Complement factor I deficiency

Abstract

ObjectiveTo raise awareness of complement factor I (CFI) deficiency as a potentially treatable cause of severe cerebral inflammation.MethodsCase report with neuroradiology, neuropathology, and functional data describing the mutation with review of literature.ResultsWe 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.ConclusionsOur 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.

Pearls & Oy-sters: Homozygous Complement Factor I Deficiency Presenting as Fulminant Relapsing Complement-Mediated CNS Vasculitis

“…8,9 The relapsing nature of this patient's disease process is curious and perhaps explained by the speculation that chronic alternative pathway activation caused by CFI deficiency is limited by the depletion of C3. 10,11 A surge of C3 can be induced by a stressor, such as viral illness. With this surge, the alternative pathway is no longer substrate limited and can mount a fulminant unchecked inflammatory response.…”

“…Homozygous partial CFI deficiency has been associated with autoinflammatory processes, which are a group of disorders often characterized by episodic inflammation driven by the innate immune system in the absence of pathogens, autoantibodies, or antigen specific T cells 8 . The relapsing nature of this patient's disease process is curious, and perhaps explained by the speculation that chronic alternative pathway activation caused by CFI deficiency is limited by depletion of C3 10,11 . A surge of C3 can be induced by a stressor, such as viral illness.…”

Complement C4 Is Reduced in iPSC-Derived Astrocytes of Autism Spectrum Disorder Subjects

“…We also found that ASD and control NPCs, neurons and astrocytes secreted and/or expressed CFB and CFD, key components of the alternative complement pathway, and CFH and CFI, inhibitors of the classic and alternative complement pathways [ 1 ]. Although abnormal expression of these complement components and regulators has been implicated in cerebral inflammation [ 34 ], degeneration [ 35 ] and retinopathies [ 36 , 37 ], the possible roles of these proteins in ASD and in the normal developing human nervous system are still largely unknown.…”

Complement C4 is Reduced in iPSC-Derived Astrocytes of Autism Spectrum Disorder Subjects

“…We also observed that all ASD and control cell lines analyzed express CFH and CFI mRNA and secrete relatively high levels of CFH and CFI proteins, which are inhibitors of the classic and alternative pathways of the complement system. Whereas the expression of these complement components and regulators are implicated in cerebral in ammation [38], degeneration [39] and retinopathies [40,41], the physiological roles of these proteins in the developing human nervous system deserve further investigation. Finally, we observed constitutive expression and secretion of the critical component of both classical and lectin cascades C4 by ASD and control NPCs, neurons and astrocytes, and also constitutive secretion of C4b by ASD and control neurons and astrocytes.…”