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X‐linked adrenoleukodystrophy (X‐ALD) and metachromatic leukodystrophy (MLD) are two relatively common examples of hereditary demyelinating diseases caused by a dysfunction of peroxisomal or lysosomal lipid degradation. In both conditions, accumulation of nondegraded lipids leads to the destruction of cerebral white matter. Because of their high lipid content, oligodendrocytes are considered key to the pathophysiology of these leukodystrophies. However, the response to allogeneic stem cell transplantation points to the relevance of cells related to the hematopoietic lineage. In the present study, we aimed to better characterize the pathogenetic role of microglia in the above‐mentioned diseases. Applying recently established microglia markers to human autopsy cases of X‐ALD and MLD we were able to delineate distinct lesion stages in evolving demyelinating lesions. The immune‐phenotype of microglia was altered already early in lesion evolution, and microglia loss preceded full‐blown myelin degeneration both in X‐ALD and MLD. DNA fragmentation indicating phagocyte death was observed in areas showing microglia loss. The morphology and dynamics of phagocyte decay differed between the diseases and between lesion stages, hinting at distinct pathways of programmed cell death. In summary, the present study shows an early and severe damage to microglia in the pathogenesis of X‐ALD and MLD. This hints at a central pathophysiologic role of these cells in the diseases and provides evidence for an ongoing transfer of toxic substrates primarily enriched in myelinating cells to microglia.

Chronic granulomatous disease (CGD) is a rare genetic immunodeficiency which is characterized by recurrent severe bacterial and fungal infections caused by a defect in phagocytic cells due to loss of superoxide production. The disease usually manifests within the first years of life. Early diagnosis allows therapeutic intervention to improve the limited life expectancy. Nevertheless, only half of the patients exceed the age of 25. Here, we present the case of a 41-year old female patient who presented with an extensive spinal cord infection and atypical pneumonia mimicking tuberculosis. The medical history with recurrent granulomatous infections and microbiological findings with multiple unusual opportunistic pathogens was the key to the diagnosis of chronic granulomatous disease which is exceptionally rare first diagnosed in patients in the fifth decade of life. The late diagnosis in this case was likely to the lack of knowledge of the disease by the treating teams before but not because the patient did not have typical CDG infections along her life. The extensive progressive developing granulomas in our patient with fatal outcome raise the question of early immunosuppressive therapy in addition to anti-infectious treatment. We recommend appropriate CGD diagnostics in adult patients with unclear granulomatous diseases of the nervous system.