Type III Glycogen Storage Disease (Forbes-Cori Disease)

Updated: Jul 22, 2021
  • Author: Ricardo R Correa Marquez, MD, EsD, FACP, FACE, FAPCR, CMQ, ABDA, FACHT; Chief Editor: George T Griffing, MD  more...
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Overview

Practice Essentials

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:

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.

See Treatment for more detail.

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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.

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Pathophysiology

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]

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Epidemiology

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.

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Prognosis

The prognosis is variable, depending on early diagnosis and treatment availability.

Morbidity/mortality

Mortality is usually due to complications of cardiac or hepatic disease.

Complications

Chronic complications include the following [13] :

  • Hepatic cirrhosis, adenoma(s), and/or hepatocellular carcinoma (11% of patients with GSD)
  • Cardiac involvement (58% of patients with GSD)
  • Decreased bone mineral density (osteoporosis and osteopenia)
  • Hypercholesterolemia (34%) and hypertriglyceridemia (40%)
  • Cardiomyopathy (15% of patients with GSD)
  • Muscle pain (34% of patients with GSD)
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