Glycogen Storage Diseases (GSDs)

Glycogen Storage Diseases (GSDs)

Use of the ketogenic diet in “muscular” glycogenoses.

Glycogen storage diseases (GSD) type III, V, and VII share a clinical picture consisting of progressive intolerance to exertion, muscle pains, and cramps with deterioration of muscle structure, leading to progressive loss of its functional capacity. At the root of this muscle damage is the enzymatic defect in these diseases that prevents the correct utilization of carbohydrates to produce energy because normal glycogenolysis activity (GSD III and GSD V) or glycolysis (GSD VII) is blocked. However, in these diseases, gluconeogenesis, that is, the ability to produce sugar from other substrates such as proteins and fats, is intact.
In addition to the muscle, there are also other organs affected, varying depending on the type of GSD. In some cases, the damage is due to glycogen accumulation, while in others it is simply due to energy deficiency. While in GSD V only skeletal muscles are involved, in GSD III the liver and/or the heart are also affected (there is also a small percentage of patients with only hepatic involvement), and in GSD VII, a picture of hemolytic anemia is also observed.

The currently recommended treatment for GSD III involves administering frequent high-protein meals (proteins, through gluconeogenesis, can produce glucose), with supplementation of raw cornstarch to prevent hypoglycemia. The proposed diet for GSD type V is carbohydrate-rich to promote hepatic glycogenolysis, which is intact in this disease, and small amounts of sugary drinks are recommended before physical exertion to ensure circulating glucose that can be used by the muscles.

Despite the currently proposed treatments, clinical observation of patients shows progressive deterioration with age. In the scientific literature, since the 1970s, there have been some reports of GSD V patients who have had significant clinical (improved exercise tolerance) and biochemical (very significant reduction in CPK) improvements following treatment with a high-fat/ketogenic diet. Even more reports concern GSD III, where a significant improvement in cardiomyopathy and exercise tolerance has been observed, along with a very clear reduction in muscle biochemical parameters.

The most evident finding, from the point of view of managing GSD III patients treated with a high-fat/ketogenic diet, is that they can suspend the nightly meal and gradually reduce and then suspend the raw cornstarch because blood glucose remains constant even during an overnight fast of 8-10 hours. Recently, reviews have been published commenting on the possibility that excess sugars may be harmful in muscular glycogenoses and suggested considering treating patients with a high percentage of proteins and fats and reducing sugars as much as possible, especially simple ones.
Although the reports in the literature always concern one or more case reports, reassessing them all together, these cases constitute good evidence of the effectiveness of the high-fat/ketogenic diet in muscular glycogenoses. The purpose of the diet is to ensure that the patient always has ketones available as an alternative energy source to glucose. In this sense, synthetic ketone bodies have been administered to patients, but this is not a sustainable long-term treatment because synthetic ketone bodies have poor palatability.

The ketogenic diet could also be prepared with only natural foods, choosing them from those with a low glycemic index. However, this would entail significant dietary restrictions that would ultimately make it difficult to maintain such a diet. Therefore, it is necessary for patients with muscular glycogenoses, who must follow the diet for life, to have the widest possible choice of ketogenic foods available to them to maintain a sufficiently varied diet that can be maintained long-term without difficulty.

Commercial preparations for the ketogenic diet are therefore indispensable for maintaining a palatable diet for a long time and to prevent the patient from discontinuing treatment. I conclude by reminding that the ketogenic diet must always be supplemented with vitamins and minerals and must be closely monitored by experienced physicians and dietitians. Patients on a ketogenic diet should have blood tests checked approximately every 3 months and, if they are still growing, weight and height should be checked at each visit (there are indeed reported cases of growth arrest after starting the ketogenic diet).