Type III Glycogen Storage Disease 

Updated: May 25, 2017
Author: Wayne E Anderson, DO, FAHS, FAAN; Chief Editor: George T Griffing, MD 

Overview

Background

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.

Metabolic pathways of carbohydrates. 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.

Pathophysiology

With an enzyme defect, carbohydrate metabolic pathways are blocked and excess glycogen accumulates in affected tissues. Each GSD represents a specific enzyme defect, and each enzyme is in specific, or most, body tissues.

The enzyme amylo-1,6-glucosidase is deficient, leading to an accumulation of dextrin. The site of glycogen accumulation is primarily cytoplasmic. Conversion generally is a one-way reaction from glycogen to glucose-1,6-phosphate. The enzyme is found in all tissues.

Disease results from a pan-deficiency of the enzyme (GSD IIIa) or muscle-specific retention of glycogen debranching enzyme (GSD IIIb). The condition is autosomal recessive. No common mutation has been described in Cori disease (types a and b), although 2 alleles have been reported for GSD IIIb and 1 allele has been found in North African Jewish people with GSD IIIa. The first report of a causative missense mutation was published in 1999 based on the work of Okubo and colleagues.[1, 2, 3, 4]

Although the most prevalent mutations have been reported in the North African Jewish population and in an isolate such as the Faroe Islands, Mili et al used molecular analysis to reveal 3 novel mutations and 5 known mutations among 22 Tunisian patients with GSD III.[5]

GSD type IIIb is caused by mutation in exon 3 of the glycogen debranching enzyme. Lam and colleagues demonstrate different haplotypes for GSD type IIIa.[6] GSD III can occur not only in humans, but also in other mammals.

Epidemiology

Frequency

International

Herling and colleagues studied the incidence and frequency of inherited metabolic conditions in British Columbia. GSDs are found in 2.3 children per 100,000 births per year. In non-Ashkenazi Jewish people of North Africa, the frequency has been reported as 1 out of 5400 people. Zimakas and Rodd report the rare presence of GSD type III in Inuit children.[7]

Mortality/Morbidity

See the list below:

  • Immediate morbidity may arise from hypoglycemic seizures that occur in the first decade of life.

  • Long-term morbidity arises from hepatic disease and progressive muscle weakness.

  • Ingle and colleagues report sudden mortality by exsanguination related to hepatocellular failure.[8]

  • Demo and colleagues report two cases of hepatocellular carcinoma as a long-term complication of GSD III, possibly emerging because of increased overall survival with GSD III.[9]

Kalkan et al conducted a study on 31 patients with GSD Ia or III to determine why patients with these conditions do not tend to develop premature atherosclerosis, even though hyperlipidemia is a feature of both diseases.[10] Marked hypertriglyceridemia was found in the GSD Ia group (22 patients), while hypercholesterolemia with elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol levels was found in the GSD III group (9 patients). The study also included 19 healthy individuals.

The authors found that despite the presence of dyslipidemia in the GSD Ia and III patients, their high sensitivity C-reactive protein levels were the same as in the healthy subjects. The GSD Ia patients had elevated antioxidant activity, although their antioxidant enzyme activity did not differ significantly from that of the healthy subjects. The authors suggested increased antioxidative protection in GSD Ia patients may be associated not only with elevated levels of uric acid (an antioxidant) found in these patients, but also with the use of supplemental vitamin E.

Age

See the list below:

  • In general, GSDs present in childhood.

  • Later onset correlates with a less severe form.

  • Consider Pompe disease if onset is in infancy.

 

Presentation

History

See the list below:

  • Although the enzyme is found in all tissues, clinical manifestations generally are nonmyopathic.

  • History usually consists of infant seizures.

  • Other features include hepatomegaly and growth retardation.

  • Muscle weakness is very slow in progressing. Vigorous exercise is not associated with cramping, tenderness, or myoglobulinuria.

  • Cortical malformations are reported. Vincentiis and colleagues report one case of polymicrogyria.

Physical

See the list below:

  • Debrancher enzyme deficiency may manifest as progressive weakness.

  • Hepatomegaly and splenomegaly are present. Unlike GSD I, kidney enlargement is not observed.

  • Growth retardation may occur.

  • In adults, it may progress to liver cirrhosis or hepatic adenomas.

  • Muscle wasting of interossei may occur.

 

DDx

 

Workup

Laboratory Studies

See the list below:

  • Because hypoglycemia may be found in some types of GSD, fasting glucose is indicated. Hypoglycemia is concerning and may lead to hypoglycemic seizures.

  • Urine studies are indicated because myoglobinuria may occur in some cases of GSD.

  • Hepatic failure occurs in some cases of GSD. Liver function studies are indicated.

  • The presence of dextrin is unique to Cori disease.

  • With a biochemical assay, debrancher enzyme activity is reduced or absent.

  • Hyperlipidemia is a common finding.

  • Fasting ketonemia is noted with the rapid metabolism of fatty acids.

Imaging Studies

See the list below:

  • Imaging may reveal hepatomegaly.

  • Cardiomegaly may be present, but heart failure is not typical of GSD II.

Other Tests

See the list below:

  • 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.

  • Electromyography

    • Electromyography patterns are diverse and vary from patient to patient.

    • The myopathic finding of polyphasic responses is found, but amplitude and duration may be either decreased, as expected, or increased in some cases.

    • Spontaneous abnormal activity (fibrillation potential and positive sharp waves) may be found.

    • Myotonic discharges are observed in some cases.

    • A study by Mogahed et al assessed the prevalence of neuromuscular and cardiac involvement in 28 children with GSD III and reported that 61% of the patients had myopathic changes detected by electromyography and that the children with myopathic changes were significantly older and all but one had elevated creatine phosphokinase.[11]

Histologic Findings

Muscle biopsy is periodic acid-Schiff positive with basophilic deposits in all tissues, including the CNS.

 

Treatment

Medical Care

See the list below:

  • In general, no specific treatment exists for GSDs.

  • In some cases, diet therapy is helpful. Meticulous adherence to a dietary regimen may reduce liver size, prevent hypoglycemia, allow for reduction in symptoms, and allow for growth and development.

  • Zingone and colleagues demonstrated the abolition of the murine clinical manifestations of Von Gierke disease with a recombinant adenoviral vector.[12] 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.[13]

  • Valayannopoulos et al reported positive treatment of an infant with GSD III complicated by severe cardiomyopathy using synthetic ketone bodies, along with a low-carbohydrate, high-lipid, and high-protein diet.[14]

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.[15]

Consultations

See the list below:

  • Consultation with a neurologist with special training in muscle physiology may help in establishing the diagnosis.

  • A consultation with a hepatologist-liver specialist may be helpful in the evaluation of liver abnormalities.

Diet

Cornstarch therapy may be beneficial in reducing hypoglycemia.

 

Follow-up

Complications

See the list below:

  • Hepatocellular carcinoma

  • Hepatic failure

Prognosis

See the list below:

  • Unfortunately, severe hepatic failure with possible malignant transformation may be fatal. Matern and colleagues presented evidence that hepatic transplant may be effective in arresting this condition.[15]