Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy

Abstract

BackgroundCSF1R-related leukoencephalopathy, also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS), is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few of CSF1R mutations have been functionally testified and the pathogenesis remains unknown.MethodsIn order to investigate clinical and pathological characteristics of patients with CSF1R-related leukoencephalopathy 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, segregation analysis and phenotypic reevaluation were utilized to substantiate findings. Functional examination of identified mutations was further explored.ResultsClinical 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 parkinsonian 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 mitochondrial vacuolation and disorganized neurofilaments in ballooned axons. A total of 7 pathogenic variants (4 novel, 3 documented) were identified with autophosphorylation deficiency, among which c.2342C > T remained partial function of autophosphorylation. Western blotting disclosed the significantly lower level of c.2026C > T (p.R676*) than wild type. 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.ConclusionsOur findings support the loss-of-function and haploinsufficiency hypothesis in pathogenesis. 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. However, whether peripheral polyneuropathy potentially belongs to CSF1R-related spectrum deserves further study with longer follow-up and more patients enrolled.Trial registrationChiCTR, ChiCTR1800015295. Registered 21 March 2018.Electronic supplementary materialThe online version of this article (10.1186/s40035-019-0171-y) contains supplementary material, which is available to authorized users.

CSF1R-Related Leukoencephalopathy Caused by CSF1R p.Arg777Trp and CSF1R p.Arg782Cys Mutations: A Report of Four Cases in Sweden

“…She had higher CSF-NFL concentration and a markedly smaller radar chart area (blue gure) on ALSP-FES (Figure 3B) than Patient 4 (Figure 3C), a male with onset at age 48 and CSF sampling at 14 months of disease duration, who had higher scoring on multiple scales in ALSP-FES (i.e., a better global function). This is consistent with previous observations that female patients tend to develop symptoms earlier (5,6,37). (32).…”

Aberrant miRNA-mRNA regulatory network in polycystic ovary syndrome is associated with markers of insulin sensitivity and inflammation

“…MAPK14 has a wide effect on regulating inflammation and metabolism, and was shown to be regulated by miRNA epigenetics in PCOS in our previous study (24). CSF1R was a key gene in leukoencephalopathy (41). SPI1 was reported as an ETS transcription factor involved in the androgen-mediated transcriptional regulation of NR4A1 in PCOS (42).…”

Microglial replacement therapy: a potential therapeutic strategy for incurable CSF1R-related leukoencephalopathy

“…Although there is no sex difference in the prevalence of CSF1R-related leukoencephalopathy, it was reported that female patients develop clinical symptoms significantly earlier than do men [8,12]. This interesting finding was further supported in a Chinese cohort containing 15 patients from 10 unrelated families, with younger age of disease onset in female than in male patients (34.2 vs. 39.2 years) [45]. Motor dysfunction was the most common initial symptom in women.…”