3965delT, c.4529dupA) or more attenuated (c.4260-12A>G) phenotype [Shaiu et al 2000, Cheng et al 2009].

Nomenclature

Abnormal glycogen with short outer chains was first reported by Illingworth & Cori [1952] in an affected individual followed by Dr GB Forbes. Hence, GSD III is also known as limit dextrinosis, Cori disease, and Forbes disease.

Other terms used to refer to GSD III include AGL deficiency and amylo-1,6-glucosidase deficiency.

Prevalence

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

Certain populations have an increased prevalence as the result of a founder effect:

• The Inuit population in Nunavik (Canada) (~1:2,500) [Rousseau-Nepton et al 2015]
• The Faroese (~1:3,100) [Santer et al 2001]
• North African Jews from Israel (~1:5,400) [Parvari et al 1997]

Evaluations Following Initial Diagnosis

Based on the 2010 ACMG practice guidelines, the investigations summarized in Table 3 are recommended to characterize the clinical phenotype and to adjust dietary treatment on an individual basis.

Treatment of Manifestations

Medical nutrition therapy. The mainstay of management of GSD III is a high-protein diet with cornstarch supplementation to maintain euglycemia while balancing macronutrient and total caloric intake.

• Frequent feedings in infancy (every 3-4 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.
• Cornstarch. Toward the end of the first year of life, cornstarch is tolerated and can be used to prevent hypoglycemia. Initially several doses per day may be required (typical starting dose ~1 g/kg). The doses can be titrated based on the results of glucose and ketone monitoring.
  As an alternative for uncooked cornstarch, Glycosade^® extended-release cornstarch can be used [Ross et al 2015]. One gram of cornstarch per kilogram of body weight may be sufficient to maintain normal blood glucose levels for four hours or longer in individuals with GSD III.
• High-protein diet. Protein intake of 3 g/kg or 25% of total energy is recommended in children or adults, respectively. With gluconeogenesis being intact, protein-derived glucogenic amino acids can be used as an alternate source for glucose during times of fasting. A high-protein diet prevents breakdown of endogenous muscle protein in times of glucose need and preserves skeletal and cardiac muscles. High-protein supplements may be needed.
• Skeletal muscle metabolism may be impaired during exercise in GSD III. Consumption of maltodextrin or rapidly absorbable carbohydrates can prevent hypoglycemia during physical activity. Fructose or sucrose prior to exercise may improve exercise tolerance but does not completely prevent exercise-induced damage [Preisler et al 2015].
• 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.
• It has been shown that high-fat diet can reduce cardiomyopathy in individuals with GSD III [Rossi et al 2020].

Emergency protocol. A personalized emergency letter based on an emergency protocol to avoid dangerous hypoglycemia should be established. Personalized emergency letters in different languages can be generated via www.emergencyprotocol.net [Rossi et al 2021]. If the enteral intake cannot be guaranteed, an intravenous (IV) infusion of 10% dextrose (with sodium chloride and potassium chloride) should be given as soon as possible. Efforts should be made to correct ketosis, as it can induce vomiting and worsen the catabolic state. Serum concentrations of electrolytes, glucose, ketones, and creatine kinase (CK) should be monitored.

Surgery. Persons with GSD III undergoing surgery should be admitted the night before the procedure and start an IV infusion containing 10% dextrose within two hours of the last cornstarch dose or the last meal. Continue glucose and ketone monitoring overnight and during the procedure. Do not stop IV dextrose infusion abruptly, as dangerous hypoglycemia can occur from an iatrogenic hyperinsulinemic state. Slowly taper IV fluids once optimal oral intake has been established and tolerated.

Liver transplantation. Hepatic complications are not the main cause of morbidity in individuals with GSD III; 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 cure the fasting intolerance-associated hypoglycemias in both GSD IIIa and GSD IIIb. However, the (cardio)muscular enzymatic defect persists in individuals with GSD IIIa. The risk of hypoglycemia decreases with age in individuals with GSD III, 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].

Osteoporosis may occur in adults with GSD III, as bone mineralization is adversely affected in acidic environments. Good metabolic control leads to decreased ketosis, improved muscle strength, and increased bone mineralization. Supplementation with vitamin D and/or calcium is also recommended to augment bone mineralization. If dietary calcium intake is insufficient, calcium supplementation should be prescribed.

