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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).

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von Gierke Disease; Hepatorenal Glycogenosis Disease; Glycogenosis Type I.

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  • 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.

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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 infections.

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Type I glycogenosis is unlikely to occur more frequently than 1:50,000 infants.

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Autosomal recessive. Two main types described:

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  • 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.

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Two other types, Ic and Id, have been reported and correspond to unusual mutations in the translocase gene at locus 11q23.

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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 ...

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