[Pre-symptomatic diagnosis of severe hereditary diseases with late onset in Lebanon: a choice or a necessity?]. / Le diagnostic présymptomatique des maladies graves héréditaires à [corrected] révélation tardive: [corrected] un choix ou une nécessité?

Progress achieved in the field of molecular genetics has opened the door to pre-symptomatic diagnosis tests of several severe hereditary disease, a majority of which are dominant and appear later in life. Given the importance of diagnosis in some of the cases where medical supervision and prevention are possible, there are a number of ethical dilemmas with regards to most of these diseases that, unfortunately, do not have a cure or any preventive treatment available. Above and beyond the capacity for medical care provision, there is a very high level of pressure and anxiety felt by every member of a family who has someone affected by one of these diseases in that they might be a carrier of a mutated gene which could be the cause or source of illness. They carry the burden of uncertainty that they may have already transmitted this gene or could give it to any of their children, and often there is also a significant level of guilt when one is the carrier but not to be affected by the disease itself. More and more frequently in these types of cases, there is a strong desire to know--in order to better organise and plan one's life and that of one's potential future family in the instance where one wishes to found one. This article discusses these problems based upon the consideration of four examples of such diseases with late onset: Huntington's disease, the common forms of thyroid cancer, the familiar forms of a predisposition to breast and ovarian cancer, and von Hippel-Lindau syndrome. However, regardless of the type of disease, the decision to take a genetic test is solely the choice of the individual in question, and the person should be accompanied and guided in his or her reflection by a multi-disciplinary team who can advise him or her and initiate useful deliberations on the various possibilities, their advantages and their disadvantages.

Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations.

Seventy-nine unrelated Lebanese patients were tested for 15 mutations in the MEFV gene: A761H, A744S, V726A, K695R, M694V, M694I, M694del, M6801 (G --> C), M680I (G --> A) in exon 10, F479L in exon 5, P369S in exon 3, T267I, E167D and E148Q in exon 2, using PCR digestion, ARMS, DGGE and/or sequencing. Mutations were detected in patients belonging to all communities, most interestingly the Maronite, Greek orthodox, Greek catholic, Syriac and Chiite communities. The most frequent mutations are M694V and V726A (27% and 20% of the total alleles respectively). M694I, E148Q and M680I mutations account respectively for 9%, 8% and 5%. Each of the K695R, E167D and F479L mutations was observed once and all the remaining mutations were not encountered. Of the alleles 33% do not carry any of the studied mutations. The mutation spectra, clinical features and severity of the disease differed among the Lebanese communities. The genotype-phenotype analysis showed a significant association (P < 0.001) between amyloidosis and the presence of mutations at codon 694 in exon 10 (both M694V and M694I). None of the patients carrying other mutations developed amyloidosis.

Familial Mediterranean Fever: association of elevated IgD plasma levels with specific MEFV mutations.

Familial Mediterranean Fever (FMF) is a recessively inherited disorder, characterized by episodic fever, abdominal and arthritic pain, as well as other forms of inflammation. Some FMF patients present higher IgD serum levels, and it is not yet known whether such an elevation is related to specific genotypes or correlated with a specific phenotype. In order to evaluate the association between known FMF-related mutations and IgD levels in confirmed patients, as well as the correlation between those levels and the presence of specific clinical signs, genotypic analysis and IgD plasma measurements were performed for 148 Lebanese and Jordanian FMF patients. Most common mutational patterns were M694V heterozygotes (19%) and homozygotes (17%), and V726A heterozygotes (18%) and homozygotes (5%), with an additional 11% combining both mutations. Twenty-one patients had higher IgD levels (superior to 100 microg/ml). The risk for higher IgD levels was significantly associated with M694V homozygote status (OR = 6.25) but not with heterozygotic one (OR = 1). Similarly, the risk for higher IgD was also found with V726A homozygotes (OR = 2.2) but not with heterozygotes (OR = 1.05). The use of colchicine was not statistically associated with IgD levels. Clinically, hyper IgD was also found significantly associated with arthritis (OR = 18). Thus, homozygotic status for M694V, and to a lesser extent V726A, is associated with increased risk for higher IgD plasma levels, regardless of colchicine use. Elevated IgD plasma levels are also correlated with the severity of FMF manifestations, and especially with arthritis.

Genetic screening of fourteen mutations in Jordanian familial Mediterranean fever patients.

Familial Mediterranean fever is an autosomal recessive disorder characterised by episodic fever, abdominal and pleuritic pain, serositis and arthritis. The FMF gene (MEFV) has been mapped to chromosome 16p13.3 and generates a protein found exclusively in granulocytes. Seventeen mutations have been reported up to the present in FMF patients. This study involves the screening of 14 mutations in 42 Jordanian patients by two methods: RFLP and ARMS. The most frequent mutations were M694V and V726A (20% and 14% of the alleles respectively), followed by M680I and E148Q (9.5% and 7% of the alleles respectively). The A744S mutation accounts for 2.5% and the M694I, T267I and F479L mutations account each for 1% of the alleles. E167D, R761H, P369S, I692del and M694del mutations were not found in this population. Forty-four percent of the alleles did not have any of the 14 mutations. The results show the diversity and the frequency of the mutations in the Jordanian patients, and open the way for further investigations on patients diagnosed to have FMF and in whom no mutations were found. Hum Mutat 15:384, 2000.

Effects of verapamil, ouabain, and ethacrynic acid on calcium retention in perfused rat kidneys.

A Sprague-Dawley rat kidney perfusion technique was used in situ to study the effect of verapamil, ouabain, and ethacrynic acid on renal calcium retention. The technique involves perfusion of the kidneys via the abdominal aorta and then through the left and right renal arteries and dorsal aorta. Verapamil (1 mM) in Krebs-improved Ringer solution increased calcium retention in the kidneys by approximately 117% compared with controls. With Na-free Krebs-improved Ringer solution, calcium retention increased by only 92%. However, in Krebs-improved Ringer solutions containing 59 and 122 mequivalents of Na, calcium retention in the kidney increased by 46 and 43%, respectively, compared with controls. With Krebs-improved Ringer solution containing 15 mM ouabain, calcium retention in the kidney decreased by 29.5%, whereas with 15 mM ouabain plus 1 mM ethacrynic acid in the perfusate, the effect on calcium retention in the kidney was insignificant compared with controls. These results suggest that two sodium-dependent calcium-transporting systems exist at the peritubular side of the kidney tubules: (1) a Na(+)-Ca+2 countertransport system sensitive to verapamil and (2) a Na(+)-Ca+2 cotransport system sensitive to the intracellular concentration of sodium.