Form Of Familial Mediterranean Fever Research Articles

Heterozygous E148Q Mutation in an Indian Family with a Milder Form of Familial Mediterranean Fever

Dear Editor, Familial Mediterranean fever (FMF, OMIM no. 249100) is an inherited autoinflammatory disorder resulting from MEFV gene mutations. A 15-year-old girl from Kerala, South India, born of a nonconsanguineous union presented with recurrent fever, diffuse abdominal pain, and left knee joint pain for 1 year. She had fever for 3 days every week associated with left knee arthritis. Some of the episodes were associated with diffuse abdominal pain, oral ulcers, and an erythematous facial rash. She also had right hip and ankle pain with swelling on a few occasions. On examination, she had swollen and warm left knee joint. Her 12-year-old sibling also had similar problems (recurrent fever, diffuse abdominal pain, and joint pain) for 10 months. Both the parents were asymptomatic. Blood tests showed neutrophilic leukocytosis, high erythrocyte sedimentation rate, and C-reactive protein. Ultrasonography of the abdomen showed mild ascites. Immunological testing showed normal C3 complement and the absence of rheumatoid factor, antinuclear, anti-double-stranded DNA, and anti-neutrophilic cytoplasmic antibodies. The periodicity of symptoms and positive family history made us consider inherited autoinflammatory disorder. Targeted mutational analysis showed the MEFV variant E148Q in the heterozygous state in both siblings. No pathogenic variants were identified in the MEFV exon, TNFRSF1A, and MVK genes [Table 1]. The patient and her younger sister were managed with colchicine (1.0 mg daily), and on follow-up up to 1 year, the patients were asymptomatic. Genetic counseling was given to the patient family.Table 1: The results of targeted mutational analysis of the MEFV, TNFRSF1A, and MVK genes in the two siblingsFMF is common among certain ethnic groups of the Eastern Mediterranean region. More than 300 different mutations of the MEFV gene related to FMF have been identified, although only a few are pathogenic.[1] Previous studies testing the pathogenicity of E148Q alteration showed conflicting results. In a study of 646 FMF patients by Tirosh et al., 1% had a heterozygous E148Q variant with a milder clinical phenotype compared with patients having M694V homozygosity.[2] A Turkish FMF cohort of 153 patients had 33 (21.6%) patients with E148Q variant and 34 compound heterozygous patients (with E148Q and exon 10 mutations).[3] E148Q allele frequency among FMF patients was found to be 25% in Jewish, Arab, and Druze patients living in Israel, 20% in Turkish, 34% in Japanese, 17% in Azeri Turk patients living in Iran, and 2% in Armenian patients.[3] Several studies noted that the E148Q mutation was associated with a milder FMF phenotype. However, there was no significant difference in the frequency of clinical findings among the Turkish cohort.[3] Two patients from a South Indian family with recurrent fever, diffuse abdominal pain, and left knee joint pain for 1 year were found to have the MEFV variant E148Q in the heterozygous state. Both of them responded well to colchicine. The diagnosis of a milder phenotype of FMF was thus confirmed. Even though autoinflammatory disorders were reported from the Indian subcontinent,[4,5] we do not have data regarding the E148Q allele frequency and other mutations causing FMF. We report FMF in two members of a family with E148Q mutation which was not previously reported from the Indian subcontinent. This case reminds the readers to consider hereditary periodic fever syndromes when evaluating recurrent fever and the importance of E148Q mutation in the Indian population. Ethics approval All procedures performed in studies involving human participants were by the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Declaration of patient consent The authors certify that informed consent was taken from the father of both patients and assent was obtained from the children for participating in the study. The informed consent from the father and assent from the children were also obtained for using the clinical information to be reported in the journal. The patients and parents understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Dynamic disequilibrium-based pathogenicity model in mutated pyrin’s B30.2 domain—Casp1/p20 complex

