Genetics of Glycogen-Storage Disease Type III Clinical Presentation

Updated: Oct 24, 2014
  • Author: David H Tegay, DO, FACMG; Chief Editor: Maria Descartes, MD  more...
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Presentation

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. [18]

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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. [19] 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. [20] The molecular biology of GSD IIIa and IIIb is an extremely active area of research; several quite different mutations, including different types of mutations, 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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