A 16-year-old boy of Armenian descent presents with recurrent self-limited attacks of high fever (39–40°C), acute abdominal pain mimicking appendicitis, and sterile peritonitis occurring every 4–6 weeks. Between attacks he is completely well. His parents are consanguineous. Genetic testing confirms biallelic mutations in the MEFV gene marked **A** in the diagram. Which of the following best explains the pathophysiological mechanism underlying his recurrent inflammatory attacks?
A. Haploinsufficiency of MEFV results in reduced pyrin expression, impairing the clearance of bacterial lipopolysaccharide from peritoneal macrophages
B. Gain-of-function mutations in MEFV cause constitutive activation of the NLRP3 inflammasome independent of ASC speck formation
C. Loss-of-function mutations in MEFV remove the normal brake on inflammasome activation, leading to unrestrained caspase-1 activity and excessive IL-1β production
D. Mutations in MEFV impair the normal degradation of pro-caspase-1, leading to accumulation of inactive zymogen in the cytoplasm
Explanation
Why option 1 is correct
The MEFV gene on chromosome 16p13.3 encodes pyrin (MARENOSTRIN, TRIM20), a critical negative regulator of the inflammasome. Pyrin normally restrains inflammasome activation by inhibiting the formation of the ASC speck, which is essential for caspase-1 activation. Loss-of-function mutations in MEFV remove this inhibitory brake, allowing unrestrained caspase-1 activation, processing of pro-IL-1β to active IL-1β, and the characteristic recurrent sterile inflammatory attacks seen in this patient. This is the defining pathophysiology of familial Mediterranean fever as a monogenic autoinflammatory disease (Harrison's 21e Ch 367; Eurofever Registry 2019).
Why each distractor is wrong
Option 2: Gain-of-function mutations would cause constitutive activation, but FMF is caused by loss-of-function mutations that remove the normal inhibitory function of pyrin. Additionally, the inflammasome is not activated independently of ASC speck formation — ASC speck formation is the critical step that pyrin normally suppresses.
Option 3: Haploinsufficiency does not apply to FMF, which follows autosomal recessive inheritance requiring biallelic mutations (as confirmed in this patient). Heterozygous carriers are typically asymptomatic. Furthermore, the pathology is not related to bacterial LPS clearance but to inflammasome dysregulation.
Option 4: The problem in FMF is not impaired degradation of pro-caspase-1 but rather unrestrained activation of caspase-1 due to loss of pyrin's inhibitory function. Pro-caspase-1 accumulation would not explain the acute episodic attacks characteristic of the disease.
High-YieldNEET PG
FMF is the prototype monogenic autoinflammatory disease caused by loss-of-function MEFV mutations that remove the brake on inflammasome-mediated IL-1β production — not a bacterial infection or immune deficiency.
Harrison's 21e Ch 367; Eurofever Registry 2019
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