Common neuropathological features underlie distinct clinical presentations in three siblings with hereditary diffuse leukoencephalopathy with spheroids caused by CSF1R p.Arg782His
© Robinson et al. 2015
Received: 8 June 2015
Accepted: 15 June 2015
Published: 4 July 2015
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) presents with a variety of clinical phenotypes including motor impairments such as gait dysfunction, rigidity, tremor and bradykinesia as well as cognitive deficits including personality changes and dementia. In recent years, colony stimulating factor 1 receptor gene (CSF1R) has been identified as the primary genetic cause of HDLS. We describe the clinical and neuropathological features in three siblings with HDLS and the CSF1R p.Arg782His (c.2345G > A) pathogenic mutation. Each case had varied motor symptoms and clinical features, but all included slowed movements, poor balance, memory impairment and frontal deficits. Neuroimaging with magnetic resonance imaging revealed atrophy and increased signal in the deep white matter. Abundant white matter spheroids and CD68-positive macrophages were the predominant pathologies in these cases. Similar to other cases reported in the literature, the three cases described here had varied clinical phenotypes with a pronounced, but heterogeneous distribution of axonal spheroids and distinct microglia morphology. Our findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis of HDLS.
KeywordsLeukoencephalopathy Microglia HDLS CSF1R Frontotemporal degeneration Corticobasal syndrome Dementia with Lewy bodies
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare, autosomal-dominant neurodegenerative disease that presents with diverse phenotypes including motor impairments such as gait dysfunction, rigidity, tremor and bradykinesia along with cognitive impairments like personality changes and dementia . The onset of symptoms is usually in the fourth or fifth decade, progressing to dementia and death within 5–10 years. Magnetic resonance imaging (MRI) typically shows patchy cerebral white matter abnormalities . A definite diagnosis of HDLS requires pathology demonstrating widespread myelin loss and abundant axonal spheroids. Since the discovery of mutations in the colony stimulating factor 1 receptor gene (CSF1R) that are pathogenic for HDLS , genetic screening of CSF1R has increased the number of individuals diagnosed with HDLS [4–9]. Here we describe the clinical and neuropathological features of three siblings with a previously published pathogenic CSF1R mutation, p.Arg782His .
Clinical characteristics of individuals with the CSF1R p.Arg782His mutation
Age at death
Affected family members
Cognitive decline, depression, slowed movement
Severe dorsolateral frontal white matter loss, disrupted axons, axonal spheroids
Poor balance, cognitive and memory decline, slowed movement
Severe orbital frontal white matter loss, disrupted axons, axonal spheroids
Poor balance, cognitive decline, slowed movement
Severe orbital frontal and parietal white matter myelin loss, disrupted axons, axonal spheroids
Cognitive decline, aphasia, epileptic seizures
3 uncles, cousin
Disrupted axons, axonal spheroids (biopsy)
Cognitive and memory decline
Disrupted axons, axonal spheroids (biopsy)
Poor balance, stuttering, dysarthria
sibling, mother, uncle
Frontal and parietal white matter myelin loss, disrupted axons, axonal spheroids
Case #1’s gross examination revealed severe frontal and temporal atrophy with severe ventricular enlargement and a 1092 g brain weight. Microscopically, besides the numerous spheroids (Fig. 3a), additional pathology included obvious neuronal loss and degeneration of long axonal projections, extensive cell loss and gliosis with relative sparing of the granule cells in the hippocampus, rare Aβ plaques and focal cortical amyloid angiopathy (CAA), but no neurofibrillary tangles (NFTs). Case #2 had moderate frontal atrophy with mild ventricular enlargement and weighed 1338 g. There were focal areas of dystrophic calcification and mild demyelination in the corpus callosum (Fig. 4g) and entorhinal cortex that were not apparent in the MRI. Rare ballooned neurons were noted in the cingulate, along with tau-positive grains and neurites in limbic areas, occasional tau-positive coiled bodies, mild CAA without Aβ plaques and NFTs in the medial temporal lobe. Case #3 had mild, diffuse atrophy with mild ventricular enlargement and weighed 1278 g. The limbic regions and brainstem were relatively spared, although spheroids were observed in the medulla. Similar to Case #2, irregular, tau-positive ballooned neurons were also noted in the cingulate (Fig. 4h) while no Aβ plaques were seen but some NFTs were present only in the entorhinal cortex.
Abundant white matter spheroids and CD68-positive macrophages were the predominant pathologies in these cases. Cases #2 and #3 had rare ballooned neurons, coiled bodies and tau-positive grains and neurites, which are found in other tauopathies such as corticobasal degeneration, progressive supranuclear palsy, Pick’s disease and argyrophilic grain disease . What role pathological tau plays in HDLS has yet to be determined.
The p.Arg782His mutation has been previously reported in three families from Japan (Case #4) , USA (Case #5)  and Korea (Case #6) . The clinical similarities and differences of our three cases and the additional published cases with the same mutation are highlighted in Table 1. Cognitive difficulties were noted for all cases. Our three patients all presented with slowed movements, as did Case #6 in the Table, but Cases #4 and #5 did not. Postural instability was also common, although this was a late symptom for Case #5. The motor deficits in Cases #4 and #6 were eventually severe, while the others had relatively mild impairments.
CSF1R is a key regulator of myeloid lineage cells and microglia in the adult brain  and HDLS-associated CSF1R mutations are all located in the protein’s tyrosine kinase domain. Experimental evidence indicates that these mutations cause loss of function [16, 17]. CSF1R mutations may also result in haploinsufficiency  which, in mice, causes a HDLS-like phenotype . CSF1R’s role as a microglial regulator and the functional deficits associated with CSF1R mutations supports the hypothesis that microglia dysfunction may precede the accumulation of axonal spheroids in HDLS. Here we present three familial cases with full neuropathological characterization that demonstrate the range of pathology and clinical phenotypes that can be seen in individuals with the same CSF1R mutation. Since the three siblings studied here were diagnosed clinically with FTD, CBS, and DLB, our findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis of HDLS.
Informed consent was obtained from next of kin in accordance with institutional review board guidelines of the University of Pennsylvania.
Hereditary diffuse leukoencephalopathy with spheroids
Magnetic resonance imaging
- CSF1R :
Colony stimulating factor 1 receptor gene
Dementia with Lewy bodies
Cortical amyloid angiopathy
This study was supported by National Institute of Health (NIH) Grant PO1 AG017586 and P30 AG010124. We would like to thank the family of the patients studied here for their meaningful contributions that made this study possible.
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