Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations

Abstract

Atypical Parkinsonism associated with white matter pathology has been described in cerebrovascular diseases, mitochondrial cytopathies, osmotic demyelinating disorders, leukoencephalopathies including leukodystrophies, and others. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder with symptomatic onset in midlife and death within a few years after symptom onset. Neuroimaging reveals cerebral white matter lesions that are pathologically characterized by non-inflammatory myelin loss, reactive astrocytosis, and axonal spheroids. Most cases are caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. We studied neuropathologically verified HDLS patients with CSF1R mutations to assess Parkinsonian features. Ten families were evaluated with 16 affected individuals. During the course of the illness, all patients had at least some degree of bradykinesia. Fifteen patients had postural instability, and seven had rigidity. Two patients initially presented with Parkinsonian gait and asymmetrical bradykinesia. These two patients and two others exhibited bradykinesia, rigidity, postural instability, and tremor (two with resting) early in the course of the illness. Levodopa/carbidopa therapy in these four patients provided no benefit, and the remaining 12 patients were not treated. The mean age of onset for all patients was about 45 years (range, 18-71) and the mean disease duration was approximately six years (range, 3-11). We also reviewed HDLS patients published prior to the CSF1R discovery for the presence of Parkinsonian features. Out of 50 patients, 37 had gait impairments, 8 rigidity, 7 bradykinesia, and 5 resting tremor. Our report emphasizes the presence of atypical Parkinsonism in HDLS due to CSF1R mutations.

CSF-1 receptor signalling is governed by pre-requisite EHD1 mediated receptor display on the macrophage cell surface

“…This is seen upon expression of the HIV protein NEF, which inhibits glycosylation through an incompletely understood mechanism involving NEF activation of the SRC-family tyrosine kinase HCK as well as through an HCK-independent mechanism [50,51]. Naturally-occurring loss-of-function mutations of CSF-1R have been identified in patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS), and most of these mutations result in reduced CSF-1R protein expression [8]. In both of the aforementioned cases, CSF-1R glycosylation in the Golgi is defective.…”

“…Macrophages are key contributors to highly prevalent immunological diseases [3–5] such as rheumatoid arthritis, inflammatory bowel disease, and demyelinating neurological diseases [6–8]. Macrophages also play key homeostatic roles in non-immune tissues and contribute to diseases such as atherosclerosis and cancer [9–11].…”

Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP)

“…ALSP patients initially present with memory loss, apathy, depression and repetitive behaviors, as well as cognitive and sensorimotor symptoms (Axelsson et al, 1984; Freeman et al, 2009; Mitsui et al, 2012; Sundal et al, 2013; van der Knaap et al, 2000). Cognitive assessment revealed significantly impaired visuospatial memory in Csf1r+/− mice, compared with Csf1r+/+ control mice, that was evident as early as 6-8-months of age (Fig.…”

Diagnostic Value of Brain Calcifications in Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia

“…Some patients show parkinsonian features 6 , while others, particularly young women, are sometimes misdiagnosed as having multiple sclerosis (MS). 7,8 Imaging findings may be helpful to distinguish between these differential diagnoses.…”