Abstract
A growing number of familial Mediterranean fever (FMF) patients in Israel do not have a single country of origin for all four grandparents. We aimed to predict the Mediterranean fever gene (
...MEFV
) variant most likely to be found for an individual FMF patient, by a machine learning approach. This study was conducted at the Sheba Medical Center, a referral center for FMF in Israel. All Jewish referrals included in this study carried an FMF associated variant in
MEFV
as shown by genetic testing performed between 2001 and 2017. We introduced the term ‘origin score’ to capture the dose and different combinations of the grandparents’ origin. A machine learning approach was used to analyze the data. In a total of 1781 referrals included in this study, the p.Met694Val variant was the most common, and the variants p.Glu148Gln and p.Val726Ala second and third most common, respectively. Of 26 countries of origin analyzed, those that increased the likelihood of a referral to carry specific variants were identified in North Africa for p.Met694Val, Europe for p.Val726Ala, and west Asia for p.Glu148Gln. Fourteen of the studied countries did not show a highly probable variant. Based on our results, it is possible to describe an association between modern day origins of the three most common
MEFV
variant types and a geographical region. A strong geographic association could arise from positive selection of a specific
MEFV
variant conferring resistance to endemic infectious agents.
Although familial Mediterranean fever (FMF) was originally defined as an autosomal recessive disorder, approximately 10-20% of FMF patients do not carry any FMF gene (MEFV) mutations. Fine phenotype ...characterization may facilitate the elucidation of the genetic background of the so called "FMF without MEFV mutations". In this study we clinically and demographically characterize this subset.
MEFV mutation-negative FMF and control patients were recruited randomly from a cohort followed in a dedicated FMF clinic. The control subjects comprised 2 groups: 1. typical population of FMF, consisting of genetically heterogeneous patients manifesting the classical spectrum of FMF phenotype and 2. a severe phenotype of FMF, consisting of FMF patients homozygous for the p.M694V mutation.
Forty-seven genetic-negative, 60 genetically heterogeneous and 57 p.M694V homozygous FMF patients were enrolled to the study. MEFV-mutation negative FMF patients showed a phenotype closely resembling that of the other 2 populations. It differed however from the p.M694V homozygous subset by its milder severity (using Mor et al. scoring method), as determined by the lower proportion of patients with chest and erysipelas like attacks, lower frequency of some of the chronic manifestations, lower colchicine dose and older age of disease onset.
MEFV mutation-negative FMF by virtue of its classical FMF phenotype is probably associated with a genetic defect upstream or downstream to MEFV related metabolic pathway.
Objective To characterize the clinical and genetic features of familial Mediterranean fever (FMF). Study design Clinical presentation and MEditerranean FeVer mutation type of all patients with FMF, ...who first manifested the disease at ≤2 years of age were analyzed and compared with patients who first presented with FMF between 2 and 16 years. Results Of 814 patients with FMF, in 254 patients (31.2%) the first FMF attack was at ≤2 years of age, with a mean age at onset of 1.1 ± 0.8 years. They were compared with 242 patients who presented with their first manifestation of FMF at 2 to 16 years. The clinical manifestations of FMF were comparable in the 2 patient groups, but the delay of diagnosis was longer in patients with early presentation (3.2 ± 3.2 years vs.1.9 ± 2.7 years in the group with onset at 2-16 years, P < .001). A subgroup of patients (60/254), who were diagnosed at ≤2 years had the highest rate of attacks of fever alone as their sole manifestation (40.0% vs 8.4%, P < .05), and less peritonitis (45% vs 86.1%, P < .05) and pleuritis (3.4% vs 32.9%, P < .05). Most of these patients were homozygous for the M694V mutation and were of North African (Sephardic Jewish) extraction. Conclusion In early life, FMF often begins with an atypical presentation, characterized by attacks of fever alone, and its diagnosis and initiation of treatment is therefore significantly delayed.
Amyloid A (AA) amyloidosis is a complication of chronic inflammatory conditions that develops when proteolytic fragments of serum amyloid A protein (SAA) are deposited in tissues as amyloid fibrils. ...Amyloid deposition in the kidney causes progressive deterioration in renal function. Eprodisate is a member of a new class of compounds designed to interfere with interactions between amyloidogenic proteins and glycosaminoglycans and thereby inhibit polymerization of amyloid fibrils and deposition of the fibrils in tissues.
We performed a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of eprodisate in patients with AA amyloidosis and kidney involvement. We randomly assigned 183 patients from 27 centers to receive eprodisate or placebo for 24 months. The primary composite end point was an assessment of renal function or death. Disease was classified as worsened if any one of the following occurred: doubling of the serum creatinine level, reduction in creatinine clearance by 50% or more, progression to end-stage renal disease, or death.
