Mutations of Complement Factor I and Potential Mechanisms of Neuroinflammation in Acute Hemorrhagic Leukoencephalitis
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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.
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.
Two novel mutations in FI were identified in our patients, which result in failure to secrete FI. Immunohistochemical evaluation of brain tissue demonstrated positive staining for C3, membrane attack complex (MAC) and IL-1.
We propose AHLE is an unreported, rare phenotype for partial FI deficiency. The upregulation of C3, MAC and IL-1 with subsequent demyelination support a pathologic role for complement activation in AHLE, and suggest anakinra as an important adjunctive therapy in this disease.
KeywordsAcute hemorrhagic leukoencephalitis complement factor I IL-1 IL-1 receptor antagonist
Acute hemorrhagic leukoencephalitis
Atypical hemolytic uremic syndrome
Complement factor I gene
Central nervous system
Experimental autoimmune encephalitis
Complement factor I
Factor I/membrane attack complex
IL-1 receptor antagonist
Membrane attack complex
Scavenger receptor cysteine-rich
The authors would like to thank Dr. Sara C. Nilsson and Dr. Anna M. Blom (Lund University, Malmo, Sweden) for generously providing the FI cDNA, Nikki Bowen (San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA and University of California-San Diego School of Medicine, La Jolla, CA) for guidance with protein purification, the Ludwig Institute for Cancer Research (San Diego, CA) for sequencing support, Jeff Murray (University of Iowa, Iowa City, IA) for providing Filipino DNA control samples, and Keith Rapp, Justin Breisch, Barbara Carter and Gordon Pendergrass (Rady Children’s Hospital, San Diego, CA) for assistance with immunohistochemistry. Funding was provided by National Institutes of Health Training Grant T32 AI007469 (CG, LB).
Declaration of Funding
NIH Training Grant T32 AI007469 (CG, LB)
Conflict of Interest
Dr. Hoffman is a consultant for Sobi Biovitrum.
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