The body of scientific literature supporting low-carb and ketogenic diets for numerous health issues is undeniable. Carbohydrate restriction is a powerful dietary therapy for managing blood sugar and insulin in people with type 2 diabetes or metabolic syndrome, for improving the signs and symptoms of PCOS, and for non-alcoholic fatty liver disease (NAFLD). Reduced carb diets are also proving effective in applications for which they haven’t been traditionally employed, such as acid reflux/GERD and migraines, and they’re showing promise in conditions for which conventional treatments are lackluster, such as Parkinson’s disease and mild Alzheimer’s disease. An exciting new area for research into the potential therapeutic effects of ketogenic diets is glycogen storage diseases (GSDs).

There are numerous different types of GSDs, each one caused by abnormalities in a different enzyme or biochemical process. For example, GSD 0 involves deficiency of glycogen synthase, so these patients do not produce glycogen effectively. Most other GSDs have to do with breaking down, accessing, or using glycogen: GSD III is caused by reduced activity of a glycogen debranching enzyme; GSD IX involves deficiency of phosphorylase kinase, which plays a key regulatory role in the breakdown of glycogen. Research suggests that ketogenic diets may be helpful for various forms of GSD. McArdle disease (GSD V) is one for which there’s the most supportive data so far.

McArdle disease is an autosomal recessive genetic disorder based in mutations to the PYGM gene. (Heterozygous individuals are asymptomatic.) This mutation causes a deficiency in skeletal muscle glycogen phosphorylase, which manifests as “complete inability to use muscle glycogen stores,” resulting in exercise intolerance, rapid muscle fatigue, myalgia, and cramps in exercising muscles. (A “second wind” phenomenon is well-known in this condition: relief of fatigue and myalgia is relieved after a few minutes of rest, after which the patient is able to exercise again. It’s believed the increased stamina “is attributable to an enhanced sympathoadrenal response and to an improved delivery of extramuscular energy substrates, free fatty acids, and glucose to working muscles, which partially compensates for the impaired glycogen breakdown.”

Because glycogen breakdown is impaired, local glucose supply to working muscles is limited, which then limits the availability of pyruvate that would have been produced via glycolysis. Limited supply of pyruvate then reduces oxidative phosphorylation and leads to an abnormally low amount of substrate for energy generation via the Krebs cycle. This explains the rapid muscle fatigue and exercise intolerance McArdle patients experience. Oxygen consumption in McArdle patients is just 35-40% of that in people without the condition, and they also experience a disproportionate increase in heart rate and ventilation during exercise.

Higher protein diets may be beneficial for improving the symptoms of McArdle disease, since amino acids are substrates for gluconeogenesis, and the branched-chain amino acids (BCAAs), in particular, can serve as direct fuel for muscle cells, although it may be best to directly supply the TCA cycle intermediates these compounds become, since enzyme activity to convert them may not be able to keep up with demand in the context of McArdle disease.

Dramatically reducing dietary carbohydrate intake and increasing fat and protein may be even more effective for those with this condition. If the primary problem is that McArdle patients are not able to break down glycogen, which limits the glucose supply to working muscle cells, then a potential solution is to provide these cells with alternative fuels, namely, fatty acids and ketones. Glucose is the primary fuel for muscles during high intensity efforts, but fat predominates at lower intensity. However, the proportional use of fuel shifts depending on the available supply. Athletes on ketogenic diets burn proportionally more fat even at higher intensities compared to those on high-carb diets. It appears that if more fat is available and the body is adapted to using it efficiently, more fat will be used.

Although clinical trials studying ketogenic diets for McArdle disease are few, the results are encouraging, especially when combined with a growing number of anecdotal reports from patients attesting to substantial improvements from the dietary shift. One case report involves a 55 year-old man with McArdle disease. Following a ketogenic diet (80% fat; 14% protein [1 g/kg/d] and the remainder from carbohydrate) resulted in elevated blood levels of the ketone beta-hydroxybutyrate (2-6 mmol/L), and exercise tolerance was increased 3- to 10-fold depending on the endurance level. Dramatically elevated creatine kinase (CK) is a feature of McArdle disease owing to skeletal muscle damage, likely due to the breakdown of muscle tissue to create a local glucose supply. In this case report, CK dropped from 5,300 U/L to 890 U/L on the ketogenic diet.

As we’ve written about previously with regard to type 1 diabetes, patients with McArdle disease are taking matters into their own hands and are adopting ketogenic diets for self-management of their condition. While they have not yet published clinical trial data, we should not ignore anecdotal evidence, particularly when numerous patients report improvements, and also particularly when these improvements occur in a condition that is typically difficult to treat.

Members of a Facebook group (Ketosis in McArdle’s) presented the results of a group survey at a conference at Columbia Medical Center in 2015. Many respondents reported being unable or unwilling to implement a ketogenic diet, partly owing to lifestyle factors (inconvenient, difficult to follow, conflicting advice about nutrition), and partly to their physician not being supportive of the approach. However, among those who did adhere to the diet, results were very intriguing:

• 73% of respondents reported feeling as though they are in permanent second wind
• 85% reported an improvement of everyday symptoms; 12% slight improvement; 3% no change 
• 76% reported improvement in exercise tolerance; 18% slight improvement; 6% no change

Reported side-effects were not unusual for individuals on ketogenic diets (e.g., headaches, fatigue, dizziness, constipation), and are most often caused by electrolyte imbalances which are easily managed by ensuring adequate sodium intake and sometimes supplemental magnesium and/or potassium.

It will be interesting to watch as results from more recent clinical trials studying ketogenic diets in McArdle disease are published, and others are currently underway. Perhaps some of them will also employ exogenous ketones or MCT oil formulations for those who find it difficult to adhere to the diet. We’re learning from researchers and from patients themselves that the therapeutic effects of ketogenic diets go far beyond their powerful use for epilepsy, weight loss and blood sugar control.