Severe inborn liver dysfunction caused by an almost
total deficiency of hepatic glucose-6-phosphatase (type Ia) or a defect in
intracellular transport of the enzyme substrate (type Ib), resulting in
severe hypoglycemia and its consequences (seizures, cyanosis, apnea).
von Gierke Disease; Hepatorenal Glycogenosis Disease;
Glycogenosis Type I.
- Type Ia:Glucose-6-Phosphate Deficiency: Characterized by a deficiency in the enzyme glucose-6-phosphatase.
- Type Ib: Glucose-6-Phosphate Translocase Deficiency: Characterized by a deficiency of the specific translocase T1. The clinical
consequences are related to the result of altered neutrophil functions
predisposing them to Gram-positive bacterial infections.
- Type Ic: Glucose-6-Phosphate Translocase T2 Deficiency: Characterized by a deficiency of translocase T2, which carries anorganic
phosphates from microsomes into the cytosol and pyrophosphates from the
cytosol into microsomes
- Type Id: Glucose-6-Phosphate Transporter Deficiency: Characterized by a deficiency in the transporter that translocates free
glucose molecules from microsomes into the cytosol.
First described by Edgar Otto C. von Gierke, a German
pathologist (1877-1945), in 1929 under the name hepatonephromegalia glycogenica.
In 1952, Cori and Cori demonstrated that glucose-6-phosphatase deficiency was a cause of
GSD type I. In 1978, Narisawa proposed that a transport defect of glucose-6-phosphate
into the microsomal compartment may be present in some patients with GSD type I.
Following this observation, GSD type I was divided into GSD Ia resulting from deficiency
in glucose-6-phosphatase and GSD type Ib resulting from deficiency of a specific
translocase T1. Apart from the substrate translocation defect, patients with GSD type Ib
have altered neutrophil functions predisposing them to Gram-positive bacterial
Type I glycogenosis is unlikely to occur more frequently
than 1:50,000 infants.
Autosomal recessive. Two main types described:
- Type Ia: Deficient activity of glucose-6-phosphatase enzyme as a result of
mutations (at least 14 allelic variants described) at locus 17q21.
- Type Ib: Deficient activity of glucose-6-phosphate translocase as a result of
mutations at locus 11q23.
Two other types, Ic and Id, have been reported and correspond to unusual
mutations in the translocase gene at locus 11q23.
Inability of the liver to release free glucose and
accumulation of glycogen in the liver. Hypoglycemia elicits a flood of
glucose-6-phosphate that cannot be released from the cell.
Glucose-6-phosphate is also the substrate for glycolysis and produces
lactate, which exits the hepatocyte, thus producing lactic acidosis with a
large anion gap. At the same time, accumulated phosphorylated intermediate
compounds of glycolysis inhibit rephosphorylation of adenine nucleotides,
thus activating the nucleic acid degradation pathway and increasing the
production of uric acid (danger of nephrolithiasis). Hypoglycemia stimulates
the release of epinephrine, thus activating lipoprotein lipase and
secretion of free fatty acids, which are used for triglyceride synthesis and
exported as very-low-density lipoproteins (VLDLs, which are increased in GSD
I patients). GSD I patients do not develop significant ketosis because the
abundance of acetyl-coenzyme A (derived from glycolysis) activates the
acetyl-CoA carboxylase that produces malonyl-CoA ...