[Genetic aspects of valvulopathies]. / Aspects Génétiques des Valvulopathies.

Valvular dystrophies due to myxoid degeneration are common and potentially serious cardiac pathologies. They constitute a heterogeneous group of which the most usual is idiopathic mitral valvular prolapse (Barlow's disease). The majority of mitral valvular prolapses are sporadic, but there are several familial forms. Transmission is usually autosomal dominant with incomplete penetrance and variable expression. The first chromosomal location to be identified was on the 16p11-13 chromosome. Since then, two other loci have been identified on the 11p15.4 and 13q31-32 chromosomes. Our team has recently identified the first gene responsible for myxoid valvulopathy linked to the X chromosome, from a large family of 318 members. This is the gene that codes for filamin A, which is a cytoskeleton protein. The frequency of mutations in this gene is still unknown, but out of 7 families in which transmission was compatible with X-linked transmission, mutations were discovered in 4 of the families. Thanks to a genetic epidemiological approach, we have also demonstrated that there are familial forms of aortic stenosis, which are probably common. Identification of the genes implicated in these common forms of valvular pathology is important, as it will allow a better understanding of the pathophysiology of these valvular disorders and could lead to better therapeutic management in the future.

Founder effect in GLC1A-linked familial open-angle glaucoma in Northern France.

Open-angle glaucoma (POAG) is a highly prevalent cause of visual impairment. Six families grouping 71 living patients affected with juvenile-onset and middle-age POAG (age at diagnosis ranging from 10 to 65 years) were linked to the GLC1A locus. All patients carried a mutation of an evolutionarily conserved asparagine residue to a lysine at position 480 (N480K) in the olfactomedin-homology domain, which is encoded by the third exon of the GLC1A gene. The N480K mutation was also identified in 14 unaffected carriers who are at high risk of developing POAG. Although four of the families had ancestors identified in Northern France, the pedigrees could not be interconnected by genealogical investigation. However, haplotype analysis indicated that all the carriers had inherited the N480K mutation from the same founder. Screening of a selected set of 67 POAG patients who originated from Northern France and underwent trabeculectomy before the age of 50, detected one patient with the N480K mutation associated with the same disease haplotype already characterized in the 6 families. This group of 72 POAG patients is the largest one having a GLC1A mutation in common and provides a unique tool to investigate the factors influencing the variable expressivity of the GLC1A gene.

[Familial medullary thyroid cancer. Contribution of genealogy and genetics to the study of two families]. / Cancer médullaire familial de la thyroïde. Apport de la généalogie et de la génétique à l'étude de deux familles.

A geneological study made it possible to establish a link between two medullary thyroid carcinoma families from Normandy totalling 9 sick subjects, and a probable link with a third family. The study contributed to the diagnosis of multiple endocrine neoplasia type IIa, whereas the condition had been diagnosed for 6 years as familial medullary thyroid carcinoma, without phaechromocytoma. Group in these two families together increased the number of subjects tested, thereby facilitating genetic link analysis and enabling the link with markers of the disease on chromosome 10 to be asserted. The genetic study can now be used to detect individuals at risk, and with regular laboratory tests the diagnosis will be made at the "precancerous" stage. A genealogical study going back to the family-founding couple will increase the population which will benefit from screening in this region north of Rouen.

Endemic cretinism in a traditional society in Mali: from the collectivity to the individual.

The prevalence of endemic cretinism was measured in a village belonging to the Bwa ethnic group in Mali liable to iodine deficiency and suffering from endemic goitre. In this village according to mental and motor handicaps found in cretinism, we used two psychometric tests: the Raven's Progressive Matrice (PM 47) and a "peg test". Using the fiduciary inference method on the two tests associated with a clinical and qualitative approach, we obtained a prevalence of myxedematous cretinism close to 1.2%.

Genetic factors in iodine deficiency disorders: a general review.

This review presents a summary of what is known about genetic factors possibly involved in iodine deficiency disorders. After an overview on thyroid iodine metabolism and the role of environmental factors in endemic goitre, we analyse genetic studies on endemic goitre reported in the literature. We hypothesize that endemic goitre is a multifactorial disease in which the major factor would be of environmental nature (iodine deficiency) with a lesser role for genetic factors. Mutations, in a heterozygote state, of one of the genes involved in tiered hormonogenesis could lead to a less effective metabolic pathway in the iodine transport or hormonogenesis. We also briefly review various hereditary disorders which may be involved in endemic goitre. Then, we postulate that the presence of some genetic variants in the population or the heterozygote status of individuals for thyroid hereditary disorders may influence the degree of the thyroid enlargement and/or hypothyroidism.

