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
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. [24]
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. [25] 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. [26] 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.
Complications
Complications include the following:
-
Profound hypoglycemia, cerebral edema, coma, and death
-
Cirrhosis and liver failure [9]
-
Hepatic adenoma and hepatocellular carcinoma [9]
-
Myopathy with progressive muscle weakness and distal muscle wasting
-
Hypertrophic cardiomyopathy
-
Acute renal failure secondary to rhabdomyolysis and myoglobinuria following strenuous activity at times when blood glucose levels are not within reference ranges
-
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.
