A clinicopathological and genetic study of sporadic diffuse leukoencephalopathy with spheroids: a report of two cases

Kimura, Tatsuki; Ishizawa, Keisuke; Mitsufuji, Takashi; Abe, Tohru; Nakazato, Yoichi; Yoshida, Katsumi; Sasaki, Atsushi; Araki, Nobuhito

doi:10.1111/nan.12046

Cited by 11 publications

(18 citation statements)

References 26 publications

(93 reference statements)

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“…The present case, together with other isolated reported cases with unknown mutation, do not rule out the possibility that POLD, HDLS, ALSP and PLOSL are related diseases linked to a convergent metabolic pathway but caused by different genes, as suggested by many authors. However, the present findings, together with other reported cases, point to the likelihood that some cases may result from the combination of individually non‐pathogenic variations of selected genes or that this group of diseases is not as homogeneous as postulated, as genetic defects are still barely known in a substantial number of adult leucodystrophies.…”

Section: Discussioncontrasting

confidence: 82%

“…These observations suggest that sporadic and inherited leucoencephalopathies comprising POLD, HDLS, ALSP and PLOSL phenotypes, among other diffuse leucoencephalopathies with spheroids, may have distinct genetic bases. In this line, no mutations in CSFF1R (exons 1–22), DAP12 (exons 1–5) and TREM2 (exons 1–5) were identified in a recent case affected by diffuse leucoencephalopathy with spheroids …”

Section: Introductionmentioning

confidence: 80%

“…In this line, no mutations in CSFF1R (exons 1-22), DAP12 (exons 1-5) and TREM2 (exons 1-5) were identified in a recent case affected by diffuse leucoencephalopathy with spheroids. 40…”

Section: Introductionmentioning

confidence: 99%

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Sporadic adult‐onset leucodystrophy with axonal spheroids and pigmented glia with no mutations in the known targeted genes

et al. 2015

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Section: Discussioncontrasting

confidence: 82%

Section: Introductionmentioning

confidence: 80%

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Sporadic adult‐onset leucodystrophy with axonal spheroids and pigmented glia with no mutations in the known targeted genes

et al. 2015

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“…There have been several cases in which clinical and pathologic findings were consistent with ALSP, but CSF1R mutations were not identified. [17][18][19] Notably, no CSF1R mutation has been found in the original Swedish family, 20 implying that other genes may be associated with these cases. In 2016, homozygous or compound heterozygous mutations in AARS2 gene encoding mitochondrial alanyl-transfer RNA synthetase were identified in 5 patients who were clinically suspected to have ALSP, but were negative for CSF1R mutations.…”

Section: Historical Background and Nosologymentioning

confidence: 95%

CSF1R -related leukoencephalopathy

et al. 2018

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Since the discovery of CSF1R gene mutations in families with hereditary diffuse leukoencephalopathy with spheroids in 2012, more than 70 different mutations have been identified around the world. Through the analyses of mutation carriers, CSF1R-related leukoencephalopathy has been distinctly characterized clinically, radiologically, and pathologically. Typically, patients present with frontotemporal dementia-like phenotype in their 40s–50s, accompanied by motor symptoms, including pyramidal and extrapyramidal signs. Women tend to develop the clinical symptoms at a younger age than men. On brain imaging, in addition to white matter abnormalities, thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks. Primary axonopathy followed by demyelination was suggested by pathology. Haploinsufficiency of colony-stimulating factor-1 receptor (CSF1R) is evident in a patient with a frameshift mutation, facilitating the establishment of Csf1r haploinsufficient mouse model. These mice develop clinical, radiologic, and pathologic phenotypes consistent with those of human patients with CSF1R mutations. In vitro, perturbation of CSF1R signaling is shown in cultured cells expressing mutant CSF1R. However, the underlying mechanisms by which CSF1R mutations selectively lead to white matter degeneration remains to be elucidated. Given that CSF1R mainly expresses in microglia, CSF1R-related leukoencephalopathy is representative of primary microgliopathies, of which microglia have a pivotal and primary role in pathogenesis. In this review, we address the current knowledge of CSF1R-related leukoencephalopathy and discuss the putative pathophysiology, with a focus on microglia, as well as future research directions.

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“…Many diseases or pathological conditions widely involving the cerebral white matter in adult humans have been reported, but among them, only five are characterized by extensive spherically swollen axons (spheroids and globules): hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) , Nasu–Hakola disease (N‐HD) , pigmentary orthochromatic leukodytrophy (POLD) , sudanophilic leukodystrophy (SLD) and traumatic diffuse brain injury . Recently adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) was proposed as a comprehensive term encompassing HDLS and POLD because of similar characters of clinical and pathological features, and presence of mutations of colony stimulating factor 1 receptor (CSF1R) in the diseases .…”

Section: Introductionmentioning

confidence: 99%

Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and Nasu–Hakola disease: lesion staging and dynamic changes of axons and microglial subsets

et al. 2017

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The brains of 10 Japanese patients with adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD) and eight Japanese patients with Nasu-Hakola disease (N-HD) and five age-matched Japanese controls were examined neuropathologically with special reference to lesion staging and dynamic changes of microglial subsets. In both diseases, the pathognomonic neuropathological features included spherically swollen axons (spheroids and globules), axon loss and changes of microglia in the white matter. In ALSP, four lesion stages based on the degree of axon loss were discernible: Stage I, patchy axon loss in the cerebral white matter without atrophy; Stage II, large patchy areas of axon loss with slight atrophy of the cerebral white matter and slight dilatation of the lateral ventricles; Stage III, extensive axon loss in the cerebral white matter and dilatation of the lateral and third ventricles without remarkable axon loss in the brainstem and cerebellum; Stage IV, devastated cerebral white matter with marked dilatation of the ventricles and axon loss in the brainstem and/or cerebellum. Internal capsule and pontine base were relatively well preserved in the N-HD, even at Stage IV, and the swollen axons were larger with a higher density in the ALSP. Microglial cells immunopositive for CD68, CD163 or CD204 were far more obvious in ALSP, than in N-HD, and the shape and density of the cells changed in each stage. With progression of the stage, clinical symptoms became worse to apathetic state, and epilepsy was frequently observed in patients at Stages III and IV in both diseases. From these findings, it is concluded that (i) shape, density and subsets of microglia change dynamically along the passage of stages and (ii) increase of IBA-1-, CD68-, CD163- and CD204-immunopositive cells precedes loss of axons in ALSP.

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A clinicopathological and genetic study of sporadic diffuse leukoencephalopathy with spheroids: a report of two cases

Cited by 11 publications

References 26 publications

Sporadic adult‐onset leucodystrophy with axonal spheroids and pigmented glia with no mutations in the known targeted genes

Sporadic adult‐onset leucodystrophy with axonal spheroids and pigmented glia with no mutations in the known targeted genes

CSF1R -related leukoencephalopathy

Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and Nasu–Hakola disease: lesion staging and dynamic changes of axons and microglial subsets

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