Abnormal glycogen in astrocytes is sufficient to cause adult polyglucosan body disease

Abstract

Background: A 45-year old woman of Cambodian ethnic background presented with fatal respiratory failure due to a severe diaphragmatic dysfunction. Two years before, she had developed early onset of urinary symptoms.

Methods and results: Neuroimaging showed atrophy of the spine and medulla as well as a leukodystrophy affecting both supra- and infra-tentorial regions. At autopsy, polyglucosan bodies (PB) were seen in several peripheral tissues, including the diaphragm, and nervous tissues such as peripheral nerves, cerebral white matter, basal ganglia, hippocampus, brainstem and cerebellum. Immunohistochemistry and electron microscopy of the brain revealed an exclusive astrocytic localization of the PB. The diagnosis of adult polyglucosan body disease (APBD) was confirmed by enzymatic and molecular studies.

Conclusion: Storage of abnormal glycogen in astrocytes is sufficient to cause the leukodystrophy of APBD. Since brain glycogen is almost exclusively metabolized in astrocytes, this observation sheds light on the pathophysiology of APBD. In addition, this is the first report of an APBD patient presenting with a subacute diaphragmatic failure.

Fig. 1

Brain and spinal MRI. A) T1 sagittal scan showing important medulla and spinal cord atrophy. B) FLAIR axial scans showing hyperintense white matter changes in the periventricular regions, the external capsule and the posterior limb of the internal capsule (dashed circles), the cerebellar hemispheres and in the pyramidal tracts and medial lemniscus of the medulla and pons (solid circles).

Fig. 2

Cellular localization of PB in the brain (specimen of frontal lobe white matter). A) Anti-GFAP immunostaining of astrocytes. Astrocytic processes contain PB (arrow). B) Anti-AQP4 immunostaining of reactive astrocytes. PB are surrounded by a positively stained rim showing their intra-astrocytic localization (arrow). C) Anti-NF immunostaining of axonal swellings. PB are not surrounded by the immunostaining, suggesting an extra-axonal localization (arrow). D) Anti-MBP immunostaining of myelin. PB are not surrounded by the immunostaining, suggesting an extra-axonal localization (arrow). Note that there is no evidence of demyelination. Scale bar 10 μm.

Fig. 3

Electron microscopy of the dentate gyrus. A) Low power, showing PG of different sizes, at a distance from neuron nuclei. Scale bar 20 μm. B) Blood vessel surrounded by basal lamina in contact with astrocytes, forming the blood–brain barrier. PB have an electron dense core with a less dense periphery and a characteristically fibrillar pattern. A PB is found in an astrocyte close to a blood vessel (arrow). Scale bar 10 μm.