Type III glycogen storage disease (GSD III) is an autosomal recessive disease caused by mutations in the AGL gene, which codes for glycogen debranching enzyme. Hepatomegaly and hypoglycemia in a child should raise suspicion for GSD III.
Signs and symptoms
Hepatomegaly is the most common presenting sign in patients with GSD III. Other early clinical findings include hypoglycemia, failure to thrive, and recurrent illness and/or infections. The most common cardiac abnormality in patients with GSD III is left ventricular hypertrophy[1] ; findings on physical examination include a sustained, displaced point of maximal impulse.
See Presentation for more detail.
Diagnosis
Laboratory studies
The American College of Medical Genetics and Genomics (ACMG) suggests performing the following tests in a patient with hypoglycemia and hepatomegaly[2] :
Blood glucose
Blood lactate
Uric acid
Hepatic profile including liver function studies
Serum lipid profile
Plasma creatine kinase
Plasma total and free carnitine
Plasma acylcarnitine profile
Plasma amino acids
Urinalysis
Urine organic acids
Laboratory results suggestive of GSD III include ketotic hypoglycemia after short fasting, elevated transaminase levels, and elevated fatty acid concentrations.[3]
Other studies
The following tests may be included in the workup:
Electromyography
Glucagon administration
Ischemic forearm test
Liver biopsy
See Workup for more detail.
Management
The mainstay of GSD III treatment is dietary modification. A dietary regimen consisting of high protein intake and cornstarch supplementation is recommended. Simple carbohydrate intake should be limited, as excess sugar is stored as glycogen, which cannot be broken down.[4] Avoidance of prolonged fasting may prevent hypoglycemia.
Liver transplantation may be indicated for patients with hepatic malignancy.
A glycogen storage disease (GSD) results from the absence of enzymes that ultimately convert glycogen compounds to glucose. Enzyme deficiency results in glycogen accumulation in tissues. In many cases, the defect has systemic consequences, but, in some cases, the defect is limited to specific tissues. Most patients experience muscle symptoms, such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly.
The following list contains a quick reference for 8 of the GSD types:
0 - Glycogen synthase deficiency
Ia -Glucose-6-phosphatase deficiency (von Gierke disease)
II -Acid maltase deficiency (Pompe disease)
III - Debranching enzyme deficiency (Forbes-Cori disease)
IV - Transglucosidase deficiency (Andersen disease, amylopectinosis)
V - Myophosphorylase deficiency (McArdle disease)
VI - Phosphorylase deficiency (Hers disease)
VII - Phosphofructokinase deficiency (Tarui disease)
The chart below demonstrates where various forms of GSD affect metabolic carbohydrate pathways.
View Image
Metabolic pathways of carbohydrates.
Although at least 14 unique GSDs are discussed in the literature, the 4 that cause clinically significant muscle weakness are Pompe disease (GSD type II, acid maltase deficiency), Cori disease (GSD type IIIa, debranching enzyme deficiency), McArdle disease (GSD type V, myophosphorylase deficiency), and Tarui disease (GSD type VII, phosphofructokinase deficiency). One form, Von Gierke disease (GSD type Ia, glucose-6-phosphatase deficiency), causes clinically significant end-organ disease with significant morbidity. The remaining GSDs are not benign but are less clinically significant; therefore, the physician should consider the aforementioned GSDs when initially entertaining the diagnosis of a GSD. Interestingly, a GSD type 0 also exists, which is due to defective glycogen synthase.
These inherited enzyme defects usually present in childhood, although some, such as McArdle disease and Pompe disease, have separate adult-onset forms. In general, GSDs are inherited as autosomal recessive conditions. Several different mutations have been reported for each disorder.
Unfortunately, no specific treatment or cure exists, although diet therapy may be highly effective at reducing clinical manifestations. In some cases, liver transplantation may abolish biochemical abnormalities. Active research continues.
Diagnosis depends on patient history and physical examination, muscle biopsy, electromyelography, ischemic forearm test, and creatine kinase levels. Biochemical assay for enzyme activity is the method of definitive diagnosis.
The debranching enzyme converts glycogen to glucose-1,6-phosphate. Deficiency leads to liver disease, with subsequent hypoglycemia and seizure. Progressive muscle weakness also occurs.
