Complement factor I deficiency: A potentially treatable cause of fulminant cerebral inflammation

Abstract

Objective: To raise awareness of complement factor I (CFI) deficiency as a potentially treatable cause of severe cerebral inflammation.

Methods: Case report with neuroradiology, neuropathology, and functional data describing the mutation with review of literature.

Results: We present a case of acute, fulminant, destructive cerebral edema in a previously well 11-year-old, demonstrating massive activation of complement pathways on neuropathology and compound heterozygote status for 2 pathogenic mutations in CFI which result in normal levels but completely abrogate function.

Conclusions: Our case adds to a very small number of extant reports of this phenomenon associated with a spectrum of inflammatory histopathologies including hemorrhagic leukoencephalopathy and clinical presentations resembling severe acute disseminated encephalomyelitis. CFI deficiency can result in uncontrolled activation of the complement pathways in the brain resulting in devastating cerebral inflammation. The deficit is latent, but the catastrophic dysregulation of the complement system may be the result of a C3 acute phase response. Diagnoses to date have been retrospective. Diagnosis requires a high index of suspicion and clinician awareness of the limitations of first-line clinical tests of complement activity and activation. Simple measurement of circulating CFI levels, as here, may fail to diagnose functional deficiency with absent CFI activity. These diagnostic challenges may mean that the CFI deficiency is being systematically under-recognized as a cause of fulminant cerebral inflammation. Complement inhibitory therapies (such as eculizumab) offer new potential treatment, underlining the importance of prompt recognition, and real-time whole exome sequencing may play an important future role.

Figure 1. Representative MR images

Representative neuroradiologic images. (A–C) Acute imaging on day 2 of admission shows bilateral, asymmetrical, predominantly white matter changes, although some gray matter involvement of thalami is also seen. Patchy enhancement postcontrast and mass effect and effacement of the sulci. Diffusion-weighted imaging (not shown) did not indicate any area of restricted diffusion. (D) Approximately 1 month later showing postcraniectomy changes and substantial resolution of the acute inflammation. (A, B, and D = T2-weighted; C = postcontrast T1-weighted).

Figure 2. Immunohistochemistry

Immunohistochemistry of parietal cortical sample obtained at the time of craniectomy demonstrate reactive astrogliosis, microgliosis, and complement deposition. Top row (A–D) indicates controls (secondary antibody only). Bottom row (E–H) indicates antibody staining. A and E, Reactive astrocyte marker glial fibrillary acidic protein. B and F, Pan-microglial marker ionized calcium binding adapter molecule 1. C and G, In-house anti-C3b/iC3b monoclonal antibody C3/30. D and H, Anti-C9 neoantigen-specific monoclonal antibody B7 (membrane attack complex). Scale bars = 50 μm.

Figure 3. Complement biology

Highly simplified cartoon of complement amplification loop pathways indicating (left, normal healthy condition) how C3/C3b levels reflect an equilibrium between 2 cycles: one of C3 cleavage to form C3b that interacts with factor B, which is then cleaved by factor D to form the C3 convertase (C3bBb) to cleave more C3 and a CFI-dependent C3b inactivation cycle. In factor I deficiency (right), a lack of C3b inactivation causes uncontrolled accumulation of C3b, rapid consumption of C3, and activation of the downstream terminal pathway. Excessive activation of the C3b amplification loop can be inferred from CFB levels that are markedly reduced because of consumption. CFB = complement factor B; CFI = complement factor I.