期刊
EUROPEAN JOURNAL OF HUMAN GENETICS
卷 21, 期 11, 页码 1232-1239出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ejhg.2013.20
关键词
exome sequencing; neurodegeneration; cerebellar white matter; familial hemophagocytic lymphohistiocytosis; interleukin-1 beta
资金
- Intramural Research Program of the NHGRI
- Rare Disease Foundation
- Canadian Institutes for Health Research
- Canadian Child Health Clinician Scientist Program
- Child and Family Research Institute
- University of British Columbia
Inflammation is an important contributor to pediatric and adult neurodegeneration. Understanding the genetic determinants of neuroinflammation provides valuable insight into disease mechanism. We characterize a disorder of recurrent immune-mediated neurodegeneration. We report two sisters who presented with neurodegeneration triggered by infections. The proband, a previously healthy girl, presented at 22.5 months with ataxia and dysarthria following mild gastroenteritis. MRI at onset showed a symmetric signal abnormality of the cerebellar and peritrigonal white matter. Following a progressive course of partial remissions and relapses, she died at 5 years of age. Her older sister had a similar course following varicella infection, she died within 13 months. Both sisters had unremarkable routine laboratory testing, with exception of a transient mild cytopenia in the proband 19 months after presentation. Exome sequencing identified a biallelic perforin1 mutation (PRF1; p. R225W) previously associated with familial hemophagocytic lymphohistiocytosis (FHL). In contrast to FHL, these girls did not have hematopathology or cytokine overproduction. However, 3 years after disease onset, the proband had markedly deficient interleukin-1 beta (IL-1 beta) production. These observations extend the spectrum of disease associated with perforin mutations to immune-mediated neurodegeneration triggered by infection and possibly due to primary immunodeficiency.
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