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Peripheral nerve and neuromuscular junction pathology in Pompe disease.

Publication ,  Journal Article
Falk, DJ; Todd, AG; Lee, S; Soustek, MS; ElMallah, MK; Fuller, DD; Notterpek, L; Byrne, BJ
Published in: Hum Mol Genet
February 1, 2015

Pompe disease is a systemic metabolic disorder characterized by lack of acid-alpha glucosidase (GAA) resulting in ubiquitous lysosomal glycogen accumulation. Respiratory and ambulatory dysfunction are prominent features in patients with Pompe yet the mechanism defining the development of muscle weakness is currently unclear. Transgenic animal models of Pompe disease mirroring the patient phenotype have been invaluable in mechanistic and therapeutic study. Here, we demonstrate significant pathological alterations at neuromuscular junctions (NMJs) of the diaphragm and tibialis anterior muscle as prominent features of disease pathology in Gaa knockout mice. Postsynaptic defects including increased motor endplate area and fragmentation were readily observed in Gaa(-/-) but not wild-type mice. Presynaptic neuropathic changes were also evident, as demonstrated by significant reduction in the levels of neurofilament proteins, and alterations in axonal fiber diameter and myelin thickness within the sciatic and phrenic nerves. Our data suggest the loss of NMJ integrity is a primary contributor to the decline in respiratory and ambulatory function in Pompe and arises from both pre- and postsynaptic pathology. These observations highlight the importance of systemic phenotype correction, specifically restoration of GAA to skeletal muscle and the nervous system for treatment of Pompe disease.

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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

February 1, 2015

Volume

24

Issue

3

Start / End Page

625 / 636

Location

England

Related Subject Headings

  • Tibia
  • Phrenic Nerve
  • Neuromuscular Junction
  • Muscle, Skeletal
  • Mice, Knockout
  • Mice
  • Membrane Glycoproteins
  • Humans
  • Glycogen Storage Disease Type II
  • Genetics & Heredity
 

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Falk, D. J., Todd, A. G., Lee, S., Soustek, M. S., ElMallah, M. K., Fuller, D. D., … Byrne, B. J. (2015). Peripheral nerve and neuromuscular junction pathology in Pompe disease. Hum Mol Genet, 24(3), 625–636. https://doi.org/10.1093/hmg/ddu476
Falk, Darin J., Adrian Gary Todd, Sooyeon Lee, Meghan S. Soustek, Mai K. ElMallah, David D. Fuller, Lucia Notterpek, and Barry J. Byrne. “Peripheral nerve and neuromuscular junction pathology in Pompe disease.Hum Mol Genet 24, no. 3 (February 1, 2015): 625–36. https://doi.org/10.1093/hmg/ddu476.
Falk DJ, Todd AG, Lee S, Soustek MS, ElMallah MK, Fuller DD, et al. Peripheral nerve and neuromuscular junction pathology in Pompe disease. Hum Mol Genet. 2015 Feb 1;24(3):625–36.
Falk, Darin J., et al. “Peripheral nerve and neuromuscular junction pathology in Pompe disease.Hum Mol Genet, vol. 24, no. 3, Feb. 2015, pp. 625–36. Pubmed, doi:10.1093/hmg/ddu476.
Falk DJ, Todd AG, Lee S, Soustek MS, ElMallah MK, Fuller DD, Notterpek L, Byrne BJ. Peripheral nerve and neuromuscular junction pathology in Pompe disease. Hum Mol Genet. 2015 Feb 1;24(3):625–636.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

February 1, 2015

Volume

24

Issue

3

Start / End Page

625 / 636

Location

England

Related Subject Headings

  • Tibia
  • Phrenic Nerve
  • Neuromuscular Junction
  • Muscle, Skeletal
  • Mice, Knockout
  • Mice
  • Membrane Glycoproteins
  • Humans
  • Glycogen Storage Disease Type II
  • Genetics & Heredity