De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS)

Karle, Kathrin N.; Biskup, Saskia; Schüle, Rebecca; Schweitzer, Katherine J.; Krüger, Rejko; Bauer, Peter; Bender, Benjamín; Nägele, Thomas; Schöls, Lüdger

doi:10.1212/01.wnl.0000436945.01023.ac

Cited by 67 publications

(59 citation statements)

References 18 publications

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“…The median age of onset is 42 ± 13 years (range 8-78) with a disease duration of 5 ± 7 (range 1-34) years that is unrelated to the time of onset (Ahmed et al, 2013; Freeman et al, 2009; Guerreiro et al, 2013; Hoffmann et al, 2014; Karle et al, 2013; Kinoshita et al, 2014; Kleinfeld et al, 2013; Kondo et al, 2013; Konno et al, 2014; Mitsui et al, 2012; Rademakers et al, 2011; Sundal et al, 2012; Van Gerpen et al, 2008; Wider et al, 2009). Symptoms may vary according to gender (Hoffmann et al, 2014), and clinical presentation is variable.…”

Section: Discussionmentioning

confidence: 99%

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

Chiţu

Gökhan

Gulinello

et al. 2015

Neurobiology of Disease

162

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Mutations in the colony stimulating factor-1 receptor (CSF1R) that abrogate the expression of the affected allele or lead to the expression of mutant receptor chains devoid of kinase activity have been identified in both familial and sporadic cases of ALSP. To determine the validity of the Csf1r heterozygous mouse as a model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) we performed behavioral, radiologic, histopathologic, ultrastructural and cytokine expression studies of young and old Csf1r+/− and control Csf1r+/+ mice. Six to 8-month old Csf1r+/− mice exhibit cognitive deficits, and by 9-11 months develop sensorimotor deficits and in male mice, depression and anxiety-like behavior. MRIs of one year-old Csf1r+/− mice reveal lateral ventricle enlargement and thinning of the corpus callosum. Ultrastructural analysis of the corpus callosum uncovers dysmyelinated axons as well as neurodegeneration, evidenced by the presence of axonal spheroids. Histopathological examination of 11-week-old mice reveals increased axonal and myelin staining in the cortex, increase of neuronal cell density in layer V and increase of microglial cell densities throughout the brain, suggesting that early developmental changes contribute to disease. By 10-months of age, the neuronal cell density normalizes, oligodendrocyte precursor cells increase in layers II-III and V and microglial densities remain elevated without an increase in astrocytes. Also, the age-dependent increase in CSF-1R+ neurons in cortical layer V is reduced. Moreover, the expression of Csf2, Csf3, Il27 and Il6 family cytokines is increased, consistent with microglia-mediated inflammation. These results demonstrate that the inactivation of one Csf1r allele is sufficient to cause an ALSP-like disease in mice. The Csf1r+/− mouse is a model of ALSP that will allow the critical events for disease development to be determined and permit rapid evaluation of therapeutic approaches. Furthermore, our results suggest that aberrant activation of microglia in Csf1r+/− mice may play a central role in ALSP pathology.

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Section: Discussionmentioning

confidence: 99%

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

Chiţu

Gökhan

Gulinello

et al. 2015

Neurobiology of Disease

162

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“…Indeed, white matter changes have been observed in elderly asymptomatic mutation carriers. 20,21 Additionally, the calcifications may diminish along while white matter pathology progresses. However, to elucidate the mechanism by which CSF1R mutations cause such unique calcifications, further investigation is still required.…”

Section: Discussionmentioning

confidence: 99%

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

Konno¹,

Broderick

Mezaki³

et al. 2016

AJNR Am J Neuroradiol

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Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is a rare neurodegenerative disease resulting from mutations in the colony stimulating factor 1 receptor gene. Accurate diagnosis can be difficult as the associated clinical and MRI findings are nonspecific. We present nine cases with intracranial calcifications distributed in two brain regions: the frontal white matter adjacent to the anterior horns of the lateral ventricles and the parietal subcortical white matter. Thin-slice (1-mm) CT scans are particularly helpful in detection due to the small size of the calcifications. These calcifications had a symmetric “stepping stone appearance” in the frontal pericallosal regions, which was clearly visible on reconstructed sagittal CT images. Intrafamilial variability was seen in two of the families, and calcifications were seen at birth in a single individual. These characteristic calcification patterns may assist in making a correct diagnosis and may contribute to understanding of its pathogenesis.

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“…The sarcoidosis patients were studied before diagnostic bronchoscopy and before any treatment with glucocorticoids. HDLS cases 693, 745, and 766 have been described in Schuberth et al, 18 and case 667 was reported in Karle et al 19 The study was approved by the local ethics committee of the Ludwig-Maximilians-Universität München.…”

Section: Blood Samplesmentioning

confidence: 99%

slan-defined subsets of CD16-positive monocytes: impact of granulomatous inflammation and M-CSF receptor mutation

Hofer

Zawada

Frankenberger

et al. 2015

Blood

110

116

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De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS)

Cited by 67 publications

References 18 publications

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

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

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

slan-defined subsets of CD16-positive monocytes: impact of granulomatous inflammation and M-CSF receptor mutation

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