Forbes-Cori disease (GSD type III) is caused by mutations in the AGL gene, the gene coding for glycogen debranching enzyme, a key enzyme of the glycogen degradation pathway. The AGL gene is located on the chromosome 1p21, consists of 35 exons, and is 85 kb long and produces several isoforms of the enzyme by alternative splicing.[5] Over 200 mutations—including missense, nonsense, splice site, small frame shift deletions and insertions, and large gene deletions and duplications—of the AGL gene have been identified.[6, 7, 8] [9, 10]
The glycogen debranching enzyme catalyze one of the last steps in the conversion of glycogen to glucose-1-phosphate; it breaks up the branches in glycogen that have been exposed by glycogen phosphorylase. It has two independent catalytic activities: oligo-1, 4-1, 4-glucantransferase (transferase) and amylo-1, 6-glucosidase (glucosidase). A mutated, nonfunctional debranching enzyme thwarts glycogen degradation, resulting in accumulation of partially broken glycogen in tissues, especially the liver and muscle tissue.
The main subtypes of GSD III are GSD IIIa (85% of cases), which is caused by glycogen debranching enzyme deficiency in both liver and muscle, and GSD IIIb (15% of cases), which is caused by enzyme deficiency in the liver.[4]
GSD type III is an autosomal recessive disease, with an estimated incidence of 1:100,000.[4] The frequency of the disease is higher in North African Jews in Israel (1:5400)[11] and in the Faroe Islands (1:3100).[12]
GSD type III usually presents in childhood. Later onset correlates with a less severe form.
Early clinical findings include hepatomegaly (98%), hypoglycemia (53%), failure to thrive (49%), and recurrent illness and/or infections (17%).[13]
Laboratory findings include ketonic hypoglycemia, hyperlipidemia, and elevated hepatic transaminases.[2]
Myopathy presents as muscle weakness and elevated creatine kinase (CK); it progresses slowly and becomes prominent in the third to fourth decade of life.
Cognitive deficits—impaired working memory, planning skills, the capacity to elaborate and maintain strategies, conceptualization and rule generation, and a generalized slowness—have been described in patients with GSD III.[14]
Hepatomegaly is the most common presenting sign in patients with GSD III. Hepatomegaly usually resolves during puberty, and growth accelerates, with the attainment of normal adult height.[15] In adult patients with GSD III, a decrease in liver progression may be a sign of liver cirrhosis; the median age of cirrhosis diagnosis is 18 years old.[13]
Cardiac findings vary according to the degree and type of cardiac involvement. The most common cardiac abnormality in patients with GSD III is left ventricular hypertrophy[1] ; findings on physical examination include a sustained, displaced point of maximal impulse.
Hepatomegaly and hypoglycemia in a child should raise suspicion for a beta oxidation disorder, galactosemia, and glycogen degradation pathway disorder—in particular GSD I, GSD III, and GSD VI.
The American College of Medical Genetics and Genomics (ACMG) suggests performing the following tests in a patient with hypoglycemia and hepatomegaly[2] :
Blood glucose
Blood lactate
Uric acid
Hepatic profile including liver function studies
Serum lipid profile
Plasma creatine kinase (CK)
Plasma total and free carnitine
Plasma acylcarnitine profile
Plasma amino acids
Urinalysis
Urine organic acids
Laboratory results suggestive of GSD III include ketotic hypoglycemia after short fasting, elevated transaminase levels, and elevated fatty acid concentrations.[3] Levels of CK can be elevated in GSD IIIa. Uric acid and lactate levels can help in the differential diagnosis of GSD: lactate and uric acid levels are usually elevated in GSD I but normal in GSD III.
Additional clinical features help differentiate the GSD subtypes. GSD I presents early in life with severe fasting hypoglycemia. GSD III and GSD VI usually have a less severe disease because gluconeogenesis compensates for the lack of glycogenolysis.
According to the ACMG guidelines,[2] diagnosis of GSD III is based on the following: (1) demonstration of excessive and structurally abnormal glycogen accumulation with shorter outer branches and deficient debranching enzyme activity in frozen liver and/or muscle biopsy samples or (2) identification of pathogenic mutations in the AGL gene on both alleles.
