Abstract Details

Title Hereditary Diffuse Leukoencephalopathy with Spheroids caused by R777W and R782C mutations in CSF1R: A report of four cases in Sweden

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) Behavioral and Cognitive Neurology Posters (7:00 AM-5:00 PM)

Poster/Presentation
Number 039

Objective To describe four cases of HDLS from three families with two different likely pathogenic mutations in the tyrosine kinase domain of CSF1R and to present clinical features with a variety of scoring scales in order to capture reproducible inter-individual diversity of clinical presentations.

Background

HDLS is a rare and devastating genetic disease caused by heterozygous mutations in the CSF1R gene. It is characterized by rapidly progressive neurodegeneration and variable behavioral, cognitive and motor disturbances, and seizures.

Design/Methods Each patient was evaluated with eight standardized functional estimation scores (FES), to capture the diverging clinical phenotypes. Patients underwent lumbar puncture including CSF analysis of neurofilament light (NFL), Glial fibrillary protein (GFAP), tau, β-amyloid, and phospho-tau. CT and MRI were performed according to clinical routine and were systematically re-evaluated by an experienced radiologist. A genetic sequence analysis was performed as well as a functional phosphorylation assay in order to confirm the pathogenicity of the mutations found.

Results Two mutations were identified, a missense variant c.2344C>T, p. (Arg782Cys), and a missense variant c.2329C>T, p. (Arg777Trp). A functional assay showed markedly reduced autophosphorylation in cells expressing the CSF1R mutations p.R777W and p. R782C, confirming the pathogenicity of these mutations. A radiological investigation revealed typical changes for HDLS in all of the cases. Table 1 summarizes results of the CSF-analysis. FES illustrate the wide variability of the clinical picture in different time points along the disease course (table 2).

Conclusions This case-series highlights the variability of CSF1R-related leukoencephalopathies, semi-quantitatively along the axes of frontal, motor neuron, and extrapyramidal disease. The present cases may serve as a nucleus of a future Swedish registry of this and similar disorders. Our ambition is to be able to increase awareness for genetic leukoencephalopathies among neurologists and psychiatrists who may encounter similar cases in their practices and encourage for genetic testing.

Authors/Disclosures
Igal Rosenstein, MD (Sodra Alvsborgs Sjukhus) PRESENTER	Dr. Rosenstein has nothing to disclose.
Oluf Andersen, MD (University of Gothenburg)	Dr. Andersen has nothing to disclose.
	No disclosure on file
Tobias Granberg, MD, PhD (Karolinska Institutet)	The institution of Dr. Granberg has received research support from Karolinska Institutet. The institution of Dr. Granberg has received research support from Region Stockholm. The institution of Dr. Granberg has received research support from Merck. The institution of Dr. Granberg has received research support from Swedish Society for Medical Research.
	No disclosure on file
	No disclosure on file
Takeshi Ikeuchi, MD (Brain Research Institute, Niigata University)	Dr. Ikeuchi has nothing to disclose.
Virginija D. Karrenbauer, MD, PhD (Karolinska University Hospital)	Dr. Karrenbauer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck.

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