Academic journal article Population

Thirty Years of Research into Rendu-Osler-Weber Disease in France: Historical Demography, Population Genetics and Molecular Biology

Academic journal article Population

Thirty Years of Research into Rendu-Osler-Weber Disease in France: Historical Demography, Population Genetics and Molecular Biology

Article excerpt

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Rendu-Osler-Weber disease, also known as hereditary hemorrhagic telangiectasia (HHT) is characterized by small vascular malformations. It was first differentiated from haemophilia by the physicians Rendu (1896) and Osler (1901). Diagnosis is based on the simultaneous presence of three parameters: spontaneous nosebleeds (called epistaxis), telangiectasias (abnormal connections between venules and arterioles, with no intervening capillary bed) in specific regions such as the mouth or the fingertips, and a family history of the disease (Plauchu et al., 1992). An international conference in 1999 (Shovlin et al., 2000) confirmed the importance of these three diagnostic criteria, while adding a fourth: the presence of visceral lesions liable to cause life-threatening complications in the lungs, digestive tract, liver and brain (Plauchu et al., 1989). The symptoms of the disease develop gradually, and age at onset may vary. It is a genetic disorder with an autosomal dominant pattern of inheritance, transmitted directly from parents to children without skipping a generation. This means that the offspring of a carrier have a 50% risk of inheriting the mutation.

Demographic and genetic research into HHT in France began in the 1970s, when Professor Robert, head of the genetics department at Hôtel-Dieu in Lyon, identified a cluster of carriers in a region around hundred kilometres to the north-east of Lyon straddling the Ain and Jura départements. Headed by Henri Plauchu (geneticist) and Alain Bideau (historian-demographer), a research team was set up, bringing in students from a range of disciplines, including medicine, genetics, demography and history. The team published data that made it possible to analyse the frequency of the disease at regional and national levels (Bideau et al., 1979 and 1989), and to track its progression