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Common neuropathological features underlie distinct clinical presentations in three siblings with hereditary diffuse leukoencephalopathy with spheroids caused by CSF1R p.Arg782His.

Robinson JL, Suh E, Wood EM, Lee EB, Coslett HB, Raible K, Lee VM, Trojanowski JQ, Van Deerlin VM - Acta Neuropathol Commun (2015)

Bottom Line: Abundant white matter spheroids and CD68-positive macrophages were the predominant pathologies in these cases.Similar to other cases reported in the literature, the three cases described here had varied clinical phenotypes with a pronounced, but heterogeneous distribution of axonal spheroids and distinct microglia morphology.Our findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis of HDLS.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA.

ABSTRACT
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) presents with a variety of clinical phenotypes including motor impairments such as gait dysfunction, rigidity, tremor and bradykinesia as well as cognitive deficits including personality changes and dementia. In recent years, colony stimulating factor 1 receptor gene (CSF1R) has been identified as the primary genetic cause of HDLS. We describe the clinical and neuropathological features in three siblings with HDLS and the CSF1R p.Arg782His (c.2345G > A) pathogenic mutation. Each case had varied motor symptoms and clinical features, but all included slowed movements, poor balance, memory impairment and frontal deficits. Neuroimaging with magnetic resonance imaging revealed atrophy and increased signal in the deep white matter. Abundant white matter spheroids and CD68-positive macrophages were the predominant pathologies in these cases. Similar to other cases reported in the literature, the three cases described here had varied clinical phenotypes with a pronounced, but heterogeneous distribution of axonal spheroids and distinct microglia morphology. Our findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis of HDLS.

No MeSH data available.


Related in: MedlinePlus

Common neuropathological features of the 3 cases of HDLS studied here. Spheroids were abundant (a) primarily in the deeper white matter without affecting the short association fibers; b spheroids had a heterogeneous distribution as is evident by comparing the left and right side of the image; c focal very dense clusters of spheroids were seen (Case #3, orbital frontal cortex). d Microglia were not diffusely distributed and were of two distinct populations. Many microglia had morphologies indicative of (e) activated phagocytic macrophages that were CD68 positive and Iba1 negative with unusually ramified morphologies (f) while others were Iba1 positive microglia with more simple morphologies (Case #2, anterior corpus callosum). Occasionally, additional pathologies included (g) patches of calcifications (Case #2, blue-black splotchy areas in the anterior corpus callosum) and (h) irregular neuronal accumulations of pathological tau (Case #3, anterior cingulate). i Spheroids could also be visualized by tau, ubiquitin and α-synuclein antibodies (not shown here as well as by anti-neurofilament antibodies (shown here for Case #1 in the angular gyrus). Antibodies and stains used: (a-c) 22c11, (d-e) CD68, (f) Iba1, (g) H&E, (h) PHF1, (i) RMO24.9
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Fig4: Common neuropathological features of the 3 cases of HDLS studied here. Spheroids were abundant (a) primarily in the deeper white matter without affecting the short association fibers; b spheroids had a heterogeneous distribution as is evident by comparing the left and right side of the image; c focal very dense clusters of spheroids were seen (Case #3, orbital frontal cortex). d Microglia were not diffusely distributed and were of two distinct populations. Many microglia had morphologies indicative of (e) activated phagocytic macrophages that were CD68 positive and Iba1 negative with unusually ramified morphologies (f) while others were Iba1 positive microglia with more simple morphologies (Case #2, anterior corpus callosum). Occasionally, additional pathologies included (g) patches of calcifications (Case #2, blue-black splotchy areas in the anterior corpus callosum) and (h) irregular neuronal accumulations of pathological tau (Case #3, anterior cingulate). i Spheroids could also be visualized by tau, ubiquitin and α-synuclein antibodies (not shown here as well as by anti-neurofilament antibodies (shown here for Case #1 in the angular gyrus). Antibodies and stains used: (a-c) 22c11, (d-e) CD68, (f) Iba1, (g) H&E, (h) PHF1, (i) RMO24.9

Mentions: Each case showed abundant white matter Aβ precursor protein (APP) positive spheroids that were heterogeneously distributed in subcortical regions (Figs. 3 and 4a-c). These spheroids were also observed by neurofilament (Fig. 4i), tau and ubiquitin antibodies and H&E (not shown). The spheroids were more numerous in deep white matter with the U-fibers relatively spared (Fig. 4a). Phagocytic cells (macrophages and microglia) were also heterogeneously distributed in the subcortical white matter and these cells showed highly varied and distinctly unusual morphologies. The most distinctive morphology was characteristic of activated phagocytic macrophages (Fig. 4d-e) that were strongly positive for CD68, but not Iba1 positive. Other, Iba1 positive microglia had a more classic microglia shape (Fig. 4f). Prominent spongiosis in neocortical regions was another common feature. Neither TDP-43 nor α-synuclein inclusions were observed.Fig. 3


Common neuropathological features underlie distinct clinical presentations in three siblings with hereditary diffuse leukoencephalopathy with spheroids caused by CSF1R p.Arg782His.

