Central nervous system pathology contributes to respiratory deficits in Glycogen Storage Disease Type II (GSDII)

Abstract

GSDII is caused by deficiency of the enzyme acid α-glucosidase (GAA) and results in systemic glycogen accumulation. Respiratory deficits that accompany GSDII have been attributed to diaphragmatic muscle weakness. However, case reports suggest that motoneuron pathology is present in GSDII. Thus, we hypothesized that respiratory neural control is impaired in mice lacking GAA (Gaa−/−). Using plethysmography, breathing was quantified in Gaa−/− mice and age/gender matched controls (B6/129; Gaa−/−background strain). During quiet breathing, minute ventilation (mL/min) was attenuated (n=8/group, p<0.001) in Gaa−/− (43±4) vs. control mice (60±6). Phrenic motor output was assessed via nerve recordings in anesthetized, paralyzed, ventilated mice. Preliminary data suggest that phrenic inspiratory burst amplitude is lower (p<0.001) in Gaa−/− (0.2 ± 0.0 mV, PaCO2 = 51.5 ± 1.4 mmHg, n=3) vs. controls (15.4 ± 4.9 mV, PaCO2 = 54.5 ± 1.5 mmHg, n=2). Glycogen accumulation was quantified in the spinal segments containing phrenic motoneurons (C3-C5) via the acid hydrolysis method. Glycogen (μg/mg wet wt) was elevated (n=6/group, p<0.001) in Gaa−/− (37.6±2.4) vs. control (17.4±0.5). We conclude: 1) Gaa−/− mice recapitulate clinical GSDII respiratory deficits, 2) spinal glycogen accumulation may impair motor output, and 3) respiratory neural control may be impaired in GSDII. NIH HL59412 T32 HD043730 UF Alumni Assoc