Mutations of Complement Factor I and Potential Mechanisms of Neuroinflammation in Acute Hemorrhagic Leukoencephalitis

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. Results 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. Conclusions 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.

Canonical Nlrp3 Inflammasome Links Systemic Low-Grade Inflammation to Functional Decline in Aging

“…These data lend additional support to the recent evidence suggesting that complement activation promotes aging-related phenotypes (Naito et al, 2012). Consistent with our findings, treatment of acute onset demyelinating disorders in humans with IL-1 receptor antagonist Anakinra, reduces complement C3 (Broderick et al, 2013). Our data demonstrates that IL-1 is required for Nlrp3 inflammasome mediated age-related increase in complement C3 and interferon activation.…”

Complement factor I deficiency

“…In keeping with other reports, 5 our patient showed no response to plasma exchange or rituximab, although case B in Shields et al 6 did show a response to methylprednisolone. Broderick et al 5 saw modest benefits coinciding with anakinra use. Eculizumab is the only currently available complement inhibitor.…”

“…In both instances, absolute levels of CFI were normal; however, functional analysis demonstrated almost complete abrogation of enzymatic activity. 9 Thus, unlike previous cases, 5 our patient was in the highly unusual situation of having antigenically normal CFI levels but severely deficient CFI activity from both mutant alleles. In addition, the unexpected finding of normal serum C3 level in the serum reflects the fact that routine clinical assays may also detect other forms of C3, in this setting, most likely C3b.…”

“…3 CFI-mediated complement regulation may also be important in the progression of early phase Alzheimer disease. 4 A report of 2 unrelated children of Filipino descent 5 and a recent adult brief report 6 describe acute hemorrhagic leukoencephalopathy (AHLE) in association with complete CFI deficiency. All had infrequently recurrent episodes, at intervals of several years, commencing in the second decade of life.…”

ZNS-Vaskulitiden und entzündliche Hirnerkrankungen bei Kindern und Jugendlichen

“…Diese können im Rahmen von Virusinfektionen insbesondere mit Influenzaviren, aber auch ohne virale oder andere Trigger auftreten. Eine Vielzahl oftmals genetisch bedingter Erkrankungen können mit dem Auftreten einer akut verlaufenden nichtinfektiösen Enzephalitis assoziiert sein, wie beispielsweise eine Mutation in den neuronalen Natriumkanälen (25), RANBP2-Genmutationen (26) und Komplementfaktorendefekte (27).…”