Microsatellite haplotypes associations with 5 CFTR mutations in "Grande Brière", an isolate located in southern Brittany.

The variability at three microsatellites in the Cystic Fibrosis Transmembrane Conductance Regulator Gene (CFTR) locus has been studied for frequent mutations encountered in an isolated population of "Grande Brière", a small region located in Southern Brittany. Fluorescent multiplex PCR of these microsatellites were assayed in 16 Cystic Fibrosis (CF) families carrying 5 different mutations. The four most frequent haplotypes on df508 chromosomes were the same as those found in Northern France and Europe but the distribution of these haplotypes provides new enlightenment on the population origin of this insular community.

Anthropogenetical analysis of abnormal human alpha-globin gene cluster arrangement on chromosome 16.

An earlier study of human globin gene polymorphism in two Adriatic islands of Olib and Silba showed an abnormal arrangement of alpha-globin genes in two different individuals. The next step was to determine the degree of the kinship relationship between the two probands, one with a deleted and another with triplicated alpha-globin gene on the island Silba, and to determine the stability of this disorder through generations. We reviewed the parish registers (Status Animarum) of the island of Silba, dating from the year 1527, and constructed family trees for the two probands. Restriction endonuclease mapping was performed to study the arrangement of the alpha-globin genes in the offspring of our probands. A total of 183 ancestors completed the two family trees. The kinship relationship between them was established in the 5th, 6th, and 7th generation. The analysis of alpha-globin genes in the offspring of our probands showed the triplicated alpha-globin genes in two persons. We also found alpha-globin gene triplication in other three relatives. We did not find any deleted alpha-globin genes. We determined the kinship relationship between the two probands, one with deleted and the other with triplicated alpha-globin genes. This finding enabled us to determine the stability of this gene disarrangement through generations. It also showed new possibilities in anthropogenetic research, by combining the analyses of parish registers with those of modern genetic methods, such as restriction endonuclease mapping.

Epidemiology and prophylaxis of endemic goitre in the Bwa village of Sirao (Mali).

A study was conducted in Mali, in some villages exposed to iodine deficiency disorders (IDD). To treat and, above all, prevent endemic goitre, Lipiodol UF was dispensed in two ways: by intra-muscular injection (475 mg I) or by oral administration (48 mg I to 240 mg I). In two cases, hormone levels regained normal values and thyroid hypertrophies regressed significantly. Nevertheless, the impact of the treatment on the size of the goitres seems to be in favour of injections; which is probably due to the fact that in the village which received Lipiodol UF per os, many goitres were nodular.

Registers and follow-up methods of populations in a public health survey: the example of the village Glanlé in Ivory Coast.

Demography has a fundamental place in a public health survey, and it is essential to provide the population follow-up. A population exhaustive census is the first compulsory phase. It turns out that this phase is necessary if we want to know with precision the size of the population studied and its main demographic characteristics (sex, age ...). The census allows us to provide a real population follow-up, in order to measure the evolution of the different disorders and to estimate the effects of a prophylaxis on each individual in a precise time. This follow-up requires a computerized population register which contains all the information concerning every individual. This data file is updated with new data collected by next surveys. The realization of the nominal population pyramid, is a complementary tool to the population follow-up. Each individual, characterized by sex and age, is allocated a position in the pyramid by his identification number. The figurative contrasts show several cases noticed according to the studied events. The reconstruction of the genealogy represents another form of the population follow-up, by reconstructing biological kinship relationships between the inhabitants.

The analysis of population structure based on morphometric dimensions of metacarpal bones (the Island of Krk, Croatia).

