Differentials
Glycogen storage disease type III (GSD III)
SIGNS / SYMPTOMS
Differentiating features for GSD III include growth retardation. About 70% of patients have muscle weakness, but this is usually not clinically significant in childhood.
Hypoglycemia is common, but after infancy is usually less severe than in GSD I because gluconeogenesis is intact. Patients may be able to tolerate longer periods of fasting than those with GSD I.
Infants may be asymptomatic with a typical schedule of frequent feedings and do not become as severely ill with infections and other stressors that disrupt feeding as do children with GSD I.
INVESTIGATIONS
Plasma cholesterol, creatine kinase (CK), and beta-hydroxybutyrate concentrations should be measured early in childhood to distinguish from GSD I.
Elevations in AST and ALT are usually higher (may be >1000 U/L) than in GSD I.
The kidneys are not enlarged and renal function is normal.
Mutation analysis is now the preferred method used to establish a specific diagnosis for this disease.
Glycogen storage disease type VI and IX (GSD VI and IX)
SIGNS / SYMPTOMS
Patients with GSD VI (glycogen phosphorylase deficiency) and GSD IX (phosphorylase kinase deficiency) are often clinically indistinguishable.
Hypoglycemia typically is not as severe as in GSD I or GSD III; symptomatic hypoglycemia during infancy is uncommon unless there is a prolonged fast, which may be associated with hyperketosis.
Metabolic acidosis is rare.
Common presenting symptoms are an enlarged liver and distended abdomen noted during a physical exam.
Physical growth may be impaired during childhood and onset of puberty is frequently delayed, but catch-up growth during puberty results in normal adult height.
Clinical and biochemical abnormalities gradually ameliorate, and most adult patients are asymptomatic.
INVESTIGATIONS
At the time of hypoglycemia, uric acid levels are usually normal, as is blood lactate (though lactate levels are elevated in patients with a specific mutation in the gamma subunit).
Hypercholesterolemia may occur, and ketosis occurs with fasting. This disorder should be considered in the differential diagnosis of “ketotic hypoglycemia”.
After an overnight fast, blood lactate level is normal.
Mutation analysis is now the preferred method used to establish a specific diagnosis for these diseases.
A diagnosis of GSD VI or IX can be established by assaying the activity of phosphorylase in erythrocytes and leukocytes: muscle phosphorylase activity, muscle histology, and glycogen content are normal.
Glycogen storage disease type XI (GSD XI)
SIGNS / SYMPTOMS
GSD XI (Fanconi-Bickel syndrome) is an extremely rare disorder caused by a deficiency in the facilitative glucose transporter GLUT-2 that has an essential role in the liver, pancreas, intestine, and kidney.
Patients usually present in infancy with symptoms of renal tubulopathy, faltering growth, and hypoglycemia as the interval between meals increases.
Differentiating signs and symptoms include hypophosphatemic rickets and a Fanconi-like tubulopathy, which are characteristic features.
Many patients have short stature and may have chronic diarrhea from carbohydrate malabsorption.
INVESTIGATIONS
Fasting ketotic hypoglycemia and postprandial hyperglycemia are essential distinguishing features, developing due to impaired hepatic uptake of glucose and disordered insulin secretion.
Other laboratory findings include glucosuria, proteinuria, phosphaturia, hypergalactosemia, generalized aminoaciduria, and elevated alkaline phosphatase.
Mutation analysis of the SLC2A2 gene encoding the GLUT2 transporter confirms a diagnosis of GSD XI.
Fructose-1-6-bisphosphatase deficiency
SIGNS / SYMPTOMS
Fructose 1-6-bisphosphatase deficiency is an extremely rare gluconeogenesis disorder that shares many clinical and laboratory features with GSD I.
Some infants present with recurrent hypoglycemia and severe lactic acidosis in the first month of life.
Hypoglycemia occurs between feedings, with prolonged fasting or intercurrent illness.
Hepatomegaly develops due to fatty infiltration and is not due to glycogen accumulation.
INVESTIGATIONS
The biochemical abnormalities are similar to those in GSD I, but in contrast to GSD I, when glucagon administration is performed in the fed state it elicits a brisk glycemic response.
Urinary glycerol may be increased.
Genetic testing for variants in FBP1, the gene that encodes fructose-1-6-bisphosphatase, is now the preferred method confirming the diagnosis.
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