Type I Glycogen Storage Diseases

GeneReviews Link for Type I GSD

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Enzymes of Type I Glycogen Storage Diseases

The mechanism by which free glucose is released from glucose-6-phosphate involves several different steps. Glucose-6-phosphate must first be transported from the cytosol where it is generated either through phosphorylation of free glucose or from gluconeogenesis, into the lumen of the endoplasmic reticulum, ER. Inside the ER the phosphate is removed through the action of ER localized glucose 6-phosphatase. The free glucose must then be transported back to the cytosol as well as the released inorganic phosphate, Pi. Defects in the process of glucose release from glucose-6-phosphate result in elevations in cytosolic glucose-6-phosphate which then leads to increases in incorporation into glycogen and subsequent excessive storage.

Reactions in the ER to convert glucose-6-phosphate conversion to glucose

Mechanism of glucose-6-phosphate conversion to free glucose.

Type I glycogen storage disease (GSD) is an autosomal recessive disorder that was first described in 1929 by E. von Gierke as a "hepato-nephromegalia glycogenica". For this reason the disease is still more commonly referred to von Gierke disease. In 1952, G. Cori and C. Cori identified that the absence of glucose 6-phosphatase activity was the cause of von Gierke disease. This discovery was the first ever identification of an enzyme defect in a metabolic disorder. Subsequent to the identification of the pathway of glucose release from glucose-6-phosphate, additional patients with similar clinical manifestations to von Gierke disease were identified. However, these patients were not deficient in glucose-6-phosphatase. These latter patients were identified as having type Ib GSD. Type Ia GSD is caused by a defect in the ER localized glucose 6-phosphatase. Type Ib disease results from defects in the glucose-6-phosphate transporter 1. Type Ic GSD was identified in 1983 and found to be the result of defects in the microsomal pyrophosphate transporter. This form of type I GSD has only been found in few cases. As shown in the Figure above, there are 4 enzyme activities that function in the release of free glucose in the cell and as such there is the theoretical possibility that type Id GSD would be caused by defects in the microsomal glucose transporter (identified as GLUT in the Figure). However, no individuals have been reported to exist with a defect in this latter enzyme activity.

The metabolic consequences of the hepatic glucose-6-phosphate deficiency of von Gierke disease extend well beyond just the obvious hypoglycemia that results from the deficiency in liver being able to deliver free glucose to the blood. The inability to release the phosphate from glucose-6-phopsphate results in diversion into glycolysis and production of pyruvate as well as increased diversion onto the pentose phosphate pathway. The production of excess pyruvate, at levels above of the capacity of the TCA cycle to completely oxidize it, results in its reduction to lactate resulting in lactic acidemia. In addition, some of the pyruvate is transaminated to alanine leading to hyperalaninemia. Some of the pyruvate will be oxidized to acetyl-CoA which can't be fully oxidized in the TCA cycle and so the acetyl-CoA will end up in the cytosol where it will serve as a substrate for triglyceride and cholesterol synthesis resulting in hyperlipidemia. The oxidation of glucose-6-phophate via the pentose phosphate pathway leads to increased production of ribose-5-phosphate which then activates the de novo synthesis of the purine nucleotides. In excess of the need, these purine nucleotides will ultimately be catabolized to uric acid resulting in hyperuricemia and consequent symptoms of gout. The interrelationships of these metabolic pathways is diagrammed in the Figure below.

metabolic pathway disruption in von Gierke disease

Interrelationships of metabolic pathway disruption in von Gierke disease: In the absence of glucose-6-phosphatase activity free glucose cannot be release from the liver contibuting to severe fasting hypoglycemia. In addition the increased glucose-6-phosphate levels lead to increased pentose phosphate pathway (PPP) activity as well as increased glycolysis to pyruvate. The incresased levels of pyruvate lead to increased lactate produciton via lactate dehydrogenase (LDH) and alanine via alanine transaminase (ALT). In addition, the increased pyruvate is oxidized via the pyruvate dehydrogenase complex (PDHc) leading to increased production of acetyl-CoA which is, in turn, used for the synthesis of fatty acids and cholesterol. The excess glycolysis also results in increased production of glycerol-3-phosphate (G3P) from DHAP via the action of glycerol-3-phosphate dehydrogenase (GPD1). Increased G3P and fatty acids leads to increased triglyceride synthesis which, in conjunction with the increased cholesterol, leads to hyperlipidemia as well as fatty infiltration in hepatocytes contributing to hepatomegaly and cirrhosis.

