T helper 17 polarization in familial Mediterranean fever.

Autoinflammatory attacks in familial Mediterranean fever (FMF) are accompanied by elevated levels of interleukin-6 (IL-6), and are controllable by IL-1-targeting drugs. In combination, IL-6 and IL-1 are known to be potent inducers of T helper (Th) 17 cells development. Therefore, we studied the Th17 population size, and activation potential, of FMF patients. Based on the relative mRNA expression of the Th1, Th2, Treg and Th17 transcription factors T-bet, GATA3, FOXP3 and retinoic acid-related orphan receptor γT (RORγT), respectively, the Th17 population in peripheral blood mononuclear cells (PBMCs) of healthy subjects was estimated at 2.5% of the entire Th population and 4.4% in FMF patients in remission (n=6 for each group, P=0.03). IL-17 secretion after universal stimulation of the T-cell receptor in PBMCs culture was twice higher in cultures of patients with frequent attacks (n=18) than in those of patients with infrequent attacks (n=10, 1124±266 vs 615±196 pg ml(-1), P=0.009). IL-17 secretion correlated well with IL17A mRNA level. Part of the increased secretion was related to the deleterious, MEFV p.M694V homozygous genotype (n=19, 1.5-fold, P=0.03). Almost all IL-17 producer cells were CD4-positive (CD4(+)IL-17(+)). In conclusion, frequent attacks and the deleterious FMF genotype appear to drive FMF patients to a heightened Th17 response.

Guidelines for the genetic diagnosis of hereditary recurrent fevers.

Hereditary recurrent fevers (HRFs) are a group of monogenic autoinflammatory diseases characterised by recurrent bouts of fever and serosal inflammation that are caused by pathogenic variants in genes important for the regulation of innate immunity. Discovery of the molecular defects responsible for these diseases has initiated genetic diagnostics in many countries around the world, including the Middle East, Europe, USA, Japan and Australia. However, diverse testing methods and reporting practices are employed and there is a clear need for consensus guidelines for HRF genetic testing. Draft guidelines were prepared based on current practice deduced from previous HRF external quality assurance schemes and data from the literature. The draft document was disseminated through the European Molecular Genetics Quality Network for broader consultation and amendment. A workshop was held in Bruges (Belgium) on 18 and 19 September 2011 to ratify the draft and obtain a final consensus document. An agreed set of best practice guidelines was proposed for genetic diagnostic testing of HRFs, for reporting the genetic results and for defining their clinical significance.

'Silent' carriage of two familial Mediterranean fever gene mutations in large families with only a single identified patient.

The presence of two mutations in the familial Mediterranean fever gene, without overt familial Mediterranean fever (FMF), designated as phenotype III, predisposes to developing 'silent' AA amyloidosis, recognized as phenotype II, due to the absence of medical supervision and colchicine prophylaxis. We sought to determine the prevalence of phenotype III in large families with only one subject affected with FMF, in order to assess the population at risk for transformation to phenotype II. A total of seven large families were recruited for the study. Siblings were screened for MEFV mutations and underwent a clinical interview to assess for unrecognized FMF manifestations. Phenotype III, most commonly associated with a V726A/E148Q genotype, was detected in 10% of siblings of index cases from informative families, corresponding to a 10-fold increase in comparison to the expected rate in the general population (p < 0.01). Unnoticed 'FMF-like' manifestations were detected among two siblings in the five families in which the index case was heterozygous, but in none of the siblings of the homozygous index cases. The enrichment for phenotype III and detection of occult FMF in large families, in which only a single member is afflicted with FMF, mandates routine clinical evaluation and genetic screening of siblings.

Familial Mediterranean FeVer gene (MEFV) mutations as a modifier of systemic lupus erythematosus.