Surveillance

Agents/Circumstances to Avoid

Avoid the following:

• High carbohydrate intake. Excess sugar is stored as glycogen, which cannot be broken down, resulting in hepatomegaly.
• Steroid-based drugs, which interfere with glucose metabolism and utilization. Long-term steroid usage itself can cause failure to thrive and muscle weakness.
• Growth hormone replacement therapy, which interferes with glucose metabolism and worsens ketosis. Growth hormone therapy has been associated with adenoma growth and complications in GSD I; therefore, growth hormone should only be used in individuals with documented growth hormone deficiency.
• Medications that can cause rhabdomyolysis

Use the following with caution:

• Hormonal (estrogen) contraceptives in women. Estrogen is known to contribute to both benign and malignant hepatocellular tumors.
• 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 cause hypoglycemia and mask the signs and symptoms associated with the adrenergic response during 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. The goal during all trimesters of the pregnancy and peripartum is to maintain normoglycemia and to avoid upregulation of counterregulatory hormones, which result in lipolysis, increased mitochondrial fatty acid oxidation, and hyperketosis [Kishnani et al 2010].

Throughout the entire pregnancy, adequate protein is necessary to provide an alternate source of glucose via gluconeogenesis. Hyperemesis may cause secondary hyperketosis and hypoglycemia. The metabolic requirements will gradually increase throughout the second and third trimesters, necessitating dietary adjustments to meet the glucose demands of the fetus.

Women with GSD III may be at risk of gestational diabetes, but oral glucose tests are contraindicated.

Ketonuria for healthy women in labor is generally accepted as a normal physiologic response [Toohill et al 2008] but should be prevented in women with GSD III due to the risks of hyperketosis, metabolic acidosis, and acute rhabdomyolysis. Administration of a glucose infusion and regular monitoring of blood glucose, ketones, blood gases, and CK is necessary during labor and perinatally. Glucose management requires balancing between the previously mentioned signs of undertreatment and the risks of overtreatment (e.g., fetal hyperinsulinemic hypoglycemia).

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.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• The parents of an affected child are usually heterozygotes (i.e., carriers of one AGL pathogenic variant).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an AGL pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include the following:
  • A single- or multiexon deletion in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband [Ponzi et al 2019, Xiao et al 2019].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an AGL pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial AGL pathogenic variants.
• Clinical variability may be observed between affected sibs [Lucchiari et al 2007].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• The offspring of an individual with GSD III are obligate heterozygotes (carriers) for a pathogenic variant in AGL.
• If the reproductive partner of an affected person is a carrier, the offspring are at a 50% risk of being affected. This is more likely to occur in populations with a higher prevalence of GSD III as the result of a founder effect (see Prevalence).

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an AGL pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the AGL pathogenic variants 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 and discussion of the availability of prenatal/preimplantation genetic 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.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely.

DNA banking. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic alteration/s are unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the AGL pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for GSD III are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

To make glycogen, glucose molecules forming uridine diphosphate 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 decrease 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.

With debranching enzyme deficiency, glycogen cannot be completely degraded and as a consequence, an abnormal glycogen with branched outer points called "limit dextrin" accumulates.

AGL encodes six different isoforms that differ in the 5' end by using several cryptic splice sites upstream of the translation initiation site. Isoform 1 is present in liver, muscle, kidney, and lymphoblastoid cells. Isoforms 2, 3, and 4 are present in the muscle and heart. 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 all 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].

Mechanism of disease causation. Loss of function

Author Notes

Research priorities have been defined for liver glycogen storage disease (GSD) and also for GSD III [Peeks et al 2020].

Acknowledgments

We acknowledge the individuals with GSD and their families, our institutions, collaborating health care providers treating individuals with GSD, laboratory personnel and researchers, the (inter)national patient support groups, and private companies for their untiring work and collaboration.

