Open AccessNeural deficits contribute to respiratory insufficiency in Pompe disease
Author(s) -
Lara R. DeRuisseau,
David D. Fuller,
Kai Qiu,
Keith C. DeRuisseau,
William H. Donnelly,
Cathryn Mah,
Paul J. Reier,
Barry J. Byrne
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0902534106
Subject(s) - glycogen , spinal cord , ventilation (architecture) , respiratory system , amyotrophic lateral sclerosis , endocrinology , medicine , diaphragmatic breathing , phrenic nerve , diaphragm (acoustics) , glycogen storage disease type ii , biology , pathology , enzyme replacement therapy , neuroscience , disease , mechanical engineering , physics , alternative medicine , acoustics , engineering , loudspeaker
Pompe disease is a severe form of muscular dystrophy due to glycogen accumulation in all tissues, especially striated muscle. Disease severity is directly related to the deficiency of acid α-glucosidase (GAA), which degrades glycogen in the lysosome. Respiratory dysfunction is a hallmark of the disease, muscle weakness has been viewed as the underlying cause, and the possibility of an associated neural contribution has not been evaluated previously. Therefore, we examined behavioral and neurophysiological aspects of breathing in 2 animal models of Pompe disease—theGaa −/− mouse and a transgenic line (MTP) expressing GAA only in skeletal muscle, as well as a detailed analysis of the CNS in a Pompe disease patient. Glycogen content was elevated in theGaa −/− mouse cervical spinal cord. Retrograde labeling of phrenic motoneurons showed significantly greater soma size inGaa −/− mice vs. isogenic controls, and glycogen was observed inGaa −/− phrenic motoneurons. Ventilation, assessed via plethysmography, was attenuated during quiet breathing and hypercapnic challenge inGaa −/− mice (6 to >21 months of age) vs. controls. We confirmed that MTP mice had normal diaphragmatic contractile properties; however, MTP mice had ventilation similar to theGaa −/− mice during quiet breathing. Neurophysiological recordings indicated that efferent phrenic nerve inspiratory burst amplitudes were substantially lower inGaa −/− and MTP mice vs. controls. In human samples, we demonstrated similar pathology in the cervical spinal cord and greater accumulation of glycogen in spinal cord compared with brain. We conclude that neural output to the diaphragm is deficient inGaa −/− mice, and therapies targeting muscle alone may be ineffective in Pompe disease.