Determining the origin of different variants associated with familial mediterranean fever by machine-learning.

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.

Clinical significance of E148Q heterozygous variant in paediatric familial Mediterranean fever.

Objectives: FMF results from mutations in the Mediterranean fever (MEFV) gene. The p. E148Q protein alternation is one of the most frequent in the MEFV gene, yet the exact E148Q genotype-phenotype correlation remains unclear.

Familial Mediterranean fever: Penetrance of the p.[Met694Val];[Glu148Gln] and p.[Met694Val];[=] genotypes.

The penetrance of the p.[Met694Val];[Met694Val] genotype of pyrin in adult familial Mediterranean fever (FMF) patients is close to 100%. Disease penetrance of the p.

ISSAID/EMQN Best Practice Guidelines for the Genetic Diagnosis of Monogenic Autoinflammatory Diseases in the Next-Generation Sequencing Era.

Background: Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes).

[A CLINICAL DISCUSSION: FEVER OF UNKNOWN ORIGIN IN THE MODERN ERA - MORE QUESTIONS THAN ANSWERS].

In this case report we discuss a patient who suffers from recurrent bouts of fever and as part of the clinical workup for autoinflammatory diseases was genetically tested for mutations in 26 genes related to autoinflammatory disease with a next generation sequencing test. We discuss the benefits and pitfalls of using this test.

Current practices for the genetic diagnosis of autoinflammatory diseases: results of a European Molecular Genetics Quality Network Survey.

Monogenic autoinflammatory disorders (AIDs) are rare diseases caused by variants in genes regulating the innate immune system. The identification of the first four genes responsible for the prototype group of hereditary recurrent fevers prompted the development of genetic diagnosis, followed by external quality assessment and guidelines for the interpretation of sequence variants in these diseases. Recent changes in the diagnosis of genetic diseases, namely the implementation of next-generation sequencing (NGS), lead to discovery of the new genes associated with at least 40 novel AIDs, which revolutionized patient care and prognosis.

Classification criteria for autoinflammatory recurrent fevers.

Background: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA.

Methods: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria.

New workflow for classification of genetic variants' pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID).

Background: Hereditary recurrent fevers (HRFs) are rare inflammatory diseases sharing similar clinical symptoms and effectively treated with anti-inflammatory biological drugs. Accurate diagnosis of HRF relies heavily on genetic testing.

Objectives: This study aimed to obtain an experts' consensus on the clinical significance of gene variants in four well-known HRF genes: , , and .

A high and equal prevalence of the Q703K variant in NLRP3 patients with autoinflammatory symptoms and ethnically matched controls.

Objectives: Cryopyrin associated periodic syndromes (CAPS) comprise a spectrum of autoinflammatory disorders of varying severity caused by mutations in the NLRP3 gene. The NLRP3-Q703K allele has been reported both as a functional polymorphism and as a low penetrance mutation.

Methods: To describe the clinical phenotype of subjects with the Q703K allele and to report the frequency of this allele among patients with autoinflammatory symptoms and healthy controls.

Familial Mediterranean Fever and Incidence of Cancer: An Analysis of 8,534 Israeli Patients With 258,803 Person-Years.

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.

Carriage of Mediterranean Fever (MEFV) Mutations in Patients with Postpericardiotomy Syndrome (PPS).

Background: Postpericardiotomy syndrome (PPS) is characterized by pleuro-pericardial inflammation, which occurs in patients undergoing surgical procedures involving the pleura, pericardium, or both. The syndrome is considered to be immune mediated. However, its pathogenesis is not fully understood.

Distressing Visions at the End of Life: Case Report and Review of the Literature.

There is a growing body of literature documenting dreams, visions, and other trans-personal communications that occur as part of the dying process, often called end-of-life dreams and visions (ELDVs) or deathbed communications (DBCs). This paper describes a unique case involving distressing visions at the end of life, provides a review of existing literature around ELDVs, and will provide a framework within which to approach the patient experiencing distressing ELDVs.

Acquired familial Mediterranean fever associated with a somatic MEFV mutation in a patient with JAK2 associated post-polycythemia myelofibrosis.

Background: A study was designed to identify the source of fever in a patient with post-polycythemia myelofibrosis, associated with clonal Janus Kinase 2 (JAK2) mutation involving duplication of exon 12. The patient presented with 1-2 day long self-limited periodic episodes of high fever that became more frequent as the hematologic disease progressed.

Methods: After ruling out other causes for recurrent fever, analysis of the pyrin encoding Mediterranean fever gene (MEFV) was carried out by Sanger sequencing in peripheral blood DNA samples obtained 4 years apart, in buccal cells, laser dissected kidney tubular cells, and FACS-sorted CD3-positive or depleted mononucleated blood cells.

Familial Mediterranean fever (FMF) with proteinuria: clinical features, histology, predictors, and prognosis in a cohort of 25 patients.

