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Review
. 2022 Jun 6;23(11):6341.
doi: 10.3390/ijms23116341.

The Primary Microglial Leukodystrophies: A Review

Isidro Ferrer  1
Affiliations
Review

The Primary Microglial Leukodystrophies: A Review

Isidro Ferrer. Int J Mol Sci. .

Abstract

Primary microglial leukodystrophy or leukoencephalopathy are disorders in which a genetic defect linked to microglia causes cerebral white matter damage. Pigmented orthochromatic leukodystrophy, adult-onset orthochromatic leukodystrophy associated with pigmented macrophages, hereditary diffuse leukoencephalopathy with (axonal) spheroids, and adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) are different terms apparently used to designate the same disease. However, ALSP linked to dominantly inherited mutations in CSF1R (colony stimulating factor receptor 1) cause CSF-1R-related leukoencephalopathy (CRP). Yet, recessive ALSP with ovarian failure linked to AARS2 (alanyl-transfer (t)RNA synthase 2) mutations (LKENP) is a mitochondrial disease and not a primary microglial leukoencephalopathy. Polycystic membranous lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; Nasu-Hakola disease: NHD) is a systemic disease affecting bones, cerebral white matter, selected grey nuclei, and adipose tissue The disease is caused by mutations of one of the two genes TYROBP or TREM2, identified as PLOSL1 and PLOSL2, respectively. TYROBP associates with receptors expressed in NK cells, B and T lymphocytes, dendritic cells, monocytes, macrophages, and microglia. TREM2 encodes the protein TREM2 (triggering receptor expressed on myeloid cells 2), which forms a receptor signalling complex with TYROBP in macrophages and dendritic cells. Rather than pure microglial leukoencephalopathy, NHD can be considered a multisystemic "immunological" disease.

Keywords: AARS; CRP; CSFR1; LKENP; Nasu–Hakola disease; TREM2; TYROBP; adult-onset (or dominant) leukodystrophy with axonal spheroids and pigmented glia; adult-onset orthochromatic leukodystrophy associated with pigmented macrophages; hereditary diffuse leukoencephalopathy with axonal spheroids; pigmented orthochromatic leukodystrophy; polycystic membranous lipomembranous osteodysplasia with sclerosing leukoencephalopathy.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 3
Figure 3
ALSP cerebral biopsy sample. (A) Axonal ballooning (asterisks) as seen in haematoxylin and eosin-stained sections. (B) Reduced proteolipid protein 1 (PLP1, a protein component of myelin) immunoreactivity. (C) Myelin loss and deposits of pigment in glial cells, as revealed by Klüver–Barrera (K-B) staining, demonstrating the presence of phospholipids in the pigment. (D) Pigmented glial cells are stained with PAS, and (E) Sudan black, showing the deposits of glucolipids and complex lipids; (F) glial cells showing the accumulation of lysosome-associated membrane glycoprotein 2 (LAMP2), a marker of autophagy. (G,H) Globose microglial cells and macrophages stained with allograft inflammatory factor 1(Iba1) antibody. (I) Moderate astrogliosis as revealed with glial fibrillary acidic protein (GFAP) immunohistochemistry. (J–L) different fields showing nerve fibre loss and abundance of axonal ballooning as revealed with the anti-neurofilament (200 kDa) antibody RT97. Paraffin sections, bar = 50 μm. Details of case report reference [109,110].
Figure 1
Figure 1
ALSP. (A,B) Coronal sections of the brain showing atrophy of the cerebral white matter more markedly in the anterior poles than in the posterior regions, atrophy of the corpus callosum, and enlargement of the lateral ventricles. (C,D) Hemispheric sections stained with Klüver–Barrera showing severe myelin loss of the centrum semi-ovale, corpus callosum, and internal capsule, and preservation of the short cortico-subcortical U-fibres. (E,F) Astrocytic gliosis and macrophages filled with pigment in the affected white matter. (G) Axonal ballooning. Paraffin sections, (E–G), bar = 25 μm.
Figure 2
Figure 2
ALSP. (A–C) Glial cells filled with pigment as seen with periodic acid–Schiff (PAS) (A), Klüver–Barrera (K-B) (B), and Sudan black (C) staining in the frontal white matter. (D) Microcalcifications in the frontal white matter near the lateral ventricle. (E,F) Semi-thin sections stained with toluidine blue showing loss of myelin, macrophages filled with neutral lipids (thin arrows in (E)), and axonal ballooning (thick arrow in (F)). (G) Axonal ballooning filled with neurofilaments (nf) in the white matter. (A–D), formalin-fixed samples, paraffin sections; (E–G), samples fixed with glutaraldehyde, post-fixed with osmium tetraoxide, and embedded in araldite; ultra-thin sections stained with uranyl acetate and lead citrate. (A–C), bar = 25 μm; (D) = 100 μm; (E–F) = 10 μm.
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