Article (Scientific journals)
De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS).
Karle, Kathrin N.; Biskup, Saskia; Schule, Rebecca et al.
2013In Neurology, 81 (23), p. 2039-44
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Keywords :
Adult; Female; Humans; Leukoencephalopathies/diagnosis/genetics; Male; Middle Aged; Mutation/genetics; Young Adult
Abstract :
[en] OBJECTIVE: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is caused by autosomal-dominantly inherited mutations in the colony stimulating factor 1 receptor (CSF1R) gene, and is clinically characterized by a progressive cognitive and motor decline leading to death within several years. METHODS: In a continuous series of 25 patients with adult-onset leukoencephalopathy of unknown cause, we genetically confirmed HDLS in 6 families. Affected and nonaffected individuals were examined clinically and by brain MRI studies. RESULTS: HDLS presented as prominent dementia and apraxia, often with extrapyramidal and pyramidal signs, rarely with ataxia. White matter MRI changes were detectable early in the disease course. Family history was negative in 4 of 6 index patients. In 2 of 6 index patients, we could confirm the occurrence of de novo mutations in the CSF1R gene. One family showed possible incomplete penetrance: the 69-year-old father of the index patient carried a CSF1R mutation but was clinically unaffected. In one family, the parents were apparently unaffected and not available for genetic testing. CONCLUSIONS: Typical clinical phenotype and early brain MRI alterations can help to guide the diagnosis of HDLS. Because we confirmed de novo mutations in one-third of patients with CSF1R mutations, this diagnosis should be considered even in the absence of a family history. Furthermore, we present evidence for reduced penetrance of a CSF1R mutation. These results have substantial impact for genetic counseling of asymptomatic individuals at risk and should foster research into disease-modifying factors.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Karle, Kathrin N.
Biskup, Saskia
Schule, Rebecca
Schweitzer, Katherine J.
Krüger, Rejko ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Bauer, Peter
Bender, Benjamin
Nagele, Thomas
Schols, Ludger
Language :
English
Title :
De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS).
Publication date :
2013
Journal title :
Neurology
ISSN :
1526-632X
Publisher :
Lippincott Williams & Wilkins, United States - Maryland
Volume :
81
Issue :
23
Pages :
2039-44
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
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