ReviewThe respiratory neuromuscular system in Pompe disease

•Pompe disease occurs due to mutations in the gene encoding the lysosomal enzyme acid α-glucosidase (GAA).•Respiratory insufficiency and tongue motor problems are common.•Enzyme replacement therapy targets skeletal muscle but many patients still require ventilatory assistance.•Emerging evidence indicates that respiratory neuron pathology contributes to motor unit dysfunction.•Restoration of GAA activity in respiratory muscles and neurons may be required to correct ventilatory insufficiency.

Pompe disease is due to mutations in the gene encoding the lysosomal enzyme acid α-glucosidase (GAA). Absence of functional GAA typically results in cardiorespiratory failure in the first year; reduced GAA activity is associated with progressive respiratory failure later in life. While skeletal muscle pathology contributes to respiratory insufficiency in Pompe disease, emerging evidence indicates that respiratory neuron dysfunction is also a significant part of dysfunction in motor units. Animal models show profound glycogen accumulation in spinal and medullary respiratory neurons and altered neural activity. Tissues from Pompe patients show central nervous system glycogen accumulation and motoneuron pathology. A neural mechanism raises considerations about the current clinical approach of enzyme replacement since the recombinant protein does not cross the blood-brain-barrier. Indeed, clinical data suggest that enzyme replacement therapy delays symptom progression, but many patients eventually require ventilatory assistance, especially during sleep. We propose that treatments which restore GAA activity to respiratory muscles, neurons and networks will be required to fully correct ventilatory insufficiency in Pompe disease.