CSF1R mosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids

Florian S Eichler; Jiankang Li; Yiran Guo; Paul A Caruso; Andrew C Bjonnes; Jessica Pan; Jessica K Booker; Jacqueline M Lane; Archana Tare; Irma Vlasac; Hakon Hakonarson; James F Gusella; Jianguo Zhang; Brendan J Keating; Richa Saxena

doi:10.1093/brain/aww066

CSF1R mosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids

Brain. 2016 Jun;139(Pt 6):1666-72. doi: 10.1093/brain/aww066. Epub 2016 May 5.

Authors

Affiliations

¹ 1 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA 2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA 3 Center for Rare Neurological Diseases, Massachusetts General Hospital, Boston, MA, 02114, USA feichler@partners.org.
² 4 BGI-Shenzhen, Shenzen 518083, China 5 Shenzhen Key Laboratory of Neurogenomics, BGI-Shenzhen, Shenzhen 518083, China.
³ 6 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA 7 Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA 8 Department of Paediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁴ 9 Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
⁵ 2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA 10 Program in Medical and Population Genetics, Broad Institute, Cambridge, 02142, MA, USA.
⁶ 1 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA 3 Center for Rare Neurological Diseases, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁷ 11 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
⁸ 2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA 1 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA 12 Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
⁹ 1 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA 2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA 10 Program in Medical and Population Genetics, Broad Institute, Cambridge, 02142, MA, USA 13 Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
¹⁰ 2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA 10 Program in Medical and Population Genetics, Broad Institute, Cambridge, 02142, MA, USA 12 Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.

Abstract

Mutations in the colony stimulating factor 1 receptor (CSF1R) have recently been discovered as causal for hereditary diffuse leukoencephalopathy with axonal spheroids. We identified a novel, heterozygous missense mutation in CSF1R [c.1990G > A p.(E664K)] by exome sequencing in five members of a family with hereditary diffuse leukoencephalopathy with axonal spheroids. Three affected siblings had characteristic white matter abnormalities and presented with progressive neurological decline. In the fourth affected sibling, early progression halted after allogeneic haematopoietic stem cell transplantation from a related donor. Blood spot DNA from this subject displayed chimerism in CSF1R acquired after haematopoietic stem cell transplantation. Interestingly, both parents were unaffected but the mother's blood and saliva were mosaic for the CSF1R mutation. Our findings suggest that expression of wild-type CSF1R in some cells, whether achieved by mosaicism or chimerism, may confer benefit in hereditary diffuse leukoencephalopathy with axonal spheroids and suggest that haematopoietic stem cell transplantation might have a therapeutic role for this disorder.

Keywords: dementia; leukodystrophy; neurodegeneration; neuroinflammation; whole exome sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged, 80 and over
Chimerism
Female
Genetic Predisposition to Disease / genetics
Hematopoietic Stem Cell Transplantation
Humans
Leukoencephalopathies / genetics*
Leukoencephalopathies / surgery
Male
Middle Aged
Mosaicism*
Mutation, Missense
Receptor, Macrophage Colony-Stimulating Factor / genetics*

CSF1R mosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids

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