The objective of this study was to assess the prevalence of the Mediterranean FeVer (MEFV) gene mutations in systemic lupus erythematosus (SLE) patients and their effect on organ involvement, as well as disease activity and severity. The frequencies of three familial Mediterranean fever-related MEFV gene mutations (M694V, V726A and E148Q) were investigated in 70 SLE patients. Organ involvement, Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores were correlated with mutation carriage. Eleven of 70 patients (15.7%) were found to carry an MEFV mutation. A single patient harbored two mutations, E148Q and V726A, without overt familial Mediterranean fever while the rest were heterozygous carriers. Four of the 11 carried an M694V mutation, four carried V726A and two carried E148Q. The majority of MEFV mutation carriers were Sephardic while non-carriers were mainly of Ashkenazi origin (72.7% vs. 45.7% and 47.4% vs. 9.1%, respectively, p = 0.02). SLE onset was significantly earlier in MEFV carriers (27.6 ± 9.7 vs. 38.2 ± 15.5 years, in carriers vs. non-carriers, p = 0.02). Hematologic and serologic parameters were comparable among mutation carriers and non-carriers. Febrile episodes were more common among MEFV mutation carriers (45.4% vs. 15.2%, p = 0.035) and there was a trend for excess episodes of pleuritis as well (54.5% vs. 23.7%, p = 0.06 in carriers vs. non-carriers, respectively). The frequency of secondary anti-phospholipid antibody syndrome was equivalent among the groups. Conversely, compound urinary abnormalities and renal failure was not observed among MEFV carriers yet was present in 33.4% and 18.6% of non-carriers (p = 0.027 and 0.19, respectively). SLICC damage index and SLEDAI activity index did not differ significantly between the groups. MEFV mutation carriage appears to modify the SLE disease phenotype in that it contributes to an excess of inflammatory manifestations such as fever and pleuritis on the one hand, while thwarting more severe renal involvement on the other.

Mutations in the familial Mediterranean fever gene of patients with IgA nephropathy and other forms of glomerulonephritis.

Glomerulonephritis, particularly IgA nephropathy (IgAN), seems to be more common in familial Mediterranean fever (FMF), an inherited disease caused by mutations in the MEditerranean FeVer gene (MEFV). The present study is aimed to determine, in populations not suffering from FMF, whether carriage of MEFV mutations may modify or precipitate IgAN and other forms of primary glomerulonephritis (PGN). Forty patients with biopsy proven IgAN and 40 with PGN were surveyed for the presence of the three most common MEFV mutations (M694V, V726A and E148Q), using polymerase chain reaction amplification and restriction enzyme analysis. The rate of MEFV mutations in the patients was related to the expected carrier rate in the general population of the same ethnic extraction. The effect of mutation carriage on the disease course was determined in the IgAN patient group. The frequency of MEFV mutations in IgAN or PGN was comparable to that found in ethnically adjusted general population (p = 0.1 and 0.5, respectively). Carriage of mutated MEFV was not associated with the course and severity of the disease or findings in kidney biopsy and urine analysis. In a population, mostly of Jewish extraction, MEFV mutations do not seem to predispose to the development of IgAN and other forms of PGN or affect the phenotype.

A single mutated MEFV allele in Israeli patients suffering from familial Mediterranean fever and Behçet's disease (FMF-BD).

Although familial Mediterranean fever (FMF) is an autosomal recessive disorder, preliminary partial mutation analysis suggested that about 60% of FMF patients, who also suffer from Behçet's disease (FMF-BD), have only a single mutated FMF gene (MEFV). In this study, the possibility that patients with FMF-BD may indeed be carriers of a single mutated MEFV is further analysed. The presence of mutations in the coding region of MEFV of eight patients with FMF-BD, representing six families with 47 members, was determined by sequencing. A possible role for the non-carrier chromosome and for BD in the expression of FMF in patients with a single mutated MEFV allele was determined by analysing the association between these variables and the presence of FMF in heterozygous kin. Sequence analysis revealed that all eight patients had indeed only one mutation in the coding region of MEFV. The patients' non-carrier chromosomes converged into three different MEFV haplotypes and were shared by heterozygous unaffected kin in five of six families. BD was found in 10 of 11 carriers with FMF vs one of 16 carriers without FMF (P < 0.001). These results suggest that FMF may be expressed in individuals harbouring only one coding mutation in MEFV. The findings argue against a role for the non-carrier chromosome in the induction of FMF, and suggest that the FMF phenotype in this cohort was associated with the simultaneous presence of BD. These findings may mirror a more generalised rule, that FMF may be precipitated in carriers of a single mutated FMF gene by factors unrelated to the other MEFV allele.

Analysis of allelic association between D6S461 marker and multiple sclerosis in Ashkenazi and Iraqi Jewish patients.

