Mutations of Complement Factor I and Potential Mechanisms of Neuroinflammation in Acute Hemorrhagic Leukoencephalitis
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ORIGINAL RESEARCH
Mutations of Complement Factor I and Potential Mechanisms of Neuroinflammation in Acute Hemorrhagic Leukoencephalitis Lori Broderick & Chhavi Gandhi & James L. Mueller & Christopher D. Putnam & Katayoon Shayan & Patricia C. Giclas & Karin S. Peterson & Seema S. Aceves & Robert M. Sheets & Bradley M. Peterson & Robert O. Newbury & Hal M. Hoffman & John F. Bastian Received: 3 July 2012 / Accepted: 9 August 2012 / Published online: 29 August 2012 # Springer Science+Business Media, LLC 2012
Abstract Purpose Acute Hemorrhagic Leukoencephalitis (AHLE) is a rare demyelinating disorder of acute onset, rapid deterioration and significant morbidity and mortality. Most often described as a post-infectious complication of an upper respiratory illness, its precise pathophysiology remains unclear. We describe two pediatric patients with AHLE with partial complement factor I (FI) deficiency whose successful treatment included the interleukin-1 (IL-1) receptor antagonist, anakinra, implicating a role for FI and IL-1 in this disorder.
Methods Extensive clinical workup of two patients presenting with AHLE revealed complement abnormalities, specifically related to the alternative pathway and its regulator, FI. Aggressive management with steroids, immunoglobulin, and anakinra ultimately led to improvement of clinical status and near return to neurologic baseline in both patients. Genetic sequencing of the FI coding regions of the patients and their families was performed. In vitro protein expression studies and immunohistochemistry of fixed brain tissue was used to investigate pathogenic mechanisms.
Hal M. Hoffman and John F. Bastian contributed equally to the work. Electronic supplementary material The online version of this article (doi:10.1007/s10875-012-9767-z) contains supplementary material, which is available to authorized users. L. Broderick : C. Gandhi : S. S. Aceves : H. M. Hoffman (*) Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California-San Diego, 9500 Gilman Dr. MC 0635, La Jolla, CA 92093, USA e-mail: [email protected] J. L. Mueller : C. D. Putnam : H. M. Hoffman San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA, USA L. Broderick : C. Gandhi : J. L. Mueller : C. D. Putnam : S. S. Aceves : H. M. Hoffman Department of Medicine, University of California-San Diego School of Medicine, La Jolla, CA, USA K. Shayan : R. O. Newbury Department of Pathology, University of California-San Diego, La Jolla, CA, USA
K. Shayan : K. S. Peterson : S. S. Aceves : R. M. Sheets : B. M. Peterson : R. O. Newbury : H. M. Hoffman : J. F. Bastian Rady Children’s Hospital, San Diego CA, USA P. C. Giclas ADx Complement Laboratory and Department of Pediatrics, Allergy and Immunology Division, National Jewish Health, Denver, CO, USA K. S. Peterson : S. S. Aceves : R. M. Sheets : H. M. Hoffman : J. F. Bastian Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of California-San Diego, La Jolla, CA, USA B. M. Peterson Division of Pedi
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