Ultrastructural and diffusion tensor imaging studies reveal axon abnormalities in Pompe disease mice

Abstract

Pompe disease (PD) is caused by lysosomal glycogen accumulation in tissues, including muscles and the central nervous system (CNS). The intravenous infusion of recombinant human acid alpha-glucosidase (rhGAA) rescues the muscle pathologies in PD but does not treat the CNS because rhGAA does not cross the blood–brain barrier (BBB). To understand the CNS pathologies in PD, control and PD mice were followed and analyzed at 9 and 18 months with brain structural and ultrastructural studies. T2-weighted brain magnetic resonance imaging studies revealed the progressive dilatation of the lateral ventricles and thinning of the corpus callosum in PD mice. Electron microscopy (EM) studies at the genu of the corpus callosum revealed glycogen accumulation, an increase in nerve fiber size variation, a decrease in the g-ratio (axon diameter/total fiber diameter), and myelin sheath decompaction. The morphology of oligodendrocytes was normal. Diffusion tensor imaging (DTI) studies at the corpus callosum revealed an increase in axial diffusivity (AD) and mean diffusivity (MD) more significantly in 9-month-old PD mice. The current study suggests that axon degeneration and axon loss occur in aged PD mice and are probably caused by glycogen accumulation in neurons. A drug crossing the BBB or a treatment for directly targeting the brain might be necessary in PD.

Degeneration of muscle spindles in a murine model of Pompe disease

“…Thus, the degeneration of intrafusal fibers could secondarily cause the degeneration and retraction of the proprioceptive sensory axon. On the other hand, glycogen deposits have also been observed in the peripheral nervous system and in dorsal root ganglia neurons of patients with Pompe disease 18 , 20 , 36 – 38 . Accordingly, these patients develop a polyneuropathy 38 and a loss of peripheral nerves, leading among others to peripheral areflexia 9 , 39 .…”