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Case report: a rare mutation in the complement factor I gene is associated with recurrent aseptic meningitis

Jul 4, 2023 | Neuroscience

The complement regulatory factor I (CFI) is a two-chain serine protease and an endogenous inhibitor of the classical and alternative complement pathways by cleaving C3b and C4b in the presence of cofactor proteins. The CFI gene mutations result in the inability to control the complement cascade appropriately. The complete deficiency of the CFI gene is inherited in an autosomal recessive manner, and results in a C3 deficiency and a predisposition to severe infections caused by encapsulated microorganisms. The authors from the United States and Australia presented a case of a 26-year-old man with more than 15 episodes of aseptic neutrophilic meningitis, concurrent mouth and genital ulcers, seizures, and persistent cognitive deficit. He was found to have a rare heterozygous mutation in the CFI associated with neurological manifestations, which has not been previously reported.

About the case

An 18-year-old man was referred to the emergency department (ED) with new-onset headaches, photophobia, and nausea. His medical history included recurrent painful gum and hard palate ulcers that started at the age of ten, allergic rhinitis, and asthma. His monozygotic twin brother was diagnosed with ulcerative colitis, oral ulcers, and one episode of presumed aseptic meningitis, which was never confirmed by analysis of the cerebrospinal fluid (CSF).

The patient’s general and neurologic examinations were normal except for a temperature of 38.4 °C and neck stiffness, which prompted a lumbar puncture. The CSF analyses demonstrated a cloudy colorless fluid with a total white blood cell count of 2,201/μL (reference range 05/μL) with 68% polymorphonuclear leukocytes and 31% lymphocytes, and protein concentration of 142 mg/dL (reference range 1545 mg/dL). The PCR results of gram stain, bacterial and fungal cultures, cryptococcal antigen, herpes simplex virus (HSV) type 1 and type 2, and enterovirus were negative.

Methylprednisolone, vancomycin, and meropenem were used to treat a presumed bacterial meningitis. Treatment with antibiotics was discontinued after blood cultures showed negative results. After three months, the patient again developed a temperature of 38 °C and headaches, but a lumbar puncture was not performed. He was released with supportive care.

After two years, the patient was referred to the ED with similar symptoms, which responded well to prednisone. He continued to have attacks of headaches and low-grade fevers for the next 2 years. Repeated lumbar punctures showed aseptic neutrophilic meningitis. Other tests, like the CSF metagenomic next-generation sequencing, rheumatologic testing, and autoimmune testing with autoimmune encephalopathy panel and aquaporin-4 antibodies, didn’t show anything.

After four years, the patient was referred to the ED with his first generalized tonic-clonic seizure. A magnetic resonance imaging (MRI) scan revealed symmetric T2 signal abnormalities in the hippocampus. Several previous brain MRI findings were normal. Neuropsychological testing demonstrated new deficits in verbal discrimination, attention, and working memory. He had temporal lobe seizures that decreased in frequency with the initiation of valproic acid and lamotrigine.

The patient also got painful oral and scrotal ulcers. The testing for HSV type 1 and type 2 showed negative results, and biopsies showed benign results. Considering the neuro-Behçet disease, treatment was initiated with colchicine and azathioprine. This therapy improved the ulcers but did not prevent the meningitis flares. During flares, he was treated with oral pulse prednisone. Due to persistent attacks, he was switched from azathioprine to infliximab for 5 months without any improvement.

Whole-exome sequencing revealed a rare variant in the CFI gene (c.859G>A, p.Gly287Arg). Genetic testing confirmed the presence of the same variant in his monozygotic twin brother. A complement analysis revealed that component concentrations and factor levels were normal. These analyses were completed while the patient was treated with immunosuppressive therapy, which may have affected the results.

In this situation, scientists started therapy with anakinra, a recombinant IL-1 receptor antagonist, accompanied by the gradual withdrawal of prednisone. After that, he switched to canakinumab and successfully weaned off prednisone. He continued to take 150 mg of canakinumab monthly and he had no recurrence of ulcers or meningitis in more than 20 months.


This case report demonstrated an association between a rare heterozygous mutation in the CFI associated with neurological manifestations, in this case, manifested as numerous episodes of recurrent aseptic meningitis. The authors emphasized the significance of this case because it supports the role of CFI gene mutations in neuroinflammation that may resemble infectious meningitis. These findings underscore the importance of genetic testing in patients with uncertain diagnoses. More research is needed to examine the underlying mechanisms by which CFI gene dysfunction can result in inflammation in the central nervous system.

This article was published in Neurology: Neuroimmunology & Neuroinflammation

Journal Reference

Rolfes M et al. Complement Factor I Gene Variant as a Treatable Cause of Recurrent Aseptic Neutrophilic Meningitis. Neurol Neuroimmunol Neuroinflamm 2023;10:e200121 (Open Access)

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