BackgroundThe B30.2 variants lead to most relevant severity forms of familial Mediterranean fever (FMF) manifestations. The B30.2 domain plays a key role in protein-protein interaction (PPI) of pyrin with other apoptosis proteins and in regulation the cascade of inflammatory reactions. Pyrin-casp1 interaction is mainly responsible for the dysregulation of the inflammatory responses in FMF. Lower binding affinity was observed between the mutant B30.2 pyrin and casp1 without the release of the complete pathogenicity mechanism. The aim of this study was to identify the possible effects of the interface pocked residues in B30.2/SPRY-Casp1/p20 complex using molecular mechanics simulation and in silico analysis. ResultsIt was found that Lys671Met, Ser703Ile, and Ala744Ser variants led mainly to shift of the binding affinity (∆G), dissociation constant (Kd), and root mean square deviation (RMSD) in B30.2/SPRY-Casp1/p20 complex leading to dynamic disequilibrium of the p20-B30.2/SPRY complex toward its complex form. The current pathogenicity model and its predicted implementation in the relevant colchicine dosage were delineated. ConclusionThe molecular mechanics analysis of B30.2/SPRY-p20 complex harboring Lys671Met, Ser703Ile, and Ala744Ser variants showed dynamic disequilibrium of B30.2/SPRY-casp1/p20complex in context of the studied variants that could be a new computational model for FMF pathogenicity. This study also highlighted the specific biochemical markers that could be useful to adjust the colchicine dose in FMF patients.

A mild form of Familial Mediterranean Fever associated with a polymorphisms C.NT 1588,-69G>

A mild form of Familial Mediterranean Fever associated with a polymorphisms C.NT 1588,-69G>

Two Sisters with Colchicine-Resistant form of Familial Mediterranean Fever on the Canakinumab Therapy: Clinical Case

Background. Colchicine-resistant cases of familial Mediterranean fever (FMF) are associated with high risk of kidney amyloidosis and severe episodes of the disease with pyretic fever, arthritis, pleurisies, pericarditis. It is difficult to achieve disease control in colchicine-resistant patients and it is required to use genetically engineered biologic drugs. Clinical Case Description. The observation of the family with severe course of FFL is presented. The successful use of canakinumab (monoclonal antibody to interleukin-1) in sisters with colchicine-resistant form of disease is described. Fever, articular and abdominal syndromes were completely reversed after 4 weeks of treatment as well as normalisation of laboratory tests was noted. Laboratory indexes of disease activity (erythrocyte sedimentation rate and C-reactive protein level) have stayed in reference ranges after 32 weeks of therapy, no new episodes of the disease were recorded. There were no adverse effect on the canakinumab therapy during the observation period (32 weeks). Conclusion. The high canakinumab efficacy in patients with severe colchicine-resistant forms of FMF is shown.

Increased Frequency of MEFV Genes in Patients with Epigastric Pain Syndrome.

Atypical clinical forms of familial Mediterranean fever (FMF) can be misdiagnosed as therapy-resistant epigastric pain syndrome (EPS) for they share many of the same clinical features, such as abdominal pain. Thus, we aimed to determined the frequency of FMF in patients who were followed with a diagnosis of therapy-resistant EPS. Seventy-five patients with therapy-resistant EPS and 20 controls were involved in the study. To detect the FMF in patients with therapy-resistant EPS, Tel-Hashomer criteria, family history of FMF were researched and recorded. We performed performed MEFV gene analysis on all patients. Forty-three patients with EPS (57.3%) had MEFV gene mutations and the carrier rate was 30.0%. The most common MEFV gene alteration was R202Q (55.8%), followed by E148Q (16.2%), R761H (16.2%), V726A (9.3%), M680I (9.3%) and M694V (4.6%). Rarely seen mutations in the Turkish population were also identified: K695R (2.3%), L110P (2.3%) and G304R (2.3%). Eight patients with EPS were diagnosed with FMF and started on colchicine therapy. Three patients with compound heterozygosities for three mutations, two patients with compound heterozygosities for two mutations (K695R/ V726A and R202Q/ R761H), one patient with homozygous R202Q, one patient with heterozygous R202Q mutation and one patient with non- R202Q heterozygous mutation (G304R/–) had clinical FMF symptoms and were started on colchicine therapy. Patients who have therapy-resistant EPS should also be questioned about FMF, especially in high risk populations.

