Year of grant:
Health status of heterozygous glycogen storage disease type IIIa cases in the Faroe Islands with special focus on lipid levels
Ulrike Steuerwald, David Weinstein og Laurie Minarich
Grant from the FRC in DKK:
Glycogen storage disease type IIIA is an autosomal inherited disorder caused by mutations in the amyloglucosidase gene (AGL). This gene codes for the debranching anzyme which is responsible for the breakdown of glycogen.
Normally glycogen is stored in liver and muscles andi s broken down to glucose when needed. In liver, glycogen serves as a glucose reservoir for the mainterance of normoglycemia during fasting periods. In muscle, glycogen provides energy for muscle contraction. In peaple with GSD3a, this breakdown is impaired, so only a partial breakdown is possible. As a result, massive amounts of glycogen are stored in the liver and muscles and cannot be broken down. In GSD3a patients, metabolic derangements in the form of hypoglycaemia occur when exogenous sources of glucose areexhausted and gluconeogenesis is not yet able to meet whole body glucose needs. Therefore, dietary tretment is aimed at achieving metabolic control by mimicking the demanded actual endogenous glucose production during day and night. Worldwide frequency og GSDIIIa is estimated to be 1 in 100.000.
Current recommendations for treatment focus on strict dietary control. Frequent feedings to avoid hypoglycaemia and high protein diet are recommended to avoid unnecessary glycogen storage and provide analternate source for glucose via gluconeogenesis. Complex carbohydrates are preferred to simple because they take longer to digest. Traditionally Faroese people have had a high intake of protein. Because of the remote location they have been dependent on food resources around them, mainly from the sea, e.g. fish and whales. This might explain why Faroese GSD3a cases doing better than those in other places with a lower protein intake.
Hypoglycaemia promotes elevation in blood triglyceride levels.
Some studies have shown that GSD3a cases have higher lipid levels in the blood than controls, while other studies did not come to this conclusion. Hyperlipidaemia is a well known risk factor for atherosclerosis and ischaemic heart disease.
Heterozygotes which by definition have one normal allele and one diseased allele of the gene, are considered to have normal metabolic function and no symptoms of GSD3a.
Clinical observations however could suggest that may have small signs of metabolical dysfunction.
My hypothesis is that Heterozygotes have a less efficient mobilization of glucose from the liver andmuscles compared to peaple without mutations in the AGL-gene. Therefore they are more prone to become hypoglycaemic, and as a result of that develop hyperlipidemia. This will be tested with genetic tests to find the gene status of the subjects. We will then take blood samples to investigate whether there is a difference in lipid levels between the two groups.