At 24 months, disease was worsened in 24 of 89 patients who received eprodisate (27%) and 38 of 94 patients given placebo (40%, P=0.06); the hazard ratio for worsening disease with eprodisate treatment was 0.58 (95% confidence interval, 0.37 to 0.93; P=0.02). The mean rates of decline in creatinine clearance were 10.9 and 15.6 ml per minute per 1.73 m(2) of body-surface area per year in the eprodisate and the placebo groups, respectively (P=0.02). The drug had no significant effect on progression to end-stage renal disease (hazard ratio, 0.54; P=0.20) or risk of death (hazard ratio, 0.95; P=0.94). The incidence of adverse events was similar in the two groups.
Eprodisate slows the decline of renal function in AA amyloidosis. (ClinicalTrials.gov number, NCT00035334.)
Immunoglobulin free light chain (FLC) kappa (κ) and lambda (λ) isotypes exist mainly in monomeric and dimeric forms. Under pathological conditions, the level of FLCs as well as the structure of ...monomeric and dimeric FLCs and their dimerization properties might be significantly altered. The abnormally high fractions of dimeric FLCs were demonstrated in the serum of patients with multiple myeloma (MM) and primary systemic amyloidosis (AL), as well as in the serum of anephric patients. The presence of tetra- and trimolecular complexes formed due to dimer-dimer and dimer-monomer interactions was detected in the myeloma serum. Analysis of the amyloidogenic light chains demonstrated mutations within the dimer interface, thus raising the possibility that these mutations are responsible for amyloidogenicity. Increased κ monomer and dimer levels, as well as a high κ/λ monomer ratio, were typically found in the cerebrospinal fluid from patients with multiple sclerosis (MS). In many MS cases, the elevation of κ FLCs was accompanied by an abnormally high proportion of λ dimers. This review focuses on the disease-related changes of the structure and level of dimeric FLCs, and raises the questions regarding their formation, function, and role in the pathogenesis and diagnosis of human diseases.
Systemic sclerosis (SSc) is associated with increased cardiac morbidity and mortality. Whether some electrocardiographic markers of arrhythmias predispose to early cardiogenic death in SSc remains ...controversial. This study evaluated the occurrence of previously reported as well as unstudied markers of repolarization in patients with SSc and assessed their prognostic implications.
A total of 21 patients with SSc and 31 unaffected controls were included in this prospective study. Electrocardiograms were conducted under strict standards. Repolarization and dispersion parameters and markers of late ventricular potentials were determined using designated computer software. Results of multiple beats were averaged.
There were no significant differences between the SSc and control groups in average QT intervals, average corrected QT intervals, average QT interval dispersion (QTd), average QT corrected dispersion (QTcd), and QT dispersion ratio. However, average QT apex dispersion, average JT dispersion, average JT corrected dispersion, and Tpeak-Tend corrected were significantly higher in patients with SSc than in controls. Late ventricular potentials were not found in patients with SSc or in controls. Increased QTd and QTcd were recorded in 1 patient who experienced ventricular arrhythmia before inclusion in the study. None of the remaining patients with SSc or the controls developed arrhythmia during the 9-year follow-up.
Abnormal repolarization parameters may be observed in patients with SSc. However, their prognostic significance with regard to increased risk for repolarization-associated ventricular arrhythmias and increased cardiac death could not be determined in this study. Our findings endorse additional studies on this matter.
Objective
Familial Mediterranean fever (FMF) is an autoinflammatory disease manifested as recurrent serosal inflammation. An association between FMF and malignancy has not been evaluated. The aim of ...this study was to estimate cancer risk in a large cohort of FMF patients from a single institution.
Methods
The study cohort consisted of 8,534 FMF patients registered at the National FMF Center in Tel Hashomer, Israel. We linked the study cohort to the database of the Israel National Cancer Registry using the national identity number. Cancer incidence in FMF patients was determined and then stratified by age and sex. Standardized incidence ratios (SIRs) for cancers were calculated.
Results
Among 8,534 FMF patients (4,400 men, 4,134 women), 350 developed cancer during the years 1970–2011. The overall cancer risk among patients with FMF was significantly lower than was expected in specific sex and ethnic groups of the Israeli population: for males of Jewish ethnicity, SIR 0.66 (95% confidence interval 95% CI 0.55–0.77), P < 0.001; for females of Jewish ethnicity, SIR 0.75 (95% CI 0.64–0.86), P < 0.001; and for males of Arab ethnicity, SIR 0.34 (95% CI 0.07–0.99), P = 0.024.
