Type I Glycogen Storage Diseases
OMIM Link for von Gierke Disease, Type Ia
OMIM Link for Type Ib Disease
OMIM Link for Type Ic Disease
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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.
Mechanism of glucose-6-phosphate conversion to free glucose.
Type I glycogen storage disease (GSD) 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.
Genetics of Type I Glycogen Storage Diseases
The human glucose 6-phosphatase gene (type Ia GSD) is a single copy gene located on chromosome 17q21 and the gene symbol is G6PC. The gene spans 12.5 kb and is composed of 5 exons.
The glucose-6-phosphate transporter 1 gene (type Ib GSD) is located on chromosome 11q23 and the gene symbol is G6PT1. The gene spans 5.3 kb and is composed of 9 exons that encodes a protein of 429 amino acids. The mRNA is subject to alternative splicing such that exon 7 is found in the brain form of the mRNA but not the liver mRNA.
The ER inorganic phosphate transporter (type Ic GSD) gene maps to chromosome 11q23–q24.2 which is very near the location of the 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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Michael W. King, Ph.D / IU School of Medicine / miking at iupui.edu
