Abstract
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-1β) 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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Acknowledgements
We are grateful to Dr Camilo Toro for manuscript review and critical analysis, and acknowledge Drs Patrick Tang and Rusang Tan for their collaboration. We would like to express a special thanks to the patients’ family. This study was primarily funded by the Intramural Research Program of the NHGRI and in part by the Rare Disease Foundation. Funding was supplied by the Canadian Institutes for Health Research (DPS). DPS is the Sauder Family Professor of Pediatric Infectious Diseases. CD is supported by the Canadian Child Health Clinician Scientist Program and the Child and Family Research Institute. AM is supported by the University of British Columbia.
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Dias, C., McDonald, A., Sincan, M. et al. Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation. Eur J Hum Genet 21, 1232–1239 (2013). https://doi.org/10.1038/ejhg.2013.20
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DOI: https://doi.org/10.1038/ejhg.2013.20
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