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Maha Nasser

on 30 November 2015

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Transcript of 

Glycogen Storage Disease Type I
Glycogen Storage Disease (GSD)
GSD I is the most common type of glycogen storage disease, and accounts for 90% of all glycogen storage disease cases.
Overall incidence of GSDI is one in 100,000-500,000 births.
Glycogen-storage disease Ia and Ib occur with equal frequency in both sexes.
As genetic disorders, both types are present at conception, with clinical onset at birth.
Abnormal laboratory findings including:
1-Hypoglycemia= abnormally low blood sugar.
2-Lactic acidosis = low pH in body tissues and blood (acidosis) accompanied by the buildup of lactate.
3-Hyperuricemia =excess of uric acid in the blood.
4-Hyperlipidemia = abnormally high conc. of fats or lipids in the blood.
What is glycogen storage disease type I?
Is an inherited disorder result of defects in the processing of glycogen synthesis or breakdown within muscles, liver, and other cell.

This defect is due to deficiency of the enzyme (glucose 6 – phosphatase)
GSD type Ia :
 caused by the deficiency of glucose-6-phosphatase (G6Pase) catalytic activity
GSD type Ib :
caused by a defect in glucose-6-phosphate translocase (transporter).

The lack of either G6Pase catalytic activity or glucose-6-phosphate translocase (transporter) activity in the liver leads to inadequate conversion of glucose-6-phosphate into glucose through normal glycogenolysis and gluconeogenesis pathways, resulting in severe hypoglycemia and many other signs and symptoms of the GSDI disorders.

The liver loses its capacity as a glucose-homeostatic organ because of a fundamental inability to release free glucose. Glycogen-storage disease type I (subtypes Ia and Ib) is one of the few genetic-biochemical causes of hypoglycemia in newborns. The usual homeostatic mechanism cannot halt the rapid drop in blood glucose levels that normally occurs during the first several hours after birth (reflecting consumption of maternal glucose), and the decrease continues. This decrease in circulating glucose can be precipitous, resulting in no measurable blood level. Seizures, cyanosis, and apnea may ensue. In older children, repeated episodes of hypoglycemia may result in brain damage, as measured on performance testing and assessment of brainstem auditory-evoked potentials.

2-Lactic acidosis
In the hepatocyte, the glycogen catabolic machinery normally responds to stimuli caused by hypoglycemia (eg, neural, hormonal), ending in a flood of glucose-6-phosphate that cannot be released from the cell. However, glucose-6-phosphate is also the substrate for glycolysis and produces lactate. Lactate exits the hepatocyte, causing clinically significant lactic acidemia in proportion to the degree of stimulus for glycogen breakdown. The accumulation of lactic acid in blood can cause true acidosis with a large anion gap, a characteristic of glycogen-storage disease type I.
In General:
Glycogen storage diseases (GSDs) are a group of inherited genetic disorders that cause glycogen to be improperly stored in the body. People with glycogen storage diseases have a buildup of abnormal “amounts” or “types” of glycogen in their tissues.
What is the importance of
Glucose 6-phosphatase ?!
GSD-I is also referred as “Von Gierke disease” after Dr. Von Gierke described it.

In 1929, von Gierke provided the initial description of glycogen-storage disease type I (GSD I) from autopsy reports of 2 children whose large livers contained excessive glycogen. He also reported similar findings in the kidneys. Both children had frequent nosebleeds before their deaths, consistent with histories documented in current patients.

The immense increase in the intracellular phosphorylated intermediate compounds of glycolysis concurrently inhibits rephosphorylation of adenine nucleotides, activating the nucleic acid degradation pathway and resulting in increased uric acid, the end product. Hyperuricemia can reach levels that require use of xanthine oxidase inhibitors to prevent nephrolithiasis. Nephrolithiasis secondary to increased uric acid is a constant  threat  to patients with poorly controlled disease.
Severe hypoglycemia stimulates epinephrine secretion, which activates lipoprotein lipase and the release of free fatty acids. These fatty acids are transported to the liver, where they are used for triglyceride synthesis and are exported as very-low-density lipoprotein (VLDL), which is elevated in these patients
swollen abdomen 1-Enlarged liver and kidney
2-Low blood sugar
3-High levels of lactate, fats, and uric acid in the blood
.4-Impaired growth and delayed puberty
5- ,Bone thinning from osteoporosis.
 'doll's face' due to deposition of fat.. 6-
6-Recurrent headaches
7-Sleep disturbances.
. 8- Confusion
11-chronic hunger.

Mode of Inheritance
Molecular genetic testing:
Carrier testing is possible if the family-specific mutations are known.

Biochemical genetic testing:
 Enzymatic testing is unreliable and not available for use in carrier detection.
*Glycogen-storage disease type Ia (GSD Ia) has no specific medication requirement beyond prophylactic PO iron and prompt treatment of intercurrent infections (which may interrupt PO intake).
*Hepatic transplantation has been attempted in a few cases with modified success.

Treatment depends on the type of GSD. Some GSD types cannot be treated; others are fairly easy to control by treating the symptoms.
“Diet” , is the mainstay of therapy for both types of GSDI ,requires close monitoring and adjustment by highly specialized nutritionist.
Maintain normal glucose levels and prevent hypoglycemia by :
1-Frequent daytime feedings (high carbohydrate meals) .
2-Uncooked “cornstarch” orally can be started during infancy.
3-Nighttime intragastric continuous glucose .(infusion (continuous nighttime feeding
Glycogen storage disease type I (GSDI) is inherited in an autosomal recessive manner.
*Unfortunately, most of the patients are passed away at early life ,and few of them lived after childhood .
*Currently, efforts are underway in animal models to develop gene therapy in patients with both forms of glycogen-storage disease type I.
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