Haploinsufficiency of CSF-1R and clinicopathologic characterization in patients with HDLS

Abstract

Objective:To clarify the genetic, clinicopathologic, and neuroimaging characteristics of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) with the colony stimulating factor 1 receptor (CSF-1R) mutation.Methods:We performed molecular genetic analysis of CSF-1R in patients with HDLS. Detailed clinical and neuroimaging findings were retrospectively investigated. Five patients were examined neuropathologically.Results:We found 6 different CSF-1R mutations in 7 index patients from unrelated Japanese families. The CSF-1R mutations included 3 novel mutations and 1 known missense mutation at evolutionarily conserved amino acids, and 1 novel splice-site mutation. We identified a novel frameshift mutation. Reverse transcription PCR analysis revealed that the frameshift mutation causes nonsense-mediated mRNA decay by generating a premature stop codon, suggesting that haploinsufficiency of CSF-1R is sufficient to cause HDLS. Western blot analysis revealed that the expression level of CSF-1R in the brain from the patients was lower than from control subjects. The characteristic MRI findings were the involvement of the white matter and thinning of the corpus callosum with signal alteration, and sequential analysis revealed that the white matter lesions and cerebral atrophy relentlessly progressed with disease duration. Spotty calcifications in the white matter were frequently observed by CT. Neuropathologic analysis revealed that microglia in the brains of the patients demonstrated distinct morphology and distribution.Conclusions:These findings suggest that patients with HDLS, irrespective of mutation type in CSF-1R, show characteristic clinical and neuroimaging features, and that perturbation of CSF-1R signaling by haploinsufficiency may play a role in microglial dysfunction leading to the pathogenesis of HDLS.

A Novel CSF1R Mutation in a Patient with Clinical and Neuroradiological Features of Hereditary Diffuse Leukoencephalopathy with Axonal Spheroids

“…Another point of interest was the MRI findings, which showed cerebral atrophy with parietooccipitally predominant T2 white matter hyperintensity and areas of restricted diffusion, a lack of gadolinium enhancement, thinning of the corpus callosum, and cortico-spinal involvement along the whole length of the pyramidal tract, which correlated with motor deterioration toward tetraplegia [7]. The clinical and neuroimaging findings were very similar to those of previously reported cases of HDLS.…”

Diagnostic criteria for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation

“…A majority of cases with mutation-negative leukoencephalopathy were diagnosed as 'possible,' but four cases met the 'probable' criteria, suggesting that the thinning of the corpus callosum is characteristic, but is not specific to ALSP. We assumed that brain calcifications have high sensitivity and specific diagnostic power [10,11]. However, we could not sufficiently validate this finding due to insufficient information in the literature.…”

“…Thus, thin-slice CT (1 mm) is recommended to detect them [5,11]. Characteristic 'stepping stone appearance' can be seen on sagittal view [10] …”

CSF1Rmosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids

“…All of these are recessive disorders that require both alleles to be defective for disease to occur. In contrast, HDLS is a dominant disorder where one mutant allele alone can compromise CSF1R function, with haploinsufficiency a likely cause (Konno et al, 2014). HSCT may confer benefit in recessive disorders through non-cell autonomous introduction of wild-type protein, and may similarly enhance CSF1R signalling after partial loss in HDLS.…”