In a patient with suspected GSD III, gene sequencing is usually performed first as it is a widely available, noninvasive technique. Analysis of debranching enzyme activity is reserved for cases in which molecular genetic analysis is inconclusive due to its more invasive nature—it requires liver and/or muscle biopsy.
There are no clear genotype-phenotype correlations.[13] As an exception, an association between exon 3 mutations and GSDIIIb have been previously described.
Electromyography patterns are diverse and vary from patient to patient. Electromyograms (EMG) and nerve conduction studies (NCS) show myopathic (short duration, low amplitude, increased complexity, and early recruitment) and neuropathic (long duration, large amplitude, and late recruitment) patterns.[16, 17]
Glucagon administration
In GSD III, the administration of glucagon 2 hours after a carbohydrate-rich meal provokes a normal increase in blood glucose (BG), whereas after an overnight fast, glucagon typically provokes no change in BG level.[2]
Ischemic forearm test
The ischemic forearm test is an important tool for diagnosis of muscle disorders. The basic premise is an analysis of the normal chemical reactions and products of muscle activity. Obtain consent before the test.
Instruct the patient to rest. Position a loosened blood pressure cuff on the arm and place a venous line for blood samples in the antecubital vein.
Obtain blood samples for the following tests: creatine kinase, ammonia, and lactate. Repeat in 5-10 minutes.
Obtain a urine sample for myoglobin analysis.
Immediately inflate the blood pressure cuff above systolic blood pressure and have the patient repetitively grasp an object, such as a dynamometer. Instruct the patient to grasp the object firmly, once or twice per second. Encourage the patient for 2-3 minutes, at which time the patient may no longer be able to participate. Immediately release and remove the blood pressure cuff.
Obtain blood samples for creatine kinase, ammonia, and lactate immediately and at 5, 10, and 20 minutes.
Collect a final urine sample for myoglobin analysis.
Interpretation of ischemic forearm test results
With exercise, carbohydrate metabolic pathways yield lactate from pyruvate. Lack of lactate production during exercise is evidence of pathway disturbance, and an enzyme deficiency is suggested. In such cases, muscle biopsy with biochemical assay is indicated.
Healthy patients demonstrate an increase in lactate of at least 5-10 mg/dL and ammonia of at least 100 µg/dL. Levels will return to baseline.
If neither level increases, the exercise was not strenuous enough and the test is not valid.
Increased lactate at rest (before exercise) is evidence of mitochondrial myopathy.
Failure of lactate to increase with ammonia is evidence of a GSD resulting in a block in carbohydrate metabolic pathways. Not all GSDs have a positive result on ischemic test.
Failure of ammonia to increase with lactate is evidence of myoadenylate deaminase deficiency.
In Cori disease, the ischemic forearm test result is positive
Liver biopsy shows hepatocyte distention and abundance of cytoplasmic glycogen—the stored glycogen is periodic acid-Schiff positive and diastase sensitive. Lipid vacuoles are present; however, they are less frequent and smaller than in GSD I. The presence of fibrosis ranges from minimal periportal fibrosis to micronodular cirrhosis.[2]
Muscle, when affected, exhibits glycogen particle accumulation between intact myofibrils and in the subsarcolemmal position, locations in which glycogen usually occurs but not in such abundance.
After a GSD III diagnosis is confirmed, Dagli, Sentner, and Weinstein[4] recommend the following:
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
Consultations
A cardiologist, neuromuscular specialist, gastroenterologist, physical therapist, occupational therapist, genetic counselor, and/or a metabolic dietitian may be consulted depending on the disease manifestations.
The mainstay of GSD III treatment is dietary modification. A dietary regimen consisting of high protein intake and cornstarch supplementation improves exercise tolerance, muscle strength and mass, electromyographic findings, and growth, and it reduces cardiomyopathy.[18, 19, 20] Simple carbohydrate intake should be limited, as excess sugar is stored as glycogen, which cannot be broken down.[4] Avoidance of prolonged fasting may prevent hypoglycemia.
Two studies have shown improvement of GSD III clinical findings using a recombinant adenoviral vector in mice.[21, 22] These findings suggest that corrective gene therapy for GSDs may be possible in humans.
