Hereditary diffuse leukoencephalopathy with spheroids: ultrastructural and immunoelectron microscopic studies

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration with myelin loss and axonal swellings (spheroids) leading to progressive cognitive and motor dysfunction. Histopathology of HDLS has been well characterized, but ultrastructural details are lacking. Here we report ultrastructural and immunoelectron microscopic characterization of spheroids and capillary basal lamina in white matter of HDLS brains. Spheroids had thin or discontinuous or no myelin sheaths. They contained various combinations of aggregated neurofilaments (NF), cytoplasmic organelles, dense bodies, and laminated figures. Aggregated filaments labeled with antibodies to phosphorylated NF (pNF), non-pNF and amyloid precursor protein. The gliotic white matter had many reactive astrocytes, and lipid-laden macrophages with membranous and fingerprint-like bodies. The basal laminas (BL) of many capillaries were dilated, and the enlarged space was heavily deposited with banded collagen type I and III. Some BL had focal thickenings and duplications. Fibronectin, not collagen IV, was found associated with banded collagen. The various types of axonal spheroids and changes in capillary basal lamina have not been emphasized previously. It remains to be determined if they are a reactive process or a primary mechanism of white matter degeneration in HDLS.