Molecular modeling of complete tertiary structure of pyrin and influence of mutations on it

Pyrin protein is the product of the MEFV gene, mutations in which cause the manifestation of Familial Mediterranean Fever (FMF). Complete tertiary structure of pyrin and the effects of mutations on it are still experimentally not studied. Mutations - E148Q, M680I, M694V, M694I, V726A, A744S and R761H of pyrin induce manifestation of the most widespread and severe forms of FMF. One striking feature of FMF is the phenomenon of complex allele mutations. In case of complex allele mutations, the pyrin protein will contain more than one mutated amino acids. From currently known complex allele mutations there are those that combine the most widespread and severe single mutations - M680I-M694I, E148Q-M694V, E148Q-M694I, E148Q-V726A, E148Q-A744S, E148Q-R761H, E148Q-V726A-R761H. In complex alleles, one mutation may have a modifying effect on the other one. The other striking feature of FMF is the fact that despite the fact that the FMF is considered as an autosomal recessive autoinflammatory syndrome, were detected mutations - T577N и T577S for which was proved autosomal dominant inheritance. Understanding the correlation between the FMF phenotype and genotype is further obscured by the existence of complex allele and dominant mutations. Therefore, we suggest that computational modeling of native and mutated pyrin complete tertiary structure and their comparative investigation will help to understand the effects of abovementioned mutations on pyrin and on FMF manifestation in general.

Effects of M680I and M694V pyrin mutations on the tertiary structure of domain B30.2 and its interaction with caspase-1: In silico analysis

The M680I and M694V mutations located in the B30.2 pyrin domain are responsible for the manifestation of the most common forms of Familial Mediterranean fever. It is well known that a malfunction of the pyrin–caspase-1 complex is the main cause of inflammation in FMF. The purpose of this study was to identify possible changes in the tertiary structure of mutated B30.2 domain and to determine their potential consequences in the formation of the pyrin–caspase-1 complex. Using computer modeling, it was found that the above mutations change the tertiary structure of B30.2 domain, causing shifts of binding sites and altering the energy of interaction between B30.2 and caspase-1.

Influence of M680I and M694V mutations on pyrin's domain B30.2 tertiary structure and it's complex formation ability with caspase-1

The M680I and M694V mutations located in the B30.2 pyrin domain are responsible for the manifestation of the most common forms of Familial Mediterranean fever. It is well known that a malfunction of the pyrin-caspase-1 complex is the main cause of inflammation in FMF. The purpose of this study was to identify possible changes in the tertiary structure of mutated B30.2 domain and to determine their potential consequences in the formation of the pyrin-caspase-1 complex. Using computer modeling, it was found that the above mutations change the tertiary structure of B30.2 domain, causing shifts of binding sites and altering the energy of interaction between B30.2 and caspase-1.

Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by MEditerranean FeVer gene (MEFV) mutations. In Japan, patients with FMF have been previously reported, including a mild or incomplete form. Several factors are presumed to contribute to the variable penetrance and to the phenotypic variability of FMF. We conducted the current study to investigate the correlation of variable clinical presentations and MEFV genotypic distributions in Japanese FMF patients.We analyzed demographic, clinical, and genetic data for 311 FMF patients enrolled in the study. Clinically, we classified FMF into 2 phenotypes: 1) the “typical” form of FMF, and 2) the “atypical” form of FMF according to the Tel Hashomer criteria. Patients with the typical FMF phenotype had a higher frequency of febrile episodes, a shorter duration of febrile attacks, more frequent thoracic pain, abdominal pain, a family history of FMF, and MEFV exon 10 mutations. Conversely, patients with the atypical FMF phenotype had a lower frequency of fever episodes and more frequent arthritis in atypical distribution, myalgia, and MEFV exon 3 mutations. Multivariate analysis showed that the variable associated with typical FMF presentation was the presence of MEFV exon 10 mutations. Typical FMF phenotype frequencies were decreased in patients carrying 2 or a single low-penetrance mutations compared with those carrying 2 or a single high-penetrance mutations (M694I), with an opposite trend for the atypical FMF phenotype. In addition, patients having more than 2 MEFV mutations had a younger disease onset and a higher prevalence of thoracic pain than those carrying a single or no mutations. Thus, MEFV exon 10 mutations are associated with the more typical FMF phenotype. In contrast, more than half of the Japanese FMF patients without MEFV exon 10 mutations presented with an atypical FMF phenotype, indicating that Japanese FMF patients tend to be divided into 2 phenotypes by a variation of MEFV mutations.

