Exercise & Sports Performance, Metabolic Syndrome, Musculoskeletal

Low‑carbohydrate ketogenic diet in McArdle’s disease: a single‑blinded randomized controlled trial

McArdle disease, also known as glycogen storage disease type 5 (GSD5 ), is a rare genetic disorder resulting from a deficiency of muscle glycogen phosphorylase. This enzyme is required for glycogen breakdown, and its absence impairs energy production during anaerobic exercise. Patients typically experience early fatigue, muscle pain, and risk of rhabdomyolysis. A major metabolic limitation in GSD5 involves reduced substrate entry into the tricarboxylic acid (TCA) cycle. Ketogenic diets, which increase reliance on fat-derived fuels and ketone bodies, may help bypass this limitation. However, controlled studies evaluating long-term effects are limited.

Methods

In a single-blind randomized controlled trial, 21 adults with genetically confirmed GSD5 were assigned to either a low-carbohydrate ketogenic diet (LCKD; n=11) personalized by a dietitian or their regular diet (control; n=10) for six months. Key outcomes included safety, adherence, and changes in peak oxygen uptake (VO₂ peak). Secondary outcomes assessed changes in walking capacity (12-minute walk test), peak workload, and self-reported quality of life (SF-36) and disability (WHO-DAS 2.0). Ketosis was confirmed by blood β-hydroxybutyrate (BHB) measurements taken at home daily for the first week, biweekly for the second and third week, and weekly for the remainder of the trial.

Key Results

Aerobic fitness:

• VO₂ peak increased by 2.7 ml/kg/min in the LCKD group
• No significant change in the control group

Walking performance:

• 12-minute walk distance increased by 180 feet **(**55 meters) with LCKD
• Decreased by 147 feet (44.7 meters) in controls

Body weight:

• BMI dropped significantly (-2.3 kg/m²) in the LCKD group
• No change in the control group

Exercise workload:

• Slight increase in peak power in LCKD (+1.9 watts)
• Modest decline in controls (−2.5 watts)

Heart rate response:

• Maximal heart rate rose by 14.6 beats per minute in the LCKD group

Patient-reported outcomes:

• SF-36 physical and mental scores improved modestly (not statistically significant)
• WHO-DAS 2.0 disability scores decreased slightly

Tolerability and safety:

• No serious adverse events occurred
• Mild, transient side effects included nausea, lethargy, and constipation
• All LCKD participants achieved measurable ketosis (mean BHB 1.07 mmol/L)

Notably, five LCKD participants remained on the diet and have reported maintained functional benefits after three years.

Conclusion:
The ketogenic diet was safe, tolerable, and led to significant improvements in aerobic capacity and walking performance in adults with GSD5 over six months. These results support the use of a personalized LCKD as a sustainable therapeutic strategy for enhancing functional capacity in McArdle disease.