Clinical significance of E148Q heterozygous variant in paediatric familial Mediterranean fever

Tirosh, Irit; Yacobi, Yonatan; Vivante, Asaf; Barel, Ortal; Ben-Moshe, Yishay; Granat, Ortal Erez; Spielman, Shiri; Oz, Rotem Semo; Shinar, Yael; Gerstein, Maya

doi:10.1093/rheumatology/keab128

Cited by 17 publications

(9 citation statements)

References 19 publications

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“…E148Q was found to be the fourth most common mutation in our cohort. In a recent study by Tirosh et al ( 29 ), it was reported that the presence of the E148Q variant with the M694V variant was not worsening the clinical phenotype. However, M694V/E148Q mutation was found in three of the patients who did not respond to colchicine in our study.…”

Section: Discussionmentioning

confidence: 94%

Real-Life Data From the Largest Pediatric Familial Mediterranean Fever Cohort

et al. 2022

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Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease manifesting phenotypic heterogeneity. It is a clinically diagnosed disease supported by MEditerranean FeVer (MEFV) gene mutation analysis. However, the phenotype-genotype correlation is not yet established clearly. We aimed to determine the clinical findings, phenotype-genotype correlation, and treatment outcomes within a large pediatric FMF cohort. The medical charts of children with FMF who were diagnosed and followed up at the eight pediatric rheumatology units were reviewed retrospectively. All patients in the cohort were analyzed for sequence variants in exon 2,3,5 and 10 of the MEFV gene. Patients without any mutations or with polymorphisms including R202Q were excluded. A total of 3,454 children were involved in the study. The mean ± standard deviation of current age, age at symptom onset, and age at diagnosis were 12.1 ± 5.2, 5.1 ± 3.8, and 7.3 ± 4.0 years, respectively. Of 3,454 patients, 88.2% had abdominal pain, 86.7% had fever, 27.7% had arthritis, 20.2% had chest pain, 23% had myalgia, and 13.1% had erysipelas-like erythema. The most common MEFV mutation patterns were homozygous (32.5%) and heterozygous (29.9%) mutations of exon 10. Homozygous M694V was present in 969 patients (28.1%). Allele frequencies of common mutations were M694V (55.3%), M680I (11.3%), V726A (7.6%), and E148Q (7.2%). Children carrying homozygous or compound heterozygous exon 10 mutations had an earlier age of disease onset (4.6 vs. 5.6 years, p = 0.000) and a higher number of attacks per year (11.1 vs. 9.6, p = 0.001). Although 8% of the patients had a family history of amyloidosis, 0.3% (n = 11) had the presence of amyloidosis. M694V homozygosity was detected in nine patients who developed amyloidosis. Colchicine resistance was present in 4.2% of our patients. In this largest pediatric cohort reviewed and presented to date, patients with exon 10 mutations, particularly the M694V homozygous mutation, have been demonstrated earlier disease onset, annual attack count, and more frequent colchicine-resistant cases. Although E148Q is considered as a polymorphism in some populations, it was identified as a disease-causing mutation in our cohort. Secondary amyloidosis is still happening in adults however, it is extremely rare among children, presumably due to increased awareness, tight control, and the availability of anti-IL1 agents in colchicine-resistant cases.

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Section: Discussionmentioning

confidence: 94%

Real-Life Data From the Largest Pediatric Familial Mediterranean Fever Cohort

et al. 2022

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“…Absence of history of severe attacks ( b ). a E148Q should not be considered as a pathogenic variant [ 10 ] b Severe Attacks = fever and two or more of the following: peritonitis, arthritis, pleuritis, erysipelas like erythema and orchitis …”

Section: Discussionmentioning

confidence: 99%

“…It is important to emphasize that a close clinical and laboratory follow up is required following treatment Table 3 Clinical scenarios that may trigger consideration for colchicine cessation trial when co-exist a E148Q should not be considered as a pathogenic variant [10] b Severe Attacks = fever and two or more of the following: peritonitis, arthritis, pleuritis, erysipelas like erythema and orchitis 1. Patients without biallelic MEFV pathogenic mutations ( a ).…”

