Insights into the dynamics of hereditary diffuse leukoencephalopathy with axonal spheroids

Abstract

Objective: To report a new American family with hereditary diffuse leukoencephalopathy with spheroids (HDLS), including serial, presymptomatic and symptomatic, cranial MRIs from the proband.

Methods: We report clinical and genealogic investigations of an HDLS family, sequential brain MRIs of the proband, and autopsy slides of brain tissue from the proband's father.

Results: We identified seven affected family members (five deceased). The mean age at symptomatic disease onset was 35 years (range: 20-57), and the mean disease duration was 16 years (range: 3-46). Five affected individuals initially manifested memory disturbance and behavioral changes, whereas two experienced a mood disorder as their presenting symptom. Our proband's father had been diagnosed clinically with vascular dementia, but his brain autopsy was consistent with HDLS. The proband had a cranial MRI prior to symptom onset, with two subsequent MRIs performed during follow-up. These serial images reveal a progressive, confluent, frontal-predominant leukoencephalopathy with symmetric cortical atrophy.

Conclusions: The proband of our newly identified hereditary diffuse leukoencephalopathy with spheroids (HDLS) kindred had subtle evidence of an incipient leukoencephalopathy on a presymptomatic cranial MRI. Conceivably, MRI may facilitate identifying affected presymptomatic individuals within known HDLS kindreds, increasing the likelihood of isolating the causative genes.

Figure 1 Simplified pedigree of our hereditary diffuse leukoencephalopathy with spheroids kindred Generations are numbered with Roman numerals, individuals with Arabic numerals. Circles represent females and squares represent males. Solid symbols indicate affected members, lower half solid symbols indicate possibly affected. Proband: individual V-14 (arrowed). Star sign: individual who underwent brain autopsy. Slash indicates deceased.

Figure 2 Sequential MRI study of the proband (individual V-14) Upper row, T2-weighed images; lower row, fluid-attenuated inversion recovery images. (A) Presymptomatic images (age: 29 years) show subtle right-predominant frontal white matter signal changes. (B) Symptomatic images (age: 36 years) show significant patchy and confluent bifrontal and biparietal periventricular white matter lesions, with moderate cortical and subcortical atrophy. (C) Symptomatic images (age: 37 years) show severe symmetric confluent bifrontal and biparietal white matter lesions, with marked cortical and subcortical atrophy.

Figure 3 Pathology of the proband’s father (IV-5) (A) Low power image of cortex stained with Luxol fast blue (LFB) shows gray-white junction with staining pallor of deep white matter and sparing of U-fibers. Inset shows a ballooned cortical neuron immunostained for αB-crystallin. (B) Low power image of white matter immunostained for HLA-DR shows diffuse microglial activation. (C) High power image stained with hematoxylin and eosin shows brown granular pigment in white matter macrophages (arrows). (D) High power image of white matter stained with LFB shows pale staining axonal spheroids (arrows). (E) High power image of white matter immunostained for amyloid precursor protein shows axonal spheroids (arrows). (F) High power image of white matter immunostained for ubiquitin shows only a few axonal spheroids (arrow). (G) High power image of white matter immunostained for neurofilament protein shows axonal spheroids (arrows).