Genetics of Glycogen-Storage Disease Type III Clinical Presentation

  • Author: David H Tegay, DO, FACMG; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 13, 2012
 

History

Hypoglycemia is infrequent in neonates unless the infant experiences an intercurrent illness that precludes a normal feeding schedule. These episodes may respond only partially to glucagon administration; glucagon administration may not improve the hypoglycemia of a child who has fasted longer than a few hours.

The following are the most common glycogen-storage disease (GSD) type III (GSD III) symptoms in neonates:

  • Tremulousness or tremors
  • Sweating
  • Irritability
  • Apnea
  • Seizures
  • Coma
  • Hypotonia
  • Lethargy
  • Poor feeding
  • Respiratory distress
  • Apnea
  • Bradycardia
  • Sudden death

Older infants may manifest the following signs and symptoms in addition to those noted for neonates:

  • Difficult arousal from either a nap or overnight sleep
  • Poor growth
  • Apparently voracious appetite despite poor linear growth
  • Increased abdominal girth (infrequent)
  • Symptoms that suggest hypoglycemia associated with an intercurrent illness
  • Dizziness
  • Confusion
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Physical

Affected infants are healthy at birth and are usually healthy for the first several months of life.

Hepatomegaly is rare before the second month of life but then may gradually progress. The liver is firm and uniform in consistency. Although splenomegaly often occurs, the kidneys are not enlarged. The hepatomegaly usually resolves, sometimes completely, as patients reach puberty.

Most affected patients have poor growth and short stature during infancy and childhood, although many can achieve normal growth rates by maintaining their blood glucose levels within reference ranges.

Developmental milestones are normal.

In GSD IIIa and IIId, muscle wasting and weakness begin to appear as patients reach the second or third decade of life. Some patients may develop disabling myopathy, whereas others may have only minimal signs and symptoms.

A dilated hypertrophic cardiomyopathy may develop in some patients with GSD IIIa and IIId as they reach the third and fourth decades of life, yet overt cardiac dysfunction is rare.

Some articles have reported a typical dysmorphic facial appearance characterized by midfacial hypoplasia. This has not been universally appreciated.[16]

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Causes

All forms of GSD III show autosomal recessive inheritance and are caused by various mutations in the AGL gene at chromosome band 1p21.2.[17] A number of different mutations have been described and, outside of populations displaying a strong founder effect, most affected individuals are compound heterozygotes rather than true homozygotes.

Patients with both GSD IIIa and IIId apparently have a generalized debrancher activity deficiency, which has been identified in liver, skeletal muscle, heart, erythrocytes, and cultured fibroblasts. Recent research demonstrates that the progressive myopathy and/or the progressive cardiomyopathy develop only in patients with this generalized debrancher activity deficiency.[18] The molecular biology of GSD IIIa and IIIb is an extremely active area of research; several quite different mutations, including different types of mutation, in the debrancher gene can produce GSD IIIa.

Patients with GSD IIIb are deficient in debrancher activity in the liver but have normal enzyme activity in muscle. GSD IIIb is caused by 2 different mutations in exon 3 at the amino acid codon 6. No known mechanism explains how these exon 3 mutations permit debranching enzyme activity in muscle but not in liver.

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Contributor Information and Disclosures
Author

David H Tegay, DO, FACMG  Associate Professor of Medicine and Medical Genetics, New York College of Osteopathic Medicine at the New York Institute of Technology; Assistant Professor of Pediatrics, Stony Brook University Medical Center

David H Tegay, DO, FACMG is a member of the following medical societies: American College of Medical Genetics, American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Osteopathic Association, American Society of Human Genetics, and Federation of American Societies for Experimental Biology

Disclosure: Nothing to disclose.

Coauthor(s)

Riya Jose  Medicine Department Academic Fellow, New York College of Osteopathic Medicine of the New York Institute of Technology

Disclosure: Nothing to disclose.

Specialty Editor Board

Edward Kaye, MD  Vice President of Clinical Research, Genzyme Corporation

Edward Kaye, MD is a member of the following medical societies: American Academy of Neurology, American Society of Gene Therapy, American Society of Human Genetics, Child Neurology Society, and Society for Inherited Metabolic Disorders

Disclosure: Genzyme Corporation Salary Management position

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Hagop Youssoufian, MD, MSc  Vice President of Clinical Research, ImClone Systems Incorporated

Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Howard R Sloan, MD, PhD to the development and writing of this article.

References

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Schematic illustration of the degradation of glycogen by the concerted action of the enzymes phosphorylase and debranching enzyme. First, phosphorylase removes glucose moieties (linked to their neighbors via alpha1,4 glucosidic bonds and depicted as the 7 black circles) from the unbranched outer portions of the glycogen molecule until only 4 glucosyl units (depicted as the 3 green circles and the 1 red circle) remain before an alpha1,6 branch point. The transferase component of debranching enzyme then transfers the 3 (green) glucose residues from the short branch to the end of an adjacent branch of the glycogen molecule. The glucosidase component of debranching enzyme then removes the glucose moiety (depicted as the red circle) remaining at the alpha1,6 branch point. In the process, the branch point formed by the alpha1,6 glucosidic bond is removed, hence the name debrancher.Unlike phosphorylase, which removes glucose moieties from glycogen in the form of glucose-1-phosphate, debrancher releases 1 free glucose moiety from each branch point. After the cleavage of the branch site, phosphorylase attacks unbranched portions of the glycogen molecule until the enzyme is stymied by the appearance of another branch point, at which point debranching enzyme once again is called into play. Eventually, large portions of the glycogen molecule are degraded to free glucose by the action of the amylo-alpha1,6-glucosidase activity of debranching enzyme and to glucose-1-phosphate by the action of phosphorylase.
Schematic representation of a portion of a molecule of glycogen. Open circles represent the glucose moieties connected to each other via alpha1,4 linkages. Solid circles represent the glucose moieties connected to their neighbors via alpha1,6 linkages. Thus, each solid circle represents a branch point in the molecule.
 
 
 
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