Objective: Reactive (AA) amyloidosis may complicate familial Mediterranean fever (FMF), the prototype of autoinflammatory diseases. Thus, proteinuria in FMF is commonly viewed as resulting from amyloidosis, and kidney biopsy is deemed superfluous. However, nephropathy other than amyloidosis has been described in FMF, but its rate and distinctive characteristics are unknown.

E148Q MEFV mutation carriage and longevity in individuals of Ashkenazi origin.

The high carriage rate of MEFV mutations in at risk populations suggests that they confer a selective advantage, possibly by way of protection from infections. Here, we sought to assess whether this putative protection contributes to longevity, by studying MEFV mutation status in nonagenarians and the association of mutation carriage with life-threatening conditions. DNA samples and a medical history questionnaire were obtained from 200 nonagenarians (>90 years of age), who received medical treatment at a large tertiary hospital in Israel.

NOD2/CARD15 gene mutations in patients with familial Mediterranean fever.

Objective: Familial Mediterranean fever (FMF) and Crohn's disease are autoinflammatory disorders, associated with genes (MEFV and NOD2/CARD15, respectively) encoding for regulatory proteins, important in innate immunity, apoptosis, cytokine processing, and inflammation. Although mutations in the MEFV gene were shown to modify Crohn's disease, the role of NOD2/CARD15 gene mutations in the FMF disease phenotype was never studied before.

Patients And Methods: The cohort consisted of 103 consecutive children with FMF, followed in a single referral center.

Role of the R92Q TNFRSF1A mutation in patients with familial Mediterranean fever.

Objective: To define the frequency of the R92Q tumor necrosis factor receptor-associated periodic syndrome (TRAPS) mutation in patients with familial Mediterranean fever (FMF) and to study the role of this mutation in FMF.

Methods: Ninety-two FMF patients and 250 controls were genotyped for the R92Q mutation. The frequency of R92Q was assessed among 5 groups of FMF patients.

Familial Mediterranean Fever in the first two years of life: a unique phenotype of disease in evolution.

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 < or =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.

Familial Mediterranean fever in children presenting with attacks of fever alone.

Objective: Familial Mediterranean fever (FMF) is an inherited disease characterized by attacks of febrile polyserositis. In children, attacks of fever alone, or with headache and malaise, may precede other forms of attacks. Our objective was clinical and genetic characterization of FMF and its development in pediatric patients who first presented with attacks of fever alone.

MEFV mutation carriage in Israeli Jewish individuals from ethnicities with low risk for familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a disease caused by mutations in the MEditerranean FeVer gene (MEFV), and in Israel it most commonly affects Jews of North African extraction, in whom the mutation carrier rate is as high as 1 in 5. To assess the protective as well as the modulating affect of MEFV mutation carriage on various inflammatory disease states, we sought to define the frequency of MEFV mutations in Israeli Jewish individuals of various ethnicities, including those with low frequency of FMF, which were not in the focus of our attention hitherto. A total of 163 adults of Bucharian, Turkish, Georgian, Yemenite and Bulgarian origin comprised the study group.

Transthyretin amyloidosis in a patient of Iranian-Jewish extraction: a second Israeli-Jewish case.

Background: We present a patient with late-onset progressive polyneuropathy and a Congo-red positive staining of sural nerve biopsy, where routine immunohistochemical analysis failed to determine the type of amyloid deposited. Since precise determination of the amyloid type has crucial therapeutic implications, we employed our new biochemical micro-techniques, together with molecular biology methods, to characterize the amyloid protein deposited.

Methods: We used a micro-method for extraction of amyloid proteins, amyloid typing by Western blotting, DNA sequencing, and restriction enzyme site analysis.

Neuropsychiatric and cognitive features in autosomal-recessive early parkinsonism due to PINK1 mutations.

Autosomal-recessive early-onset Parkinsonism (AREP) due to PINK1 mutations is characterized by an early-onset, slowly progressive disease, with a good response to levodopa. Psychiatric and cognitive disturbances associated with AREP have rarely been reported in the literature. We describe 2 brothers from a Jewish-Iraqi consanguineous family with a homozygous PINK1 nonsense mutation.

Long-term outcomes in difficult-to-treat patients with recurrent pericarditis.

Patients with many recurrences of acute pericarditis are commonly alarmed by the fear of constriction. We studied their long-term outcome and the possible presence of systemic diseases. Sixty-one Italian patients (36 men) were followed for an average of 8.

Role of the pyrin M694V (A2080G) allele in acute myocardial infarction and longevity: a study in the Sicilian population.

A proinflammatory genotype seems to contribute significantly to the risk of developing coronary heart disease (CHD). Conversely, the susceptibility alleles to inflammatory disease should be infrequent in the genetic background favoring longevity. In fact, in a modern environment, attainment of longevity is facilitated by an anti-inflammatory status.