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Updated: Sep 20, 2025
An In Vitro Model for the Study of Cellular Pathophysiology in Globoid Cell Leukodystrophy
Published on: October 21, 2014
The Primary Microglial Leukodystrophies: A Review
1Network Centre of Biomedical Research of Neurodegenerative Diseases (CIBERNED), Department of Pathology and Experimental Therapeutics, Bellvitge Biomedical Research Institute (IDIBELL), University of Barcelona, 08907 Barcelona, L'Hospitalet de Llobregat, Spain.
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.
Insights
Primary microglial leukodystrophies involve genetic defects affecting microglia and causing white matter damage. Nasu-Hakola disease, caused by TYROBP or TREM2 mutations, is a multisystemic immunological disorder, not a pure microglial disease.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Primary microglial leukodystrophies are genetic disorders impacting cerebral white matter due to microglial defects.
- Several terms, including adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), have been used for similar conditions.
- Distinguishing these disorders is crucial, as some, like CSF-1R-related leukoencephalopathy and LKENP, have different genetic bases and classifications.
Purpose of the Study:
- To clarify the classification and genetic underpinnings of primary microglial leukodystrophies.
- To differentiate conditions like ALSP, CSF-1R-related leukoencephalopathy, LKENP, and Nasu-Hakola disease (NHD).
- To characterize NHD as a multisystemic disorder involving TYROBP and TREM2 gene mutations.
Main Methods:
- Review of existing literature and genetic data on various leukoencephalopathies.
- Analysis of gene mutations associated with ALSP, CSF-1R-related leukoencephalopathy, LKENP, and NHD.
- Examination of the roles of TYROBP and TREM2 in NHD pathogenesis.
Main Results:
- Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) encompasses conditions with diverse genetic causes.
- CSF-1R mutations lead to CSF-1R-related leukoencephalopathy, while AARS2 mutations cause LKENP, a mitochondrial disorder.
- Nasu-Hakola disease (NHD), caused by TYROBP or TREM2 mutations, affects multiple systems and is considered an "immunological" disease.
Conclusions:
- Nasu-Hakola disease (NHD) is a multisystemic disorder, not solely a primary microglial leukoencephalopathy.
- Accurate genetic diagnosis is essential for classifying leukoencephalopathies and understanding their distinct pathologies.
- The TYROBP and TREM2 genes play critical roles in NHD, affecting myeloid cell function and systemic health.
