Clinical features and genetic characteristics of hereditary diffuse leukoencephalopathy with spheroids due to CSF1R mutation: a case report and literature review

Abstract

Background: Hereditary diffuse leukoencephalopathy with spheroid (HDLS) is an autosomal dominant white matter disease characterized by adult-onset cognitive impairment, behavioral or emotional changes, paresis, Parkinsonism, and seizures. Mutations in the gene encoding colony-stimulating factor 1 receptor (CSF1R) have been identified as the cause of HDLS.

Methods: Detail medical history, clinical features and brain imaging of a patient with adult-onset leukoencephalopathy, cognitive impairment and motor dysfunction was reviewed and next generation sequencing was performed. An extensive literature research was then performed to identify all patients with HDLS previously reported. The clinical characteristics, brain imaging and genetic features of patients with HDLS were reviewed.

Results: A novel CSF1R mutation, c.1952G>A p.G651E was identified in the patient. Extensive review showed that HDLS typically presents with broad phenotypic variability. The most common symptoms of HDLS were cognitive impairment, followed by psychiatric symptoms, Parkinsonism, gait disorder, and dysphagia. The most common brain imaging findings of HDLS were bilateral white matter lesion, mostly around the ventricles, frontal lobe, and parietal lobe. Calcifications in white matter on CT, cerebral atrophy and thinning of corpus callosum were also common features. Although HDLS demonstrates an autosomal dominant pattern, sporadic cases are not uncommon.

Conclusions: Early recognition of clinical and neuroradiographical characteristics of HDLS is key for the correct diagnosis of the disease.

Keywords: Colony-stimulating factor 1 receptor (CSF1R); clinical features; genetics; hereditary diffuse leukoencephalopathy with spheroid (HDLS).

Figure 1

Imaging features and genetic analysis of the proband carrying the colony-stimulating factor 1 receptor (CSF1R) p.G651E mutation. (A) The pedigree of the proband with hereditary diffuse leukoencephalopathy with spheroid (HDLS). Brain MRI of the proband with CSF1R p.G651E mutation showed bilateral white matter lesions in bi-frontoparietal and peri-ventricular areas, which showed hyperintensity on T2-weighted images (B) and diffusion weighted images (DWI) images (C) and hypointensity on apparent diffusion coefficient (ADC) images (D). Thinning of corpus callosum (arrow) was also seen and no enhanced lesions were seen in the enhancement sequence (E). MRA did not see obvious abnormalities (F). (G) Sequencing chromatograms of the CSF1R p.G651E mutation. (H) Evolutionary conservation of the p.G651E mutation. G651 is highly conserved across species.

Figure 2

Schematic graph of the CSF1R protein and overview of the CSF1R mutations identified in HDLS. CSF1R, colony-stimulating factor 1 receptor; Ig, immunoglobulin domain; HDLS, hereditary diffuse leukoencephalopathy with spheroid.