Patient management and the association of less common familial Mediterranean fever symptoms with other disorders

In this study, we present clinical data from 16,000 familial Mediterranean fever patients. We also discuss the clinical manifestation of a subset of these patients and their potential symptom associations with other disorders. Familial Mediterranean fever patients were confirmed using Tel-Hashomer criteria and were tested for the 12 most common mutations using the familial Mediterranean fever StripAssay. A total of 100 samples were selected, and their MEFV gene exons and intron junctions were completely sequenced. We observed that in children severe phenotypes with polyserositis, erysipelas-like erythema, splenomegaly, and vasculitis are associated with high penetrance of exon 10 mutations, particularly M694V. Several forms of arthritis were associated with familial Mediterranean fever, including acute mono/oligoarthritis in the lower extremities, destructive arthritis, ankylosing spondylitis, sacroiliitis, arthritis of the hip joint, and juvenile chronic arthritis. Severe life-threatening complications, such as adhesive intestinal obstruction, renal amyloidosis, and uncommon/rare symptoms were sometimes the only form of familial Mediterranean fever manifestation. We suggest performing familial Mediterranean fever genetic testing for patients presenting with rare/uncommon symptoms also common in other disorders, to prevent misdiagnosis or delayed diagnosis. In our experience, the most effective patient management for familial Mediterranean fever was its rapid diagnosis through genetic testing, initiation of colchicine therapy, and promotion of attack prevention through counseling.

MEFV mutations in Egyptian patients suffering from familial Mediterranean fever: analysis of 12 gene mutations

The objective of the study is to screen 12 MEFV gene mutations in Egyptian patients with familial Mediterranean fever (FMF) and to study the initial hypothesis that the phenotypic expression of the disease may be attributable to the existence of a particular mutation. We enrolled 136 Egyptian patients (74 males, and 62 females) with a clinical diagnosis of FMF. DNA was amplified by PCR and subjected to reverse hybridization for the detection of 12 MEFV gene mutations. The phenotypic expression of the disease was compared in two subgroups according to the presence of homozygote E148Q and M694V gene mutations. The most frequent gene mutations in the studied group were V726A, M694V, M680I, E148Q and M694I in 41.2, 32.4, 29.4, 25 and 20.6%, respectively. At least one of these main five founder mutations was present in 132 patients (97.1%). Thirty-two patients (23.5%) were homozygote for one of the main five founder mutations. The most common homozygote gene mutations were E148Q and M694V, each in 12 patients (8.8%). Significant increase in abdominal pain and arthritis was found in patients with homozygote M694V mutation compared to those with E148Q mutation. All patients with amyloidosis had M694V gene mutation. The increased frequency of V726A gene mutation and the rarity of amyloidosis in this study suggest that Egyptian patients may have a milder form of FMF compared to other populations. The five main founder mutations account for the vast majority of cases of FMF. M694V gene mutation may be associated with increased frequency of abdominal pain, arthritis and the presence of amyloidosis.

Amyloidosis associated with renal cell carcinoma of the AA type

Amyloid fibrils were found at postmortem examination in a 70 year old woman with generalized amyloidosis associated with renal carcinoma (hypernephroma). Clinically, her amyloid disease presented as nephrotic syndrome. It was demonstrated by electrophoretic and amino acid sequence analysis studies that the amyloid fibrils contained AA protein identical to that found in amyloidosis associated with chronic inflammatory and infectious diseases as well as in the genetic form of familial Mediterranean fever.