Clinical and diagnostic value of genetic testing in 216 Israeli children with Familial Mediterranean fever.

OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive disease with diverse clinical presentation. The FMF gene (MEFV) has recently been cloned and 30 point mutations causing the disease have been identified. We appraised the value of mutation analysis as a diagnostic test for FMF in symptomatic pediatric patients, and explored the possible correlations between MEFV genotypes and the diverse phenotypic expression of the disease. METHODS: Two hundred sixteen children who met the clinical criteria for FMF underwent molecular genetic studies to detect the 3 most common mutations in the Israeli FMF patient population (M694V, V726A, E148Q). The mutations found were related to clinical presentation and disease severity, using the Tel-Hashomer severity score. RESULTS: Of the 216 children who fulfilled the diagnostic criteria for FMF, 82 (38.0%) had 2 of the tested mutations, 73 (33.8%) had only one mutation, and 61 (28.2%) had none of the mutations studied. The M694V was the most frequent mutation, detected in 174 of 432 MEFV alleles (40.0%). The V726A mutation was found in 39 alleles (9.0%) and the E148Q mutation in 25 (5.8%). The severity score correlated with the number of mutations. Children with no mutations presented at an older age compared to children with one or 2 mutations. Children homozygous for the M694V mutation presented at a younger age, had a higher severity score, and more commonly had arthritis. CONCLUSION: Limited genetic molecular testing for MEFV mutations may explain some of the FMF clinical variability, but is diagnostically ineffective. The use of clinical criteria remains essential in establishing the diagnosis of FMF.

Detrimental effects of cyclosporin A on long-term graft survival in familial Mediterranean fever renal allograft recipients: experience of two transplantation centers.

BACKGROUND: Cyclosporin A has been associated with severe toxic side effects in patients with familial Mediterranean fever who underwent renal transplantation. Nevertheless, the impact on graft function and survival is not well documented. OBJECTIVE: To compare long-term graft function and survival, between CsA-based vs. CsA free immunosuppressive protocols in FMF recipients of renal allograft. METHODS: Data of FMF recipients were analyzed retrospectively. Graft survival and function and the incidence of acute rejection were correlated to graft source (living donor vs. cadaveric donor), colchicine dose, presence of proteinuria, and immunosuppression protocol (CsA-based triple drug therapy vs. azathioprine-prednisone alone). RESULTS: There were 35 FMF patients with primary renal grafts (13 from living donors and 22 from cadaveric donors). Mean follow-up was 10.6 +/- 6.05 years. Sixteen patients were on CsA-based triple drug therapy and 19 patients on AZA-Pred alone. Mean overall graft survival was 11.2 +/- 0.6 years and 9.4 +/- 1.36 vs. 11.6 +/- 0.4 years for CsA-treated and AZA-Pred groups respectively (P = 0.05). One-year survival was 94% and 96.6% for CsA-treated vs. non-CsA patients (not significant), but 5 and 10 years survival were 76% and 46%, compared to 94.5% and 86% respectively (P = 0.05 at 5 years and 0.001 at 10 years). Mean serum creatinine at time of data collection was 2.3 +/- 1.5 mg/dl in the CsA group vs. 1.6 +/- 0.7 mg/dl in the AZA-Pred group (P = 0.02). There were 14 and 13 reversible rejection episodes in the AZA-Pred and CsA groups respectively (not significant). CONCLUSION: It is suggested that CsA exerts detrimental effects on long-term renal graft function and survival in FMF patients.