The Primary Microglial Leukodystrophies: A Review

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.