An encouraging study by Bijvoet and colleagues provides evidence of successful enzyme replacement for the mouse model of Pompe disease, which may lead to therapies for other enzyme deficiencies.[23]
Surgical care
Liver transplantation may be indicated for patients with hepatic malignancy. Whether transplantation prevents further complications is not clear, although a study by Matern and colleagues demonstrated posttransplantation correction of metabolic abnormalities.[24]
Current American College of Medical Genetics and Genomics (ACMG) guidelines recommend the following in infants and children[2] :
Small, frequent feedings (including complex carbohydrates and protein, avoiding simple sugars) and avoidance of fasting
Introduction of cornstarch supplementation as early as the first year of life if hypoglycemia is present
Bedtime snack, cornstarch supplementation, and/or continuous enteral feedings may be needed for the overnight fast
Current ACMG guidelines recommend the following in adolescents and adults[2] :
High protein (25% of total calories), low complex carbohydrates (< 50% of total calories), avoidance of simple sugars, and avoidance of fasting, most importantly for those with GSD IIIa
Bedtime snack (low-fat milk with protein powder) or a high-protein formula for overnight enteral feeding may be of benefit to those with myopathy
Dietary restriction is transitioned to a regular well-balanced diet in GSD-IIIb
For cardiovascular disease, current ACMG guidelines recommend the following[2] :
For GSD IIIa, obtain baseline and repeat every 12-24 months
For GSD IIIb, obtain baseline echocardiography for the same parameters as noted for GSD IIIa; repeat every 5 years
For GSD IIIa, serial 12-lead ECG every 2 years
More detailed rhythm analysis if any symptoms
For liver disease, current ACMG guidelines recommend the following[2] :
Laboratory testing to include serum aspartate aminotransferase, alanine aminotransferase, prothrombin time, bilirubin, and albumin every 6 months to yearly, to monitor extent of hepatic damage and to delineate if there is progression of liver cirrhosis to end-stage liver failure
Abdominal imaging should be performed at baseline and then every 12-24 months
Abdominal computed tomography/magnetic resonance imaging with contrast should be performed in older patients every 6-12 months based on laboratory and clinical findings
A physical therapy evaluation is recommended every 6 months or more frequently based on physical status, function, or need.[2]
Prevention
Genetic counseling is recommended to all parents with a child with GSD III and to all adults with GSD III.[2]
Molecular testing is the preferred method for prenatal diagnosis when both mutations are known.[2]
Ricardo R Correa Marquez, MD, EsD, FACP, FACE, FAPCR, CMQ, ABDA, FACHT, Professor of Medicine, Program Director, Endocrinology, Diabetes and Metabolism Fellowship Program, Director for Health Equity and Inclusive Initiatives , Endocrine and Metabolisms Institute, Cleveland Clinic and Lerner College of Medicine of Case Western Reserve University
Disclosure: Nothing to disclose.
Coauthor(s)
Sergio Mellado Flores, MD, International Medical Graduate
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Wayne E Anderson, DO, FAHS, FAAN, Assistant Professor of Internal Medicine/Neurology, College of Osteopathic Medicine of the Pacific Western University of Health Sciences; Clinical Faculty in Family Medicine, Touro University College of Osteopathic Medicine; Clinical Instructor, Departments of Neurology and Pain Management, California Pacific Medical Center
Lim JA, Choi SJ, Gao F, Kishnani PS & Sun B. A Novel Gene Therapy Approach for GSD III Using an AAV Vector Encoding a Bacterial Glycogen Debranching Enzyme. Molecular Therapy. Methods & Clinical Development. 2020 Sept. 18:240-249.
Chen Y. The Metabolic and Molecular Bases of Inherited Disease. Scriver CR, Beaudet AL, Sly WS, et al. Glycogen Storage Diseases. New York, NY: McGraw-Hill; 2001. 1521-51.
Valayannopoulos V, Bajolle F, Arnoux JP, et al. Successful treatment of severe cardiomyopathy in glycogen storage disease type III With D,L-3-hydroxybutyrate, ketogenic and high-protein diet. Pediatr Res. 2011 Dec. 70(6):638-641.
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