Objective: The objective of this study is to describe milder and later onset variants of a recently described leukoencephalopathy with vanishing white matter.

Background: The diagnostic criteria used currently for this disease include an early-childhood onset of neurologic deterioration.

Methods: Clinical, MRI, and spectroscopic findings of five patients were reviewed who fulfilled all inclusion criteria for the disease of vanishing white matter, apart from the age at onset. In one patient histopathologic findings were documented.

Results: Onset of the disease was in late childhood or adolescence in four patients, and one patient was still presymptomatic in his early twenties. The course of the disease tended to be milder than in the patients with early-childhood onset. MRI revealed a diffuse cerebral hemispheric leukoencephalopathy with evidence of white matter rarefaction. MRS of the abnormal white matter showed a serious decrease but not complete disappearance of all "normal" signals and, in some patients, the presence of extra signals from lactate and glucose. Changes in relative spectral peak heights were compatible with axonal damage or loss, but not with active demyelination or substantial gliosis. Autopsy in one patient confirmed the extensive rarefaction of the cerebral white matter. There was a commensurate loss of axons and myelin sheaths. Within the brainstem, pontine lesions were present, also involving the central tegmental tracts-a phenomenon previously described in early-onset patients.

Conclusion: Later onset does occur in the disease of vanishing white matter, and both MRS and histopathology are compatible with a primary axonopathy rather than primary demyelination.