Author History

Aditi Dagli, MD; University of Florida College of Medicine (2010-2022)
Terry GJ Derks, MD, PhD (2022-present)
Sarah C Grünert, MD (2022-present)
Alessandro Rossi, MD (2022-present)
Andrea B Schreuder, MD, PhD (2022-present)
Christiaan P Sentner, MD; University Medical Center Groningen (2010-2022)
David A Weinstein, MD, MMSc; University of Connecticut (2010-2022)

Revision History

• 6 January 2022 (sw) Comprehensive update posted live
• 29 December 2016 (bp) Comprehensive update posted live
• 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

Literature Cited

• Austin SL, Proia AD, Spencer-Manzon MJ, Butany J, Wechsler SB, Kishnani PS. Cardiac pathology in glycogen storage disease type III. JIMD Rep. 2012;6:65–72. [PMC free article: PMC3565657] [PubMed: 23430941]
• Bao Y, Dawson TL Jr, Chen YT. Human glycogen debranching enzyme gene (AGL): complete structural organization and characterization of the 5' flanking region. Genomics. 1996;38:155–65. [PubMed: 8954797]
• Bao Y, Yang BZ, Dawson TL Jr, Chen YT. Isolation and nucleotide sequence of human liver glycogen debranching enzyme mRNA: identification of multiple tissue-specific isoforms. Gene. 1997;197:389–98. [PubMed: 9332391]
• Bernier AV, Sentner CP, Correia CE, Theriaque DW, Shuster JJ, Smit GP, Weinstein DA. Hyperlipidemia in glycogen storage disease type III: effect of age and metabolic control. J Inherit Metab Dis. 2008;31:729–32. [PMC free article: PMC3832627] [PubMed: 18709545]
• Ben Chehida A, Ben Messaoud S, Ben Abdelaziz R, Ben Ali N, Boudabous H, Ben Abdelaziz I, Ben Ameur Z, Sassi Y, Kaabachi N, Abdelhak S, Abdelmoula MS, Fradj M, Azzouz H, Tebib N. Neuromuscular involvement in glycogen storage disease type III in fifty Tunisian patients: phenotype and natural history in young patients. Neuropediatrics. 2019;50:22–30. [PubMed: 30308687]
• Cheng A, Zhang M, Okubo M, Omichi K, Saltiel AR. Distinct mutations in the glycogen debranching enzyme found in glycogen storage disease type III lead to impairment in diverse cellular functions. Hum Mol Genet. 2009;18:2045–52. [PMC free article: PMC2678930] [PubMed: 19299494]
• Chen YT. Glycogen storage diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York, NY: McGraw Hill; 2001:1521-51.
• Davis MK, Weinstein DA. Liver transplantation in children with glycogen storage disease: controversies and evaluation of the risk/benefit of this procedure. Pediatr Transplant. 2008;12:137–45. [PubMed: 18307661]
• 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]
• Derks TG, Smit GP. Dietary management in glycogen storage disease type III: what is the evidence? J Inherit Metab Dis. 2015;38:545–50. [PubMed: 25164784]
• Elpeleg ON. The molecular background of glycogen metabolism disorders. J Pediatr Endocrinol Metab. 1999;12:363–79. [PubMed: 10821216]
• Focardi M, Bosco A, Bugelli V, Defraia B, Donati MA, Pinchi V. "On air" diagnosis of sudden cardia death with dynamic Holter ECG in glycogen storage disease type III young female. Minerva Pediatr. 2020;72:142–4. [PubMed: 32441908]
• Goldstein JL, Austin SL, Boyette K, Kanaly A, Veerapandiyan A, Rehder C, Kishnani PS, Bali DS. Molecular analysis of the AGL gene: identification of 25 novel mutations and evidence of genetic heterogeneity in patients with glycogen storage disease type III. Genet Med. 2010;12:424–30. [PubMed: 20648714]
• Heiner-Fokkema MR, van der Krogt J, de Boer F, Fokkert-Wilts MJ, Maatman RGHJ, Hoogeveen IJ, Derks TGJ. The multiple faces of urinary glucose tetrasaccharide as biomarker for patients with hepatic glycogen storage diseases. Genet Med. 2020;22:1915–16. [PMC free article: PMC7605430] [PubMed: 32655139]
