Hypoglossal motoneuron pathology in a mouse model of Pompe disease

Abstract

Pompe disease is a lysosomal storage disorder associated with acid α‐glucosidase (GAA) deficiency. Both diaphragm and upper airway muscle dysfunction occur in Pompe disease and this may reflect central nervous system (CNS) pathology. We used a murine model of Pompe disease to test the hypothesis that systemic GAA deficiency is associated with hypoglossal (XII) motoneuron pathology and altered XII motor output. Brainstem tissue was harvested from adult Gaa−/− mice and the periodic acid Schiff (PAS) method was used to examine neuronal glycogen accumulation. Semi‐thin (2 μm) plastic sections showed extensive cytoplasmic glycogen accumulation in XII motoneuron soma. Phrenic and XII bursting was recorded in anesthetized and ventilated Gaa−/−and B6/129 mice before and after bilateral vagotomy. Vagotomy caused a robust increase in XII inspiratory burst amplitude in B6/129 mice (238 ± 44 %baseline; P < 0.01) but had little impact on burst amplitude in Gaa−/−mice (130 ± 23 %baseline; P > 0.05). Regression analysis revealed that phrenic and XII burst amplitudes were significantly correlated in B6/129 (r2 = 0.27, P < 0.05) but not Gaa−/−mice (r2 = 0.08, P = 0.27). This finding may indicate that the progression of neuropathology differs between XII and phrenic motoneurons in Gaa−/−mice. We conclude that CNS GAA deficiency is associated with glycogen accumulation in XII motoneuron cell bodies and altered XII motor output.