Yael Shinar

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.

Colchicine nonresponsiveness in familial mediterranean fever: clinical, genetic, pharmacokinetic, and socioeconomic characterization

OBJECTIVES To identify the ethnic, clinical, genetic, and pharmacokinetic correlates of colchicine treatment failure in patients with familial Mediterranean fever (FMF). METHODS Fifty-nine FMF patients, unresponsive to a daily dose of > or =2 mg colchicine, were compared with 51 colchicine-responsive patients by clinical, demographic, and socioeconomic assessment, FMF gene (MEditerranean FeVer [MEFV]) mutation and serum amyloid A1 (SAA1) gene polymorphism analysis, and plasma and white blood cell colchicine level determination. RESULTS Colchicine responders and nonresponders were comparable with respect to gender, age, duration and onset of the disease, and various demographic parameters. The 2 cohorts were found to carry mainly the M694V MEFV mutation and had a similar number of homozygotes or compound heterozygotes. Predominance of the alpha/beta alleles of SAA1 and comparable plasma and polymorphonuclear colchicine concentrations characterized both groups. Nonresponders were from lower socioeconomic backgrounds, had less education, and a more severe form of disease. A statistically significant 2-fold elevation of colchicine concentration in the mononuclear cells (MNC) of responders was found. CONCLUSIONS Colchicine treatment failure in FMF is associated with inadequate colchicine MNC concentration, probably resulting from a genetic defect unrelated to the underlying FMF.

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. To evaluate whether inflammatory alleles of pyrin, the gene responsible for familial Mediterranean fever (FMF) may play an opposite role in CHD and in longevity, we examined three FMF‐associated mutations, M694V (A2080G), M694I (G2082A), and V726A (T2177C), encoded by the FMF gene (MEFV) in 121 patients affected by acute myocardial infarction (AMI), in 68 centenarians, and in 196 age‐matched controls from Sicily. None of the Sicilian subjects studied carried the V726A and the M694I FMF‐related mutations. The proinflammatory M694V (A2080G) mutation was the only one we found, which was over‐represented significantly in CHD patients and under‐represented in oldest old, and intermediate values were in healthy, young controls. After adjustment for well‐recognized AMI risk factors, the M694V allele still predicted a significant risk to develop AMI. So, according to these results, we suggest that carrying the proinflammatory M694V pyrin allele may increase the risk to develop AMI. Conversely, the wild‐type pyrin genotype may predispose to a greater chance to live longer in a modern environment with reduced pathogen load and improved control of severe infections by antibiotics. All these data indicate a strong relationship among inflammation, genetics, CHD, and longevity.

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.

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 (31.2%) the first FMF attack was at < or =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 < or =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.

Protracted febrile myalgia of familial Mediterranean fever: Mutation analysis and clinical correlations

Protracted febrile myalgia (PFM) is a rare form of vasculitic disease that affects patients with familial Mediterranean fever (FMF). Mutation analysis performed in 15 patients who suffered from this disorder showed that 9 of the 15 patients were homozygous for M694V. FMF in these 9 patients was associated with more severe symptoms compared to a group of 30 M694V homozygous FMF patients without PFM.Protracted febrile myalgia (PFM) is a rare form of vasculitic disease that affects patients with familial Mediterranean fever (FMF). Mutation analysis performed in 15 patients who suffered from this disorder showed that 9 of the 15 patients were homozygous for M694V. FMF in these 9 patients was associated with more severe symptoms compared to a group of 30 M694V homozygous FMF patients without PFM.

Vacuolating megalencephalic leukoencephalopathy in 12 Israeli patients

Leukodystrophy with macrocephaly as the main features of infantile neurodegenerative disease are characteristics of Canavans disease, L-2-hydroxyglutaric aciduria, type I glutaric aciduria, and Alexanders disease. Also occasionally described are occidental congenital muscular dystrophy, GM2-gangliosidosis, metachromatic leukodystrophy, Krabbes 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 Alexanders 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. (J Child Neurol 2001;16:93-99).