• Hobson-Webb LD, Austin SL, Bali DS, Kishnani PS. The electrodiagnostic characteristics of glycogen storage disease type III. Genet Med. 2010;12:440–5. [PubMed: 20071996]
• Hoogeveen IJ, De Boer F, Boonstra WF, Van der Schaaf CJ, Steuerwald U, Sibeijn-Kuiper AJ, Veger RJK, Van der Hoeven JH, Heiner-Fokkema MR, Clarke KC, Cox PJ, Derks TGJ, Jeneson JAL. Effects of acute nutritional ketosis during exercise in adults with glycogen storage disease type IIIa are phenotypic specific: An investigator-initiated, randomized, crossover study. J Inherit Metab Dis. 2021;44:226–39. [PMC free article: PMC7891643] [PubMed: 33448466]
• Illingworth B, Cori GT. Structure of glycogens and amylopectins. III. Normal and abnormal human glycogen. J Biol Chem. 1952;199:653–60. [PubMed: 13022672]
• Ismail H. Glycogen storage disease type III presenting with secondary diabetes and managed with insulin: a case report. Cases J. 2009;2:6891. [PMC free article: PMC2740253] [PubMed: 19829878]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
• Kishnani PS, Austin SL, Arn P, Bali DS, Boney A, Case LE, Chung WK, Desai DM, El-Gharbawy A, Haller R, Smit GP, Smith AD, Hobson-Webb LD, Wechsler SB, Weinstein DA, Watson MS. ACMG. Glycogen storage disease type III diagnosis and management guidelines. Genet Med. 2010;12:446–63. [PubMed: 20631546]
• Lucchiari S, Santoro D, Pagliarani S, Comi GP. Clinical, biochemical and genetic features of glycogen debranching enzyme deficiency. Acta Myol. 2007;26:72–4. [PMC free article: PMC2949315] [PubMed: 17915576]
• Melis D, Rossi A, Pivonello R, Del Puente A, Pivonello C, Cangemi G, Negri M, Colao A, Andria G, Parenti G. Reduced bone mineral density in glycogen storage disease type III: evidence for a possible connection between metabolic imbalance and bone homeostasis. Bone. 2016;86:79–85. [PubMed: 26924264]
• Mundy HR, Williams JE, Lee PJ, Fewtrell MS. Reduction in bone mineral density in glycogenosis type III may be due to a mixed muscle and bone deficit. J Inherit Metab Dis. 2008;31:418–23. [PubMed: 18392743]
• Oki Y, Okubo M, Tanaka S, Nakanishi K, Kobayashi T, Murase T. Diabetes mellitus secondary to glycogen storage disease type III. Diabet Med. 2000;17:810–2. [PubMed: 11131107]
• 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]
• Peeks F, Boonstra WF, de Baere L, Carøe C, Casswall T, Cohen D, Cowan K, Ferrecchia I, Ferriani A, Gimbert C, Landgren M, Maldonado NL, McMillan J, Nemeth A, Seidita N, Stachelhaus-Theimer U, Weinstein DA, Derks TGJ. Research priorities for liver glycogen storage disease: An international priority setting partnership with the James Lind Alliance. J Inherit Metab Dis. 2020;43:279–89. [PMC free article: PMC7079148] [PubMed: 31587328]
• Perveen S, Gupta N, Kumar M, Kaur P, Chowdhury MR, Kabra M. Spectrum of amyloglucosidase mutations in Asian Indian patients with Glycogen storage disease type III. Am J Med Genet A. 2020;182:1190–200. [PubMed: 32222031]
• Ponzi E, Alesi V, Lepri FR, Genovese S, Loddo S, Mucciolo M, Novelli A, Dionisi-Vici C, Maiorana A. Uniparental isodisomy of chromosome 1 results in glycogen storage disease type III with profound growth retardation. Mol Genet Genomic Med. 2019;7:e634. [PMC free article: PMC6503021] [PubMed: 30916492]
• Preisler N, Laforêt P, Madsen KL, Prahm KP, Hedermann G, Vissing CR, Galbo H, Vissing J. Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III. Neurology. 2015;84:1767–71. [PubMed: 25832663]
• Ross KM, Brown LM, Corrado MM, Chengsupanimit T, Curry LM, Ferrecchia IA, Porras LY, Mathew JT, Dambska M, Weinstein DA. Safety and efficacy of long-term use of extended release cornstarch therapy for glycogen storage disease types 0, III, VI, and IX. J Nutr Ther. 2015;4:137–42.