A genetic factor contributing to multiple sclerosis (MS) disease risk is evident by the increased prevalence of disease among siblings of probands. A recent genome screen on Canadian sib pairs suffering from MS identified linkage between the genetic marker D6S461 and MS, and showed disequilibrium in transmission of its 260-bp allele from heterozygous parents to affected siblings (Ebers et al., 1996). The present study examined the allelic segregation of this marker among MS patients of Iraqi Jewish and Ashkenazi origin, two homogeneous ethnic groups that differ considerably from Caucasians. The frequency of the 260-bp allele reached 28.3% among Iraqi MS patients (n = 30) and 25.2% among the Ashkenazi patients (n = 121) compared with 19.6% (n = 28) and 21.3% (n = 115) in respective origin-matched controls (for the combined data set, p = 0.18). A secondary analysis of the frequency of the 260-bp allele in clinical subgroups showed a frequency of 38.1% among patients with juvenile MS (i.e., onset by 21 yr of age) of Ashkenazi origin (n = 21, p = 0.019) and 38.8% in the combined pool (n = 27, p = 0.0045). Most (90%) of the juvenile MS patients belonged to the relapsing-remitting subgroup, which itself showed a frequency of 28.5% of the 260-bp allele (n = 121, p = 0.045). The results suggest that the D6S461 region may contain a locus contributing to an early onset of relapsing-remitting MS.

Familial Mediterranean fever in two Bedouin families: mutation analysis and disease severity.

Familial Mediterranean fever (FMF) is an autosomal recessive disease prevalent among non-Ashkenazi Jews, Armenians, Arabs, and Turks. The Bedouin are nomad Arab tribes residing in desert margins of the Middle East and Arabia. FMF is quite rare in Bedouins, and here we report on two Bedouin families from southern Israel suffering from this disorder. The MEFV mutations found in the Bedouin patients M694I, V726A, and E148Q are consistent with their Arab origin. The disease severity score showed a mild to moderate severity disease in six patients. The Bedouins, leading a unique nomadic life, may prove instrumental in unraveling the role of environmental factors in the course and severity of FMF.

Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state.

Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterized by recurrent attacks of fever and inflammation of serosal membranes and gradual development of nephropathic amyloidosis. The recent cloning of the FMF gene (MEFV) and identification of disease-associated mutations in most patients made the direct determination of FMF carrier frequency feasible. The aim of the present study was to investigate the carrier rate of the most common MEFV mutations among different Jewish ethnic groups in Israel. Further, an attempt was made to elucidate the possible biological advantage that the heterozygote state may confer. Three hundred Ashkenazi, 101 Iraqi, and 120 Moroccan Jews were screened for the E148Q, V726A, and M694V mutations (at least two most common mutations per group), with a resulting overall carrier frequency in the respective ethnic group of 14%, 29%, and 21%. No difference in morbidity between Ashkenazi carriers and non-carriers of MEFV mutations was discerned, although an excess of febrile episodes in carriers of the V726A and in carriers of either V726A or E148Q was evident (P < 0.02 and P < 0.05, respectively). The frequency of subjects with two MEFV mutations but not expressing FMF (phenotype III) was 1:300 in Ashkenazi Jews and 1:25 in Iraqi Jews, exceeding the reported rate of overt FMF in these ethnic groups by 40-240 fold. These results affirm the high carrier rate among the studied Jewish ethnic groups in Israel and suggest that most subjects with FMF mutations are unaffected.

Late-onset familial Mediterranean fever (FMF): a subset with distinct clinical, demographic, and molecular genetic characteristics.

To determine the prevalence and characterize demographic, clinical, and genetic features of familial Mediterranean fever (FMF) of late onset, all patients experiencing their first FMF attack at age 40 years or more were identified using the computerized registry of our FMF clinic, and then thoroughly interviewed and examined. The control group consisted of 40 consecutive FMF patients, who arrived at the FMF clinic for their regular follow-up visit and were 40 years of age or older at the time of the examination. The severity of the disease in patients and controls was determined using a modified score, developed previously. Mutational analysis in the FMF gene was performed using a commercial kit. Only 20 of 4000 (0.5%) patients had late-onset FMF. These patients were mostly men, of non-North African origin, P < 0.05 compared to controls. All had abdominal attacks and in most these were the only manifestation of their disease, P < 0.001. None had chronic or prolonged manifestations of FMF, for example, amyloidosis, chronic arthritis, or protracted myalgia, P < 0.001. The response to treatment was good despite using low colchicine dose, P < 0.05. The overall severity score indicated a mild disease, P < 0.001. Mutational analysis revealed absence of M694V homozygosity, P < 0.01, compared to our regular FMF population. We conclude that the onset of FMF in a late age defines a milder form of disease with typical clinical, demographic, and molecular genetic characteristics.

MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a major cause of AA amyloidosis. Recently, the gene (MEFV) causing this disease was cloned and 16 disease associated mutations have been described. We have analyzed 178 FMF patients, 30 of whom also suffered from amyloidosis, for 4 mutations in MEFV. Mutations were identified in 29 of the FMF amyloidosis patients. 27 FMF amyloidosis patients were homozygous for M694V. One patient was found to be homozygous for both V726A and E148Q. In another patient E148Q and V726A were found on one allele, while V726A was found on the second allele. Amyloidosis was far more common among patients homozygous for M694V compared to patients with other mutations (P < 0.0001). In 3 patients homozygous for M694V, amyloidosis was the sole manifestation of the disease.

Regulation of oligodendrocyte development and central nervous system myelination by insulin-like growth factors.

In summary, our studies show that IGFs are potent regulators of oligodendrocyte development and myelination in vitro and in vivo. IGFs act at several levels: by promoting proliferation of oligodendrocytes and oligodendrocyte precursors, by inducing immature oligodendrocyte precursors to develop into oligodendrocytes, and by regulating myelin gene expression and the amount of myelin produced per oligodendrocyte. Our findings indicate that IGFs play a crucial role in normal oligodendrocyte development and myelination, and suggest that IGFs may have applications for the promotion of remyelination in myelin disorders such as MS.

Vacuolating megalencephalic leukoencephalopathy in 12 Israeli patients.

Leukodystrophy with macrocephaly as the main features of infantile neurodegenerative disease are characteristics of Canavan's disease, L-2-hydroxyglutaric aciduria, type I glutaric aciduria, and Alexander's disease. Also occasionally described are occidental congenital muscular dystrophy, G(M)2-gangliosidosis, metachromatic leukodystrophy, Krabbe's disease, and mucopolysaccharidosis. Since 1995, over 60 patients with a new syndrome, vacuolating megalencephalic leukoencephalopathy, have been described. The syndrome is characterized by macrocephaly, a slowly progressive clinical course of ataxia, spastic paraparesis, and seizure disorder with relatively spared cognition. Unlike other leukodystrophies with macrocephaly (except Alexander's disease), no metabolic marker has been found. We describe a similar group of 12 patients from two different Jewish ethnic origins in whom consanguinity is prominent. These patients have neuroimaging features and magnetic resonance spectroscopy findings indicating that there is an initial increase in white-matter edema with subsequent cystic formation. Consistent with loss of tissue in these areas, brain metabolites are reduced. The familial incidence in this group of patients is suggestive of autosomal-recessive inheritance.

Cranial nerve lesions and abnormal visually evoked potentials associated with the M694V mutation in familial Mediterranean fever.

A 52-year-old Turkish man with familial Mediterranean fever (FMF) due to the homozygous M694V mutation in the MEFV-gene on chromosome 16p13.3, newly developed hemicrania, blurred and double vision, ptosis, ophthalmoparesis and peripheral facial nerve palsy. Except for double vision, all the other abnormalities disappeared spontaneously within 10 days after onset. Markedly prolonged latencies of the visually evoked potentials were also found. At follow-up, 8 months after onset of the neurological abnormalities, right-sided bradydiadochokinesia, right-sided discrete weakness and right-sided hypaesthesia were found. After the exclusion of other hereditary fever syndromes, migraine, stroke, Molaret's meningitis, Behçet's syndrome and mitochondriopathy by clinical, serological, CSF investigations, funduscopy, electroencephalography, and cerebral MRI and MRI angiography, the described neurological abnormalities were regarded as CNS and PNS manifestation of vasculitis or amyloidosis in FMF.

An international external quality assessment for molecular diagnosis of hereditary recurrent fevers: a 3-year scheme demonstrates the need for improvement.

