Hereditary diffuse leukoencephalopathy with spheroids

Hereditary diffuse leukoencephalopathy with spheroids is a rare autosomal dominant disorder characterized by cerebral white matter degeneration with axonal spheroids leading to progressive cognitive and motor dysfunction.

History
This disease was first described in 1984 by Axelsson et al in Sweden.

Pathology
There is enlargement of the lateral ventricles and marked attenuation of cerebral white matter. The loss of white matter is caused by myelin loss. These changes are associated with diffuse gliosis, moderate loss of axons and many axonal spheroids. Spheroids have thin, discontinuous or lack myelin sheaths entirely. Macrophages with non-metachromatic lipid granules are common.

The pathology of this disease resembles that of Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy). Nasu-Hakola disease appears to be caused by mutations in the TYRO protein tyrosine kinase-binding protein and the Triggering receptor expressed on myeloid cells 2 protein.

Genetics
The cause of this disease appears to be due to mutations in the colony stimulating factor 1 receptor. The mutations are concentrated in tyrosine kinase domain of the protein.

Clinically
The presentation may be variable with forgetfulness, global intellectual deterioration with amnesia, spatiotemporal disorientation and impairment of judgement. The age of onset may range from 8 to 60 years. Mean age at onset is 35 years.