Section: Discussionmentioning

confidence: 99%

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Colchicine treatment can be discontinued in a selected group of pediatric FMF patients

Cohen

Spielman

et al. 2023

Pediatr Rheumatol

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Objectives Familial Mediterranean Fever (FMF) patients are required to adhere to a life-long treatment with colchicine, primarily for preventing amyloidosis. As some patients may be asymptomatic for long periods of time, it remains unclear whether it is possible to discontinue colchicine treatment in a selective group of patients. We aimed to identify predictive characteristics for a successful cessation of colchicine therapy. Methods Out of 646 FMF pediatric patients followed in our referral FMF clinic, colchicine treatment was discontinued in 51 patients. In this study we compared the genetic, demographic, and clinical characteristics between patients for whom a successful cessation of therapy was made (Group 1; n = 21) and patients for whom cessation of therapy was deemed a failure (Group 2; n = 30) and consequently had to resume colchicine therapy. Results Patients for whom a successful cessation of therapy was achieved had no biallelic pathogenic MEFV mutations, were less likely to have “severe attacks” (two or more FMF characteristic symptoms) (24% vs 80%; P = 0.000067) and did not require higher than 1 mg/day of colchicine, prior to the drug cessation. Remission duration under colchicine treatment was significantly higher in group 1 compared with group 2 (4.36 years ±2.12 vs 2.53 years ±2; P = 0.0036). Conclusion This study supports the concept of colchicine free remission in a minority of FMF patients (3%). Holding treatment, under close monitoring, may be reasonable when selecting the appropriate patients.

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“…Many published reports from different countries showed that mutations in exon 10 such as M694V, M680I, and V726A are inevitably accompanied by typical clinical manifestations of FMF. However, the effect of mutations in exon 2, specifically the E148Q variant, on phenotype remains an unresolved conundrum [9].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of E148Q and Concomitant AA Amyloidosis in Patients with Familial Mediterranean Fever

Arıcı

Romano

Piskin

et al. 2021

JCM

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The aim of the study was to compare the clinical phenotype of patients with familial Mediterranean fever (FMF)-related AA amyloidosis, according to the age of FMF diagnosis and E148Q genotype. Patients with biopsy-confirmed FMF-related AA amyloidosis were included in the study. Tel-Hashomer criteria were applied in the diagnosis of FMF. All patients had detailed baseline assessment of clinical features, renal functions, genetic testing, histopathological diagnosis of amyloidosis, and treatment received. Multiple comparisons were performed according to the age of diagnosis, disease phenotype, mutation, and mortality. Our study included 169 patients with a diagnosis of AA amyloidosis. There were 101 patients diagnosed with FMF < 18 years of age and 68 patients diagnosed who were ≥18 years of age. The three most common clinical manifestations were fever (84.6%), abdominal pain (71.6%), and arthritis (66.9%). The most common allele among FMF patients was M694V (60.6%), followed by E148Q (21.4%), and M680I (10.3%). The most frequent genotypes were M694V/M694V (45.0%), M694V/E148Q (14.8%), and E148Q/E148Q (11.2%) among 169 patients in our cohort. During the follow-up period, 15 patients (10 male, 5 female) died, of whom 14 had M694V homozygous genotype and one was homozygous for E148Q. Clinicians should be aware of patients with homozygous E148Q genotype for close monitoring and further evaluation. The possible relationship between E148Q and AA amyloidosis needs to be confirmed in other ethnicities.

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Clinical significance of E148Q heterozygous variant in paediatric familial Mediterranean fever

Cited by 17 publications

References 19 publications

Real-Life Data From the Largest Pediatric Familial Mediterranean Fever Cohort

Real-Life Data From the Largest Pediatric Familial Mediterranean Fever Cohort

Colchicine treatment can be discontinued in a selected group of pediatric FMF patients

Evaluation of E148Q and Concomitant AA Amyloidosis in Patients with Familial Mediterranean Fever

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