The aim of this study was to investigate: 1) a possibility of using the morphometric dimensions of metacarpal bones for approximation of biological distances, and 2) a relationship of biological matrices, based on the morphometric dimensions of metacarpal bones to other biological (dermatoglyphic, genetic), bio-cultural (migration) and geographic variables. The morphometry of the metacarpal bones was performed according to Barnett and Nordin procedure and biological distances were estimated using Mahalanobis D2 method. Population structure was assessed through Mantel's permutation test using E2 genetic distances for classical serogenetic markers, DA genetic distances for HLA, DSW genetic distances for STRs, geographic distances expressed in kilometres, and migration kinship matrix estimated according to the method proposed by Malécot and modified by Morton. This study clearly indicated the need for applying factorial analytical approach to study the factor structure of morphometric variables that may be measured on six metacarpal bones as well as the need for conducting complex family and segregation analyses to address not only the intriguing issue of genetic vs. ecological impact onto the bone mineral turnover, but also to test the hypothesis of major gene control in determining bone mineral density.

Endemic goitre: a research protocol elaboration for eradication.

The iodine deficiency (ID), which affects 1 person out of 6, is relatively neglected by the responsible of Public Health Service, particularly in developing countries. Consequences of ID are far from being negligible: mental retardation, hypofertility, hyperplasia, carcinoma, early ageing and, in very exposed areas, endemic cretinism. Nevertheless, eradication is easy and cheap but it requires rigorous protocols and control of results. The elaboration of these protocols is complex because it must be adapted to environment, population and financial possibilities of concerned countries. Based on our experience in this field, we propose a combined protocol, between the Public Health too liberal approach and that of too expensive research, which can be adapted to several situations.

The prevalence of goitre and cretinism in a population of the west Ivory Coast.

Iodine deficiency is a major public health problem in developing countries. The main areas where goitre is prevalent have been identified, but the different degrees of severity and the populations affected have not. Most countries are now attempting to obtain reliable and more extensive data. A pilot study was carried out in the Ivory Coast in order to improve epidemiological knowledge of iodine deficiency and collect the information required to set up an elimination programme. The aim of this study was to assess the prevalence of goitre and cretinism and to measure the main biochemical indicators of thyroid function (T3, T4 and TSH). The study involved 1433 people identified from a census. The prevalence of goitre was 50.3%. There was a significant difference between the examined ethnic groups: 52.7% of the Yacouba and 28.6% of the non-Yacouba had goitre. The most affected age group was 15-45 year. The predominance of women demonstrated the susceptibility of women at child-bearing age to develop the condition. The prevalence of cretinism was approximately 1.5%. Through the assessment carried out using a grid of clinical indicators, it was possible to identify 10 cases of laboratory proven myxedematous cretinism due to hypothyroidism. The concentration of iodine in foodstuffs was below the limit of detection (< 7.5 micrograms/kg) and iodine could not be detected in the water (< 1 microgram.l) The biological profile of the population was affected to a very limited extent, with a mean value (+/- standard deviation) for TSH of 1.93 (+/- 1.56) mIU/l (0.1-4.0) and a free T4 value of 10 (+/- 3.46) pmol/l (8.2-20). These initial results confirm the high prevalence of endemic goitre and the low iodine content of the soil, water and food in the investigated region. The study will be complemented by a nutritional investigation to improve the understanding of iodine balance, after which an appropriate action plan will be proposed.

[Management strategies for endemic goiter in developing countries]. / Stratégies de prise en charge d'une endémie goitreuse en situation de développement.

Despite significant progress in the last decades, endemic goiter remains a serious public health problem in the developing world, especially in Africa. Even in countries that have successfully reduced overall incidence to acceptable levels, endemic areas often remain. This persistence is due to the inadequacy of preventive measures and poor follow-up of control programs. The main etiologic factor in endemic goiter is inadequate dietary intake of iodine. This commonly occurs in communities depending exclusively on local produce grown on iodine-poor land, especially in mountain areas. Endemic goiter is epidemiologically associated with cretinism, deaf-mutism, and mental retardation. Even mild iodine deficiency leads to clinical hypothyroidism and moderate myxoedema with significantly reduced intellectual performance. Prevention of endemic goiter depends mainly on increasing the iodine intake of people in endemic areas. When iodine intake reaches the estimated adult minimum requirement (100 to 150 micrograms per day), the prevalence of goiter decreases. Two approaches have been used to increase iodine intake. The first consists of adding iodine to food staples such as table salt. The second consists of medical treatment using agents such as iodized oil. Iodization or iodination of salt is the most widespread and cost-effective method of prevention. Administration of iodized oil has been used only in severely endemic areas and in regions where reliable provision of iodinized salt is prevented by geographical barriers or political factors. However, iodized oil has been helpful in the start-up phase of prevention programs using iodized salt, either as an emergency measure or as a mean of convincing officials of the efficacy of iodine prophylaxis.