Conclusion
FMF patients have a significantly lower incidence of cancer than the general population of Israel. This pattern was demonstrated in 2 ethnic populations: Jewish and Arab. We speculate that the lower cancer incidence could be attributed to a direct physiologic effect of FMF or to its treatment.
Objective Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome is a sporadic disease, characterized by periodic attacks of inflammation. Mutations in the MEFV, the gene ...associated with familial Mediterranean fever (FMF), may lead to subclinical inflammation in asymptomatic carriers and modify the phenotype of some inflammatory diseases. We aimed at investigating the effect of MEFV gene mutations on disease phenotype in PFAPA. Patients and Methods The cohort of this ongoing prospective study consisted of 124 children with PFAPA syndrome, followed in a single referral center, who were tested for MEFV mutations. Demographic data, clinical characteristics, and disease course of 65 PFAPA patients with and 59 without MEFV mutations (M+ and M−, respectively) were compared. Results PFAPA attacks in carriers of MEFV mutations were shorter compared with patients without mutations (3.8 ± 1.7 versus 4.8 ± 1.9 days, P < 0.01). The difference was more pronounced in those carrying the M694V mutation. In M+ patients, the rates of patients with regularity of their attacks (49.2%) and oral aphthae (24.6%) were lower, compared with M− patients (74.5% and 43.9%, respectively, P < 0.05 for each of the 2 comparisons). M+ patients needed a lower corticosteroid (beclomethasone) dose to abort the attacks (0.16 ± 0.07mg/kg versus 0.19 ± 0.08, P = 0.028). No differences were observed in all other clinical and laboratory parameters, over a follow-up period of 4.3 years. Conclusion In PFAPA, MEFV is a modifier gene associated with an attenuated disease severity.
Systemic sclerosis (SSc) may affect the heart with microvascular dysfunction and lead to an early cardiac death, but the association between certain repolarization indexes and SSc heart disease ...remains controversial. Our goal was to evaluate a previously unstudied marker of repolarization dynamics, i.e., QT variability, in patients with SSc and to assess its prognostic implications.
A total of 17 patients with SSc and 21 healthy controls were included into this prospective study. Electrocardiograms were conducted under strict standards. The QT variability index (QTVI), normalized QT variability (QTVN), and power spectral analysis of QT dynamics, considered as markers of ventricular arrhythmias in a number of other disorders, were determined using designated computer software.
There was no significant difference in demographic and cardiac important clinical parameters between the groups. Also, the mean QTVI, QTVN, and power spectral analysis parameters were comparable between the patients with SSc and control subjects. At baseline, the QTVI values of 1 patient with SSc, who experienced ventricular arrhythmia prior to inclusion in the study, were considerably higher compared to other patients with SSc. None of the remaining patients with SSc or the control subjects developed arrhythmia during the follow-up of 8 years.
Higher than normal QTVI may be found in the minority of patients with SSc. The prognostic significance of this finding is unknown, but it may entail an increased risk of ventricular arrhythmias. Therefore, the value of QTVI as a tool for arrhythmia risk stratification in SSc merits further research.
Background
Plasma cell dyscrasias (PCD) comprise a wide spectrum of disorders, which may adversely affect the kidney. However, in some PCD cases associated with kidney disease, the routine laboratory ...tests may be incapable to determine precisely the form of PCD, i.e., benign or malignant. Moreover, the kidney biopsy needed for precise diagnosis may be risky or declined. To overcome these limitations, we have developed and reported a new non-invasive technique based on serum free light chains (FLC) monomer (
M
) and dimer (
D
) pattern analysis (FLC MDPA), which allowed differentiation between malignant and benign PCD forms. The objective of our retrospective study was to demonstrate the utility of FLC MDPA in solving ten puzzling PCD cases complicated with kidney disease (patients 1–10).
Methods
Ten patients with uncertain form of PCD or with a questionable response to treatment were studied. In addition to routine laboratory tests and clinical evaluation of the PCD patients, our previously developed FLC MDPA in sera and biochemical amyloid typing in biopsy tissues were applied.
Results
The FLC MDPA aided the diagnosis of the PCD underlying or accompanying the kidney disease in patients 1–5, and helped to interpret properly the response to treatment in patients 1, 6–10. The FLC MDPA findings were confirmed by a biochemical analysis of tissue amyloid deposits and subsequently by the outcome of these patients.
Conclusions
FLC MDPA is a non-invasive diagnostic test useful in the management of ambiguous cases of PCD associated with kidney disease.
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