Megalencephalic leukoencephalopathy with subcortical cysts; a founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews

Abstract. Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a progressive inherited neurological disorder characterized by macrocephaly, deterioration in motor functions and cerebellar ataxia. In Israel the disease is found in an increased frequency among Libyan Jews. The disease is caused by mutations in the MLC1 gene, which encodes a putative CNS membrane transporter. We describe three novel mutations (p.G59E, p.P92S, and 134_136insC) in seven MLC families. One of these mutations, p.G59E, was found in the vast majority of MLC patients in Israel. Screening of 200 normal Libyan Jewish individuals for the p.G59E mutation, revealed a carrier rate of 1/40 compared with an expected carrier rate of 1/81. Several explanations could account for this difference the most likely one is an admixture of the Libyan Jewish population.

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. Methods. Clinical characterization and MEFV genotype of all FMF patients < 16 years of age at disease onset and first presenting with attacks of fever alone were analyzed and compared for age, sex, and disease duration with matched FMF patients presenting with serositis at the onset of the disease. Results. There were 814 patients with FMF in our registry. Fifty patients formed the study group and 234 patients the control group. In the study group, the first (febrile) attacks appeared at a younger age than in the control group (1.7 ± 1.6 yrs vs 5.0 ± 4.1 yrs, respectively; p < 0.0001), diagnosis was made earlier (4.2 ± 2.7 yrs vs 6.7 ± 4.1 yrs; p < 0.0001), despite a trend for a longer delay in diagnosis. In the study group, attacks were shorter (1.6 ± 0.8 days vs 2.1 ± 1.0 days; p = 0.023) and homozygosity to the M694V mutation was more prevalent (46% vs 31%; p = 0.03). Attack rate, colchicine dose, and the MEFV mutation carrier rates were comparable between the groups. In 40/50 (80%) of the patients with fever alone, serositis had developed over a course of 2.9 ± 2.2 years after disease onset. Conclusion. FMF in young children may begin with attacks of fever alone, but it progresses to typical FMF disease over the next 2.9 ± 2.2 years. Our study demonstrates that clinical heterogeneity at presentation is more likely to indicate a feature of a disease in development, rather than to mark distinct phenotypes of FMF.

A common ancestral haplotype in carrier chromosomes from different ethnic backgrounds in vacuolating megalencephalic leucoencephalopathy with subcortical cysts

Vacuolating megalencephalic leucoencephalopathy with subcortical cysts (VL) is a newly described, inherited leucodystrophy (MIM 604004). Clinically, the disease is characterised by accelerated head growth beginning in the first year of life and resulting in extreme macrocephaly and mild delays in gross motor milestones. In most cases, these early manifestations are followed by evolution of pyramidal symptoms and signs, cerebellar ataxia, epilepsy, and in older patients dystonia and athetosis.1 Cognitive function is relatively spared in most patients. Brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) shows diffuse cerebral white matter swelling with progressive cystic-like changes, prominent in the frontotemporal regions, with preservation of grey matter structures.1,2 Pathological specimens from VL patients showed splitting of the myelin sheaths between the lamellae consistent with an oedematous process, with sparing of the exons.3 Although progressive in nature, VL is characterised by a relatively mild clinical course compared to the severity of the neuroradiological findings.4,5 About 70 cases of the disease have been described in different ethnic groups. The molecular basis of this disorder remains unknown. The inheritance is autosomal recessive and the disease gene was recently mapped to a 3 cM interval between D22S1161 and the telomere of chromosome 22q.6 Linkage was established in a group of 13 Turkish families all originating from rural areas of central and south eastern Anatolia. No shared alleles or shared haplotypes were detected between the Turkish families. Six of the seven families included in this study (fig 1) have been described in detail by Ben Zeev et al .7 Families 1, 2, 4, and 6 are of Libyan Jewish origin and family 3 is of Turkish Jewish origin. …