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JAMA Neurol. 2013 Jul;70(7):875-882. doi: 10.1001/jamaneurol.2013.698.

Genetic analysis of inherited leukodystrophies: genotype-phenotype correlations in the CSF1R gene.

Author information

1
Reta Lilla Weston Laboratories, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, England.
2
Inserm, UMR_S975, CRICM, UPMC Univ Paris 06, UMR_S975, CNRS UMR 7225, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.
3
Centre de reference des Démences Rares, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.
4
Dementia Research Centre, Institute of Neurology, University College London, London, England.
5
Queen Square Brain Bank, Institute of Neurology, University College London, London, England.
6
Neuropathology Unit, Hospital Santo Antonio, Centro Hospitalar do Porto, Oporto, Portugal.
7
Département de Génétique et Cytogénétique, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.
8
Département de Neurologie, Hôpital Charles Nicolle, CHU Rouen, Rouen, France.
9
Département de Neurologie, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.
10
Service de Neurologie, CH Yves Le Foll, Saint Brieuc, France.
11
Département de Neurologie, Centre de mémoire de ressource et de recherche, CHU de Poitiers, Poitiers, France.
12
MRC Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, England.
#
Contributed equally

Abstract

IMPORTANCE:

The leukodystrophies comprise a clinically and genetically heterogeneous group of progressive hereditary neurological disorders mainly affecting the myelin in the central nervous system. Their onset is variable from childhood to adulthood and presentation can be with a variety of clinical features that include mainly for adult-onset cases cognitive decline, seizures, parkinsonism, muscle weakness, neuropathy, spastic paraplegia, personality/behavioral problems, and dystonia. Recently, Rademakers and colleagues identified mutations in the CSF1R gene as the cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS), offering the possibility for an in-life diagnosis. The detection of mutations in this gene in cases diagnosed with different clinical entities further demonstrated the difficulties in the clinical diagnosis of HDLS.

OBJECTIVE:

To better understand the genetic role of mutations in this gene, we sequenced a large cohort of adult-onset leukodystrophy cases.

DESIGN:

Whole-exome sequencing and follow up-screening by Sanger sequencing.

SETTING:

Collaborative study between the Institute of Neurology, University College London and the Inserm, Paris, France.

PARTICIPANTS:

A total of 114 probands, mostly European patients, with a diagnosis of adult-onset leukodystrophy or atypical cases that could fit within a picture of leukodystrophy. These included 3 extended families within the spectrum of leukodystrophy phenotype.

INTERVENTIONS:

Whole-exome sequencing in a family and Sanger sequencing of CSF1R.

MAIN OUTCOMES AND MEASURES:

Mutations in CSF1R.

RESULTS:

We identified 12 probands with mutations in CSF1R. The clinical diagnoses given to these patients included dementia with spastic paraplegia, corticobasal degeneration syndrome, and stroke disorders. Our study shows that CSF1R mutations are responsible for a significant proportion of clinically and pathologically proven HDLS.

CONCLUSIONS AND RELEVANCE:

These results give an indication of the frequency of CSF1R mutations in a European leukodystrophy series and expand the phenotypic spectrum of disorders that should be screened for this gene.

PMID:
23649896
PMCID:
PMC4204151
DOI:
10.1001/jamaneurol.2013.698
[Indexed for MEDLINE]
Free PMC Article

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