Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred

Abstract

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration with axonal spheroids leading to progressive cognitive and motor dysfunction. We report clinical and pathological features, as well as molecular genetic analysis, of a family with HDLS. A pedigree consisting of 27 persons in 5 generations contained 6 affected individuals. Dementia and depression were common; two individuals presented with a syndrome resembling corticobasal degeneration (CBD). Postmortem neuropathologic evaluation of three affected individuals revealed enlargement of the lateral ventricles and marked attenuation of cerebral white matter, but preservation of white matter in brainstem and cerebellum, except for the corticospinal tract. Histopathologic studies showed a loss of myelinated fibers, lipid-laden macrophages and bizarre astrocytes, as well as abundant axonal spheroids that were immunoreactive for phosphorylated neurofilament protein and amyloid precursor protein (APP), but not alphaB-crystallin and variably with ubiquitin. By electron microscopy, axonal spheroids contained aggregates of intermediate filaments or of organelles that were predominantly vesicular and lamellar. The cerebral cortex had focal neuronal degeneration with alphaB-crystallin-immunoreactive ballooned neurons. In summary, the present report describes a previously unreported kindred with HDLS with individuals presenting as CBD. Immunohistochemistry for APP and alphaB-crystallin demonstrates distinctive neurodegeneration in cerebral axons and perikarya.

Corpus Callosum Atrophy in Patients with Hereditary Diffuse Leukoencephalopathy with Neuroaxonal Spheroids: An MRI-based Study

“…HDLS is neuropathologically characterized by the extensive loss of myelin sheaths, axonal destruction and the presence of numerous axonal spheroids, pigmented macrophages and astrogliosis (2,(9)(10)(11)(12)(13)(14). These changes were clearly observed in the centrum semiovale of the cerebral white matter in one of our patients (patient 2) (8).…”

“…Corpus callosum atrophy (CCA) has been noted in the postmortem examinations of advanced HDLS patients with diffuse widespread WMLs and severe brain atrophy (9)(10)(11)(12)(13)(14).…”

MRI characteristics and scoring in HDLS due to CSF1R gene mutations

“…DISCUSSION Our report describes the MRI pattern of HDLS in patients with CSF1R gene mutations. MRI findings in patients with HDLS have been described previously in 20 reports, 5,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] however, without knowledge of the CSF1R gene mutation carrier status. 4 We developed an HDLS MRI severity scoring system, modified from those devised for X-ALD, Krabbe disease, and MLD.…”

Hereditary Diffuse Leukoencephalopathy with Spheroids Characterized by Spastic Hemiplegia Preceding Mental Impairment

“…The diagnosis is usually made following a brain biopsy or autopsy based on the presence of neurodystrophy and large areas of neuroaxonal swelling known as spheroids (2). After several mutations in colony-stimulating factor 1 receptor (CSF1R) were recently shown to underlie HDLS (3), various clinical courses and imaging features of the disease were revealed through genetic diagnosis.…”