The E148Q Variant Modulates Clinical Phenotype but not Systemic Inflammation in Pediatric Familial Mediterranean Fever

Technical Summary: The E148Q Variant Modulates Clinical Phenotype but not Systemic Inflammation in Pediatric Familial Mediterranean Fever

Problem Statement
Familial Mediterranean Fever (FMF) is a monogenic autoinflammatory disorder caused by variants in the MEFV gene. While exon 10 variants (e.g., M694V) are well-established pathogenic drivers associated with severe phenotypes, the clinical significance of the E148Q variant (located in exon 2) remains controversial. Some literature suggests it is a benign polymorphism, while others propose it acts as a low-penetrance pathogenic variant. Specifically, the impact of the E148Q variant on the clinical phenotype of patients carrying the M694V heterozygous genotype is unclear. This study addresses the gap in understanding whether the presence of E148Q modifies disease expression, severity, and systemic inflammation in a genetically homogeneous pediatric cohort.

Methodology
This was a retrospective, single-center medical record review conducted at Ankara Bilkent City Hospital between January 2013 and December 2024.

• Population: The study included 320 pediatric patients (<18 years) diagnosed with FMF who met the Eurofever/PRINTO classification criteria.
• Inclusion Criteria: Patients were stratified into two groups based on genotype:
  1. M694V heterozygous (n=247).
  2. M694V/E148Q compound heterozygous (n=73).
• Exclusion Criteria: Patients with other MEFV genotypes, incomplete medical records, or follow-up durations of less than 6 months were excluded.
• Data Collection: Researchers extracted demographic data, clinical manifestations (fever, abdominal pain, chest pain, arthritis, erysipelas-like erythema), attack characteristics, and laboratory findings (WBC, CRP, ESR, SAA) during both attack and attack-free periods.
• Outcome Measures: Disease severity was assessed using the International Severity Scoring System for FMF (ISSF). Colchicine resistance was defined as active disease despite maximum tolerated colchicine doses.
• Statistical Analysis: Categorical variables were compared using Chi-square or Fisher's exact tests, while non-normally distributed continuous variables were analyzed using the Mann–Whitney U test.

Key Results
The study identified distinct clinical differences between the two genotypic groups, though systemic inflammatory markers remained comparable.

• Demographics: Patients with the M694V/E148Q genotype presented at a significantly older age (median 119 months) compared to the M694V heterozygous group (median 88 months; p=0.005).
• Clinical Phenotype:
  • Chest Pain: Significantly more frequent in the M694V/E148Q group (32.9%) compared to the M694V group (11.7%; p<0.001).
  • Fever: More frequent in the M694V heterozygous group (77.7%) than in the M694V/E148Q group (65.8%; p=0.038).
• Disease Severity: Moderate-to-severe disease (ISSF score ≥3) was more common in the M694V/E148Q group (27.4%) compared to the M694V group (17.4%; p=0.035).
• Laboratory Findings:
  • WBC: White blood cell counts during attacks were lower in the M694V/E148Q group (p=0.044).
  • Inflammatory Markers: No significant differences were observed between the groups regarding CRP, ESR, or SAA levels during attacks or remission.
• Treatment Response: Colchicine resistance was rare overall (1.6%) and was observed only in the M694V heterozygous group; no patients in the M694V/E148Q group developed resistance.

Significance and Claims
The authors conclude that the E148Q variant acts as a phenotypic modifier rather than an independent driver of systemic inflammation when co-occurring with the M694V variant.

• Phenotypic Modulation: The presence of E148Q alongside M694V is associated with a distinct clinical profile characterized by a higher frequency of chest pain and a lower frequency of fever, leading to higher ISSF severity scores. The authors suggest this may be due to E148Q enhancing pyrin inflammasome activation and IL-1β production in the presence of a pathogenic exon 10 mutation, thereby altering the clinical presentation without necessarily increasing the systemic inflammatory burden.
• Limited Inflammatory Impact: Contrary to the "gene-dose effect" seen with biallelic pathogenic exon 10 variants (which typically increase inflammatory markers), the addition of E148Q did not result in elevated CRP, ESR, or SAA levels. This suggests that while E148Q influences clinical manifestations, its effect on systemic inflammatory activity is limited and likely not clinically meaningful in terms of inflammatory burden.
• Clinical Implication: The findings support the hypothesis that E148Q contributes to phenotypic variability in FMF, potentially explaining why patients with this compound heterozygous genotype may present with specific symptoms (like chest pain) and higher severity scores despite having similar systemic inflammation to those with M694V alone.

The paper acknowledges limitations, including its retrospective nature, single-center design, and the lack of functional biomarkers (e.g., IL-18, IL-1β). However, it highlights the strength of analyzing a large, genetically homogeneous pediatric cohort to isolate the specific contribution of the E148Q variant.