• Rossi A, Hoogeveen IJ, Bastek VB, de Boer F, Montanari C, Meyer U, Maiorana A, Bordugo A, Dianin A, Campana C, Rigoldi M, Kishnani PS, Pendyal S, Strisciuglio P, Gasperini S, Parenti G, Parini R, Paci S, Melis D, Derks TGJ. Dietary lipids in glycogen storage disease type III: A systematic literature study, case studies, and future recommendations. J Inherit Metab Dis. 2020;43:770–7. [PMC free article: PMC7383479] [PubMed: 32064649]
• Rossi A, Hoogeveen IJ, Lubout CMA, de Boer F, Fokkert-Wilts MJ, Rodenburg IL, van Dam E, Grünert SC, Martinelli D, Scarpa MDekker H, Te Boekhorst ST, van Spronsen FJ, Derks TGJ, et al. A generic emergency protocol for patients with inborn errors of metabolism causing fasting intolerance: A retrospective, single-center study and the generation of www​.emergencyprotocol.net. J Inherit Metab Dis. 2021;44:1124-35. [PMC free article: PMC8518720] [PubMed: 33844307]
• Rousseau-Nepton I, Okubo M, Grabs R, Mitchell J, Polychronakos C, Rodd C, et al. A founder AGL mutation causing glycogen storage disease type IIIa in Inuit identified through whole-exome sequencing: a case series. CMAJ. 2015;187:E68–73. [PMC free article: PMC4312169] [PubMed: 25602008]
• Santer R, Kinner M, Steuerwald U, Kjaergaard S, Skovby F, Simonsen H, Shaiu WL, Chen YT, Schneppenheim R, Schaub J. Molecular genetic basis and prevalence of glycogen storage disease type IIIA in the Faroe Islands. Eur J Hum Genet. 2001;9:388–91. [PubMed: 11378828]
• Sentner CP, Caliskan K, Vletter WB, Smit GP. Heart failure due to severe hypertrophic cardiomyopathy reversed by low calorie, high protein dietary adjustments in a glycogen storage disease type IIIa patient. JIMD Rep. 2012;5:13–6. [PMC free article: PMC3509915] [PubMed: 23430911]
• Sentner CP, Hoogeveen IJ, Weinstein DA, Santer R, Murphy E, McKiernan PJ, Steuerwald U, Beauchamp NJ, Taybert J, Laforêt P, Petit FM, Hubert A, Labrune P, Smit GP, Derks TG. Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome. J Inherit Metab Dis. 2016;39:697–704. [PMC free article: PMC4987401] [PubMed: 27106217]
• 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]
• 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]
• Spengos K, Michelakakis H, Vontzalidis A, Zouvelou V, Manta P. Diabetes mellitus associated with glycogen storage disease type III. Muscle Nerve. 2009;39:876–7. [PubMed: 19334047]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Toohill J, Soong B, Flenady V. Interventions for ketosis during labour. Cochrane Database Syst Rev. 2008;(3):CD004230. [PMC free article: PMC8769494] [PubMed: 18646103]
• Valayannopoulos V, Bajolle F, Arnoux JB, Dubois S, Sannier N, Baussan C, Petit F, Labrune P, Rabier D, Ottolenghi C, Vassault A, Broissand C, Bonnet D, de Lonlay P. Successful treatment of severe cardiomyopathy in glycogen storage disease type III with D,L-3-hydroxybutyrate, ketogenic and high protein diet. Pediatr Res. 2011;70:638–41. [PubMed: 21857385]
• Wary C, Nadaj-Pakleza A, Laforêt P, Claeys KG, Carlier R, Monnet A, Fleury S, Baligand C, Eymard B, Labrune P, Carlier PG. Investigating glycogenosis type III patients with multi-parametric functional NMR imaging and spectroscopy. Neuromuscul Disord. 2010;2010;20:548–58. [PubMed: 20620060]
• Wolfsdorf JI, Weinstein DA. Glycogen storage diseases. Rev Endocr Metab Disord. 2003;4:95–102. [PubMed: 12618563]
• Xiao B, Wang L, Liu H, Fan Y, Xu Y, Sun Y, Qiu W. Uniparental isodisomy caused autosomal recessive diseases: NGS-based analysis allows the concurrent detection of homogenous variants and copy-neutral loss of heterozygosity. Mol Genet Genomic Med. 2019;7:e00945. [PMC free article: PMC6785455] [PubMed: 31454184]