Symptoms of PFK deficiency are similar to those of myophosphorylase deficiency. Patients experience premature muscle fatigue and are subject to exertional pain, cramping, and nausea, and to recurrent exertional myoglobinuria. Fixed muscle weakness associated with muscle atrophy and fatty replacement are common with advancing age.

Substrates available for working muscle are more limited in muscle PFK deficiency than in myophosphorylase deficiency, as the metabolic defect blocks utilization of glucose as well as glycogen. As a result, patients are heavily dependent on lipids to meet muscle energy requirements. Muscle oxidative metabolism and exercise capacity are augmented (second wind) by increased availability of FFAs. In contrast, exercise capacity dramatically drops when fatty acid levels are reduced by a carbohydrate meal or intravenous glucose. This state of severe deficiency is the presence of a partial enzyme defect in red blood cells, with resulting compensated hemolytic anemia.

Treatment is similar to that for McArdle's disease: attempt to optimize substrate availability by warming up before exercise; engaging in regular aerobic training to improve the capacity to oxidize fatty acids; avoiding ischemic, isometric exercise; and instituting prompt treatment of acute muscle injury with myoglobinuria.