[Climatology: annotated findings from San station]. / Climatologie: resultats commentes de la station de San.

PIP: The weather station of San, Mali, is located in a zone of tropical humid climate of North Sudanian type. West Africa is under the influence of 3 permanent anticyclones, but only the Saharan from Libya and the Sudan and the Austral from the South Atlantic influence the interior land masses. Depending on the predominant anticyclone, the winds are dry from the Sahara or humid from the Austral. The harmettan is a dry wind full of sand and other matter which is extremely dangerous for living things, especially in February. The Austral anticyclone usually arrives in May and mixes wet maritime air with dry continental air, giving rise to tornadoes that may become very violent before changing in subsequent months to brief and intense rainfalls. This season lasts from April to October. Annual rainfall averages from 1921-80 according to 3 series have ranged from 749-776 mm, but from 1981-86 only 609.66 mm fell on average, a worrisome trend partly explaining poor harvests in recent years. The monthly distribution of rainfall is extremely variable from year to year, and the amount of rainfall in adjacent areas may also vary greatly. Crops are planted in late May or early July. If rainfall is inadequate several plantings may be necessary. The maximum high temperature is recorded in April, with absolute maxima exceeding 40 degrees. Temperatures fall and rise again in October to reach the 2nd maxima. No great differences are observed between average temperatures collected beginning in 1921 and more recent series.^ieng

[The hypothesis of the genetic transmission (autosomal recessive) of subtypes of HBs Ag. The example of Kel Kummer]. / Contribution à l'hypothèse de la transmission génétique (autosomale récessive) des sous-types du HBs Ag. L'exemple des Kel Kummer.

In a study of asymtomatic carriers of hepatitis B surface antigen (HBs Ag) in a closed population, the Twareg Kel Kummer, 18% of the population (79 individuals out of 439 tested) were found to be carriers of one of the 3 sub types: HBs Ag/a2 1 dw, HBs Ag/a2 1 yw and HBs Ag/a3 yw. Evidence from genealogies and the distribution of carriers in the pyramid of ages strongly supports the hypothesis of genetic transmission of the gene sub type as an autosomal recessive.

[Gene mutations of cystic fibrosis in Brittany population]. / Les mutations du gène de la mucoviscidose dans la population Bretonne.

Eighty percent of chromosomes from cystic fibrosis children in Brittany exhibit the major gene mutation (delta F 508) consisting in deletion of three nucleotide pairs. Eighty-seven chromosomes without the delta F 508 mutation were studied for as yet undescribed gene mutations. A large number of mutations were located in exons 10 and 11. Consequently, a global strategy for identifying mutations in these exons was developed. Analysis of pedigrees of cystic fibrosis patients in Brittany evidenced a clear founder effect. Appropriate prevention strategies will therefore be developed.

Anthropometric variation and population structure of the island of Pag, Croatia.

Anthropometric variation in the population of the island of Pag (eastern Adriatic, Croatia) was investigated by using data on 14 head and 24 body dimensions. The data were related to past and present migration patterns, geography, and linguistics. The analyses revealed heterogeneity among three population groups inhabiting geographically defined regions of the island and heterogeneity among the village populations. The congruence between anthropometric variation, migration history, geographic distances, and current linguistic features says much for the strength of the isolating factors on this ecologically uniform island, which have effected the genetic structure of the population.

Screening for medullary thyroid cancer in France: a national effort. French Medullary Study Group (GETC).

Screening for medullary thyroid cancer (MTC) in France is based on a protocol that has been widely distributed nationally. A network of coordinators utilizing a common questionnaire provides for an effective national screening program. Calcitonin stimulation procedures are systematically used for all first-degree relatives of MTC patients. Pathological studies utilize special immunopathologic techniques. Genealogic information is obtained on all index cases, and blood specimens are collected for establishing permanent cell lines. The data collected are used not only to establish the diagnosis of the hereditary or sporadic form of the disease but also to expand the screening as appropriate. This common protocol has benefited patients and their families by improving early detection of cases, increasing the number of families available for follow-up, and improving the prognosis of this cancer. Studies on these families have contributed significantly to the localization of the multiple endocrine neoplasia type 2 gene.