Hereditary recurrent fevers (HRF) are rare diseases caused by molecular defects in genes involved in the regulation of innate immunity. Sixty-seven international laboratories participated in an external quality assessment (EQA) scheme, which was developed to appraise the accuracy of genetic testing. Reports were evaluated for the 12 items recommended by the OECD (Organisation for Economic Co-Operation and Development) guidelines for molecular diagnostics. The best documented items were the name of the gene, the biologist, or the patient, whereas information on the test and screening limits, and clinical interpretation of the disease inheritance were scarcely provided. The mutation nomenclature was incomplete in about 70% of the cases. In the first 2 years of EQA, we identified almost 30% genotyping error rate, which decreased markedly in the last year. The combined performance on the basis of the correct identification of all genotypes by a given laboratory in all the 3 years was only 40%, showing a critical need for improvement.

Systemic lupus erythematosus and familial Mediterranean fever: a possible negative association between the two disease entities--report of four cases and review of the literature.

Serositis is a common clinical manifestation of systemic lupus erythematosus (SLE), as well as being the hallmark of familial Mediterranean fever (FMF), the most prevalent monogenic disease in the Jewish population. We have treated four patients who suffered from both SLE and FMF since 2001 in our clinic, which also serves as the national center for FMF. Our cases illustrate both similarities and dissimilarities between the clinical manifestations of these two diseases, an aspect which should be borne in mind, especially in the young female patients. In general, it seems that co-occurrence of FMF moderates the presentation of lupus.

Common FMF alleles may predispose to development of Behcet's disease with increased risk for venous thrombosis.

BACKGROUND: Behcet's disease (BD) is an inflammatory disorder of unknown cause, associated with vasculitis. Arterial or venous thrombosis occurs in about 25% of BD patients. Familial Mediterranean fever (FMF) is another inflammatory disorder, which stems from mutations in the FMF gene (MEFV) and shares a number of features with BD. OBJECTIVE: MEFV analysis in patients with BD suggests that mutated MEFV may act as a susceptibility gene in BD. We studied the rate and the clinical correlates of MEFV mutations in Israeli BD patients. METHODS: Included were 54 BD patients who satisfied the International Study Group criteria for BD. All BD patients were genotyped using polymerase chain reaction (PCR) and restriction enzyme analysis for the three most common MEFV mutations (M694V, V726A, and E148Q). The association between BD manifestations and MEFV alleles was analysed. RESULTS: Twenty-one BD patients were found to carry a single MEFV mutation and three additional patients were compound heterozygotes, a frequency significantly higher than that expected for ethnically matched healthy individuals. There were no statistically significant differences between carriers and non-carriers with respect to gender, frequency of HLA B5 antigen, cutaneous lesions, joint disease, and severity score. However, carriers did experience thrombosis more often [54% vs. 17%, p<0.005, odds ratio (OR) = 6.9, 95% confidence interval (CI) 1.75-26.9] and uveitis less often (20% vs. 40%, p<0.05, OR = 0.2, 95% CI 0.04-0.92). CONCLUSIONS: MEFV appears to be a susceptibility and modifier gene in BD.

Unique spectrum of MEFV mutations in Iranian Jewish FMF patients--clinical and demographic significance.

OBJECTIVES: To determine the spectrum of mutations in the Mediterranean fever gene (MEFV) of Iranian Jews with familial Mediterranean fever (FMF) and to analyse their clinical manifestations. METHODS: FMF patients with both parents of Iranian-Jewish (IJ) extraction or with one IJ parent (IJ-other, 10 of each) were characterized for clinical manifestations, and the B30.2 (PRYSPRY) domain of their MEFV was sequenced for mutations. RESULTS: Only one rare mutation, R653H, and one new mutation, G632S were present in the IJ group (in 2/10 patients), whereas the new, and common mutations were present in the IJ-other patients (8/10 patients). The new mutation was traced thrice to an IJ ancestor, and although carried asymptomatically by family members, it was over-represented in the patients (3/28 unrelated IJ alleles) compared non-affected IJ subjects (1/126 alleles, P = 0.03) or with non-Jewish Iranians (0/108 alleles, P = 0.001). The mutation was associated with a distinct phenotype regarding sites involved in the attack (P = 0.001), mild severity, sole expression of febrile episodes (P = 0.01) and a male bias (P = 0.01). In two 3D PRYSPRY models the G632S mutation was localized to a surface loop and close to a putative binding site. CONCLUSIONS: Iranian Jews with FMF have a unique spectrum of mutations including a newly described mutation with a non-typical phenotype.