Complete Factor I Deficiency Due to Dysfunctional Factor I with Recurrent Aseptic Meningo-Encephalitis

Haerynck, Filomeen; Stordeur, Patrick; Vandewalle, Johan; Coster, Rudy Van; Bordon, Victoria; Baets, Frans De; Schelstraete, Petra; Javaux, Cédric; Bouvry, Marie Rose; Frémeaux‐Bacchi, Véronique; Dehoorne, Joke

doi:10.1007/s10875-013-9944-8

Cited by 24 publications

(21 citation statements)

References 31 publications

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“…All were predicted to be pathogenic using Polyphen-2 (data not shown). Two variants (p.Ile340Thr; p.Asp524Val) had no effect on FI synthesis but caused a defect of FI activity (not effective in inactivating membrane-bound C3b) (31, 32). Thirteen unrelated patients were diagnosed with a complete FH deficiency.…”

Section: Resultsmentioning

confidence: 99%

Clinical and Genetic Spectrum of a Large Cohort With Total and Sub-total Complement Deficiencies

et al. 2019

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The complement system is crucial for defense against pathogens and the removal of dying cells or immune complexes. Thus, clinical indications for possible complete complement deficiencies include, among others, recurrent mild or serious bacterial infections as well as autoimmune diseases (AID). The diagnostic approach includes functional activity measurements of the classical (CH50) and alternative pathway (AP50) and the determination of the C3 and C4 levels, followed by the quantitative analysis of individual components or regulators. When biochemical analysis reveals the causal abnormality of the complement deficiency (CD), molecular mechanisms remains frequently undetermined. Here, using direct sequencing analysis of the coding region we report the pathogenic variants spectrum that underlie the total or subtotal complement deficiency in 212 patients. We identified 107 different hemizygous, homozygous, or compound heterozygous pathogenic variants in 14 complement genes [ C1Q β ( n = 1), C1r ( n = 3), C1s ( n = 2), C2 ( n = 12), C3 ( n = 5), C5 ( n = 12), C6 ( n = 9), C7 ( n = 17), C8 β ( n = 7), C9 ( n = 3), CFH ( n = 7), CFI ( n = 18), CFP ( n = 10), CFD ( n = 2)]. Molecular analysis identified 17 recurrent pathogenic variants in 6 genes ( C2, CFH, C5, C6, C7 , and C8 ). More than half of the pathogenic variants identified in unrelated patients were also found in healthy controls from the same geographic area. Our study confirms the strong association of meningococcal infections with terminal pathway deficiency and highlights the risk of pneumococcal and auto-immune diseases in the classical and alternative pathways. Results from this large genetic investigation provide evidence of a restricted number of molecular mechanisms leading to complement deficiency and describe the clinical potential adverse events of anti-complement therapy.

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Section: Resultsmentioning

confidence: 99%

Clinical and Genetic Spectrum of a Large Cohort With Total and Sub-total Complement Deficiencies

et al. 2019

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“…G71V has also been found in the compound heterozygous state with another variant, C196S, hypothesized to disrupt a disulphide bond in the SRCR domain of CFI. The final two variants associated with neurological presentations of CFI deficiency are I340T and D524V (16). These variants lie within the serine protease domain but do not directly affect the CFI catalytic triad of H362, D411 and S507.…”

Section: Discussionmentioning

confidence: 99%

“…These variants lie within the serine protease domain but do not directly affect the CFI catalytic triad of H362, D411 and S507. I340T and D524V in trans produce dysfunctional CFI proteins that lacked activity to efficiently regulate alternative complement cascade activation, but did not significantly impact the classical cascade (16).…”

Section: Discussionmentioning

confidence: 99%

“…The same physicians successfully used a combination of high-dose corticosteroids, IVIG and anakinra to treat a 10 year old with ALHE; weaning of anakinra was not possible due disease relapses (7). Haerynck et al described the case of a 16 year old girl with recurrent aseptic meningoencephalitis treated with pulsed corticosteroids, initially with good response but with disease relapses failing to respond to plasmapheresis and requiring further treatment with cyclophosphamide and mycophenolate mofetil (16). Direct replacement of CFI using fresh frozen plasma (28) or purified CFI (29, 30) have been attempted historically with transient correction of in vitro assays of complement activity.…”

Section: Discussionmentioning

confidence: 99%

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Classical and Non-classical Presentations of Complement Factor I Deficiency: Two Contrasting Cases Diagnosed via Genetic and Genomic Methods

Shields

Pagnamenta

et al. 2019

Front. Immunol.

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Deficiency of complement factor I is a rare immunodeficiency that typically presents with increased susceptibility to encapsulated bacterial infections. However, non-infectious presentations including rheumatological, dermatological and neurological disease are increasingly recognized and require a high-index of suspicion to reach a timely diagnosis. Herein, we present two contrasting cases of complement factor I deficiency: one presenting in childhood with invasive pneumococcal disease, diagnosed using conventional immunoassays and genetics and the second presenting in adolescence with recurrent sterile neuroinflammation, diagnosed via a genomic approach. Our report and review of the literature highlight the wide spectrum of clinical presentations associated with CFI deficiency and the power of genomic medicine to inform rare disease diagnoses.

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“…MRI of brain further approved the evidence of meningoencephalitis. Mutation analysis of the complement factor I gene showed two heterozygous mutations (I322T and D506V) that resulted in a complete CFI deficiency due to a functional CFI defect (Haerynck et al, 2013). …”

Section: Role Of Host Factors and Genetic Alterations In Neuroinflammmentioning

confidence: 99%

Neuroinflammation and Infection: Molecular Mechanisms Associated with Dysfunction of Neurovascular Unit

Tohidpour

Моргун

Boitsova

et al. 2017

Front. Cell. Infect. Microbiol.

128

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Neuroinflammation is a complex inflammatory process in the central nervous system, which is sought to play an important defensive role against various pathogens, toxins or factors that induce neurodegeneration. The onset of neurodegenerative diseases and various microbial infections are counted as stimuli that can challenge the host immune system and trigger the development of neuroinflammation. The homeostatic nature of neuroinflammation is essential to maintain the neuroplasticity. Neuroinflammation is regulated by the activity of neuronal, glial, and endothelial cells within the neurovascular unit, which serves as a “platform” for the coordinated action of pro- and anti-inflammatory mechanisms. Production of inflammatory mediators (cytokines, chemokines, reactive oxygen species) by brain resident cells or cells migrating from the peripheral blood, results in the impairment of blood-brain barrier integrity, thereby further affecting the course of local inflammation. In this review, we analyzed the most recent data on the central nervous system inflammation and focused on major mechanisms of neurovascular unit dysfunction caused by neuroinflammation and infections.

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Complete Factor I Deficiency Due to Dysfunctional Factor I with Recurrent Aseptic Meningo-Encephalitis

Cited by 24 publications

References 31 publications

Clinical and Genetic Spectrum of a Large Cohort With Total and Sub-total Complement Deficiencies

Clinical and Genetic Spectrum of a Large Cohort With Total and Sub-total Complement Deficiencies

Classical and Non-classical Presentations of Complement Factor I Deficiency: Two Contrasting Cases Diagnosed via Genetic and Genomic Methods

Neuroinflammation and Infection: Molecular Mechanisms Associated with Dysfunction of Neurovascular Unit

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