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Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids

From the Department of Child Neurology (Dr. van der Knaap) and Pathology (Dr. Kamphorst), Free University Hospital, Amsterdam; Department of Neurogenetics (Dr. Naidu), Kennedy Krieger Institute, Baltimore, MD; Departments of Pathology and Neurology (Dr. Kleinschmidt-DeMasters), University of Colorado Health Sciences Center, Denver, CO; and the Department of Neurology (Dr. Weinstein), Sint Lucas-Andreas Hospital, Amsterdam.

Address correspondence and reprint requests to Dr. M.S. van der Knaap, Department of Child Neurology, Free University Hospital, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands; e-mail: ms.vanderknaap{at}azvu.nl

OBJECTIVE: To provide clinical, MRI, and histopathologic findings in a rare white matter disorder with autosomal dominant inheritance, so-called hereditary diffuse leukoencephalopathy with spheroids (HDLS).

BACKGROUND: Progressive leukoencephalopathies often constitute a diagnostic dilemma in both children and adults. In some cases, histopathologic examination of brain tissue is required for a classifying diagnosis.

METHODS: Clinical history, MRI, and autopsy findings were reviewed in three patients with HDLS: a father, his daughter, and an unrelated patient.

RESULTS: Clinical history consisted of an adult-onset neurologic deterioration with signs of frontal lobe dysfunction, epilepsy, spasticity, ataxia, and mild extrapyramidal disturbances. MRI findings included cerebral atrophy and patchy white matter changes, most pronounced in the frontal and frontoparietal area with extension through the posterior limb of the internal capsule into the pyramidal tracts of the brainstem. Autopsy in two patients revealed a leukoencephalopathy with frontoparietal and frontal preponderance and numerous neuroaxonal spheroids in the abnormal white matter. The pyramidal tracts were affected throughout the brainstem.

CONCLUSION: Similar clinical and histopathologic findings have been reported in members of a Swedish pedigree. The homogeneity of the findings strongly suggests that HDLS is a distinct disease entity. In the absence of a biochemical or genetic marker, a definitive diagnosis requires histopathologic confirmation in one of the affected family members.

Key words: Autosomal dominant—Leukoencephalopathy—Neuroaxonal spheroids

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