An autopsy case of hereditary diffuse leukoencephalopathy with spheroids, clinically suspected of Alzheimer?s disease

Abstract

We report here a case of orthochromatic leukodystrophy with spheroids. A 40-year-old woman developed forgetfulness. About 1 year after the onset, clinical examination confirmed global intellectual deterioration with amnesia, spatiotemporal disorientation, and impairment of judgment. At age 43, she experienced tonic-clonic convulsions several times, and died of pneumonia at the age of 44. Alzheimer's disease was suspected clinically. Pathologically, there was severe diffuse demyelination of the deep white matter of the frontal, parietal and occipital lobes with relative preservation of the subcortical U fibers. In the central demyelinated areas, myelin loss was severe with diffuse gliosis, moderate loss of axons, and many axonal spheroids. At the periphery of the severely degenerated regions, there were a lot of macrophages and most had non-metachromatic lipid granules. The cerebral cortex was intact. The neuropathological findings of this case are consistent with hereditary diffuse leukoencephalopathy with spheroids (HDLS). Ten cases of HDLS were reviewed and presented many findings in common. The gray matter was intact and U fibers were well preserved in most cases. In white matter lesions, severe loss of myelin, moderate to severe axonal loss, much axonal swelling, and the presence of macrophages and hypertrophic astrocytes were common findings. In some cases with HDLS, dementia appeared without obvious neurological manifestations in the early stage. We should remember that some cases with HDLS show clinical symptoms similar to Alzheimer's disease, especially in the early stage.

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.…”

CSF1R mutations link POLD and HDLS as a single disease entity

“…7,8,[13][14][15][16][17][21][22][23][24][25] The clinical presentation in POLD family FTD368 included symptoms of depression, abnormal behavior, and an inability to function, progressing to dementia in the 3 siblings from the second generation. The proband Figure 3 Functional effects of CSFR1 mutations in cell culture CSF-1 treatment leads to autophosphorylation of wild-type but not mutant CSF1R.…”

“…4,7,16,24,28 The white matter atrophy and myelin loss is similar in patients with pathologically confirmed HDLS; however, axonal spheroids are prominent in affected white matter in addition to myelinated fiber loss, gliosis, and pigment-laden glial cells. 3,8,9,23,25,29 However, they can be sparse in areas of white matter with burnt-out pathology and few residual axons, and must be sought for in areas where the white matter pathology is ongoing. In a study of the originally described POLD family in 1936, it was reported that axonal dilations consistent with axonal spheroids were present in the affected brain tissue.…”