Objective: We aimed to investigate clinical and pathological characteristics in hereditary diffuse leukoencephalopathy with spheroids (HDLS) patients and explore the potential impact of colony-stimulating factor 1 receptor gene (CSF1R) mutations.

Background: HDLS is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to CSF1R mutation. The pathogenesis still remains unknown.

Method: In order to investigate clinical and pathological characteristics in HDLS patients and explore the potential impact of CSF1R mutations, we analyzed clinical manifestations of 15 patients from 10 unrelated families and performed brain biopsy in 2 cases. Next generation sequencing was conducted for 10 probands to confirm the diagnosis. Sanger sequencing and segregation analysis were utilized to substantiate findings. Functional examination of identified mutations was further explored.

Results: Clinical and neuroimaging characteristics were summarized. The average age at onset was 35.9±6.4 years (range 24-46 years old). Younger age of onset was observed in female than male (34.2 vs. 39.2 years). The most common initial symptoms were speech dysfunction, cognitive decline and parkinsonism symptoms. One patient also had marked peripheral neuropathy. Brain biopsy of two cases showed typical pathological changes, including myelin loss, axonal spheroids, phosphorylated neurofilament and activated macrophages. Electron microscopy disclosed increased mitochondria and disorganized neurofilaments in ballooned axons. A total of 7 pathogenic variants (4 novel, 3 documented) were identified, which were further testified by functional study, showing autophosphorylation deficiency in all the mutants. The level of microtubule associated protein 1 light chain 3-II (LC3-II), a classical marker of autophagy, was significantly lower in mutants expressed cells than wild type group by western blotting and immunofluorescence staining.

Conclusion: This study suggests that polyneuropathy may be a part of CSF1R deficiency which deserves further study with longer follow-up and more patients enrolled. Our findings also support the haploinsufficiency hypothesis in pathogenesis and partial loss-of-autophosphorylation of CSF1R can lead to a relatively mild phenotype. Autophagy abnormality may play a role in the disease. Repairing or promoting the phosphorylation level of mutant CSF1R may shed light on therapeutic targets in the future.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinicopathologic-characterization-and-abnormal-autophagy-of-hdls/