Robinson JL, Suh E, Wood EM, Lee EB, Coslett HB, Raible K, Lee VM, Trojanowski JQ, Van Deerlin VM - Acta Neuropathol Commun (2015)

Common neuropathological features of the 3 cases of HDLS studied here. Spheroids were abundant (a) primarily in the deeper white matter without affecting the short association fibers; b spheroids had a heterogeneous distribution as is evident by comparing the left and right side of the image; c focal very dense clusters of spheroids were seen (Case #3, orbital frontal cortex). d Microglia were not diffusely distributed and were of two distinct populations. Many microglia had morphologies indicative of (e) activated phagocytic macrophages that were CD68 positive and Iba1 negative with unusually ramified morphologies (f) while others were Iba1 positive microglia with more simple morphologies (Case #2, anterior corpus callosum). Occasionally, additional pathologies included (g) patches of calcifications (Case #2, blue-black splotchy areas in the anterior corpus callosum) and (h) irregular neuronal accumulations of pathological tau (Case #3, anterior cingulate). i Spheroids could also be visualized by tau, ubiquitin and α-synuclein antibodies (not shown here as well as by anti-neurofilament antibodies (shown here for Case #1 in the angular gyrus). Antibodies and stains used: (a-c) 22c11, (d-e) CD68, (f) Iba1, (g) H&E, (h) PHF1, (i) RMO24.9
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Fig4: Common neuropathological features of the 3 cases of HDLS studied here. Spheroids were abundant (a) primarily in the deeper white matter without affecting the short association fibers; b spheroids had a heterogeneous distribution as is evident by comparing the left and right side of the image; c focal very dense clusters of spheroids were seen (Case #3, orbital frontal cortex). d Microglia were not diffusely distributed and were of two distinct populations. Many microglia had morphologies indicative of (e) activated phagocytic macrophages that were CD68 positive and Iba1 negative with unusually ramified morphologies (f) while others were Iba1 positive microglia with more simple morphologies (Case #2, anterior corpus callosum). Occasionally, additional pathologies included (g) patches of calcifications (Case #2, blue-black splotchy areas in the anterior corpus callosum) and (h) irregular neuronal accumulations of pathological tau (Case #3, anterior cingulate). i Spheroids could also be visualized by tau, ubiquitin and α-synuclein antibodies (not shown here as well as by anti-neurofilament antibodies (shown here for Case #1 in the angular gyrus). Antibodies and stains used: (a-c) 22c11, (d-e) CD68, (f) Iba1, (g) H&E, (h) PHF1, (i) RMO24.9
Mentions: Each case showed abundant white matter Aβ precursor protein (APP) positive spheroids that were heterogeneously distributed in subcortical regions (Figs. 3 and 4a-c). These spheroids were also observed by neurofilament (Fig. 4i), tau and ubiquitin antibodies and H&E (not shown). The spheroids were more numerous in deep white matter with the U-fibers relatively spared (Fig. 4a). Phagocytic cells (macrophages and microglia) were also heterogeneously distributed in the subcortical white matter and these cells showed highly varied and distinctly unusual morphologies. The most distinctive morphology was characteristic of activated phagocytic macrophages (Fig. 4d-e) that were strongly positive for CD68, but not Iba1 positive. Other, Iba1 positive microglia had a more classic microglia shape (Fig. 4f). Prominent spongiosis in neocortical regions was another common feature. Neither TDP-43 nor α-synuclein inclusions were observed.Fig. 3

Bottom Line: Abundant white matter spheroids and CD68-positive macrophages were the predominant pathologies in these cases.Similar to other cases reported in the literature, the three cases described here had varied clinical phenotypes with a pronounced, but heterogeneous distribution of axonal spheroids and distinct microglia morphology.Our findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis of HDLS.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA.

ABSTRACT
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) presents with a variety of clinical phenotypes including motor impairments such as gait dysfunction, rigidity, tremor and bradykinesia as well as cognitive deficits including personality changes and dementia. In recent years, colony stimulating factor 1 receptor gene (CSF1R) has been identified as the primary genetic cause of HDLS. We describe the clinical and neuropathological features in three siblings with HDLS and the CSF1R p.Arg782His (c.2345G > A) pathogenic mutation. Each case had varied motor symptoms and clinical features, but all included slowed movements, poor balance, memory impairment and frontal deficits. Neuroimaging with magnetic resonance imaging revealed atrophy and increased signal in the deep white matter. Abundant white matter spheroids and CD68-positive macrophages were the predominant pathologies in these cases. Similar to other cases reported in the literature, the three cases described here had varied clinical phenotypes with a pronounced, but heterogeneous distribution of axonal spheroids and distinct microglia morphology. Our findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis of HDLS.

No MeSH data available.


Related in: MedlinePlus