Genetics of Type I Glycogen Storage Diseases

Humans express three glucose 6-phosphatase catalytic subunit genes identified as G6PC, G6PC2, and G6PC3. Mutations in the G6PC gene are the cause of type Ia GSD (classic von Gierke disease). The G6PC gene is located on chromosome 17q21 spanning 12.5 kb and is composed of 5 exons that generate two alternatively spliced mRNAs. Mutations in the G6PC gene account for approximately 80% of all type I GSD cases.

The glucose-6-phosphate transporter 1 protein is a member of the solute carrier family of membrane transporters. The gene that encodes this transporter is the solute carrier family 37, member 4 (SLC37A4) gene. Mutations in the SLC37A4 gene result in type Ib GSD (GSDIb). The SLC37A4 gene is located on chromosome 11q23.3 and is composed of 12 exons that generate five alternatively spliced mRNAs that encode three distinct isoforms of the protein. The mRNA found in the brain contains exon 7 whereas the one in the liver does not contain this exon. Mutations in the SLC37A4 gene account for approximately 20% of all type I GSD cases.

The ER inorganic phosphate transporter (type Ic GSD) gene maps to chromosome 11q23–q24.2 which is very near the location of the SLC37A4 (G6PT1) gene described above for type Ib GSD.

Analysis of mutations resulting in type I GSD have been most extensively studied in type Ia disease. The 130X mutation is the result of a 2-base pair (bp) insertion in exon 3 of the G6PC gene resulting in a translation stop codon at nucleotides 467–469 (identified as FS130TER). This mutation has, thus far, only been found in Hispanic patients. All Ashkenazi Jews with type Ia GSD have been shown to harbor a mutation in exon 2 resulting in the mutation of arginine 83 to a cysteine (R83C). One compound heterozygote patient has been identified harboring two mutations in G6PC where one was the R83C mutation and the second was arginine 295 mutated to a cysteine (R295C). Twelve additional mutations have been mapped to the G6PC gene: R83H, I341D, G188R, A124T, IVS1DS (mutation in the splice donor site of intron 1), W77R, D38V, IVS4AS (mutation in intron 4 resulting in an alternative splice site), Q347X (mutation resulting in a termination codon), V166G, G184E, E110K.

Clinical Findings of Type I Glycogen Storage Diseases

Patients with type I glycogen storage disease can present during the neonatal period with lactic acidosis and hypoglycemia. More commonly though, infants of 3–4 months of age will manifest with hepatomegaly and hypoglycemic seizures. The hallmark features of this disease are hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. The severity of the hypoglycemia and lactic acidosis can be such that in the past affected individuals died in infancy. Infants often have a doll-like facial appearance due to excess adipose tissue in the cheeks. In addition, patients have thin extremities, a short stature, and protuberant abdomens (due to the severe hepatomegaly).

Long-term complications are usually only seen now in adults whose disease was poorly treated early on. The main problem is associated with liver function but multiple organ systems are also involved, in particular the intestines and kidneys. Growth will continue to be impaired and puberty is often delayed. Affected female patients will have polycystic ovaries but none of the other symptoms of polycystic ovarian syndrome (PCOS) such as hirsutism.

The common treatment for type I glycogen storage disease is to maintain normal blood glucose concentration. With normoglycemia will come reduced metabolic disruption and a reduced morbidity associated with the disease. To attain normoglycemia patients are usually treated in infancy with nocturnal nasogastric infusion of glucose. Total parenteral nutrition or the oral feeding of uncooked cornstarch can also achieve the desired results.

In the past the prognosis for type I glycogen storage disease patients was poor. However, with proper nutritional intervention growth will improve and the lactic acidosis, cholesterol and lipidosis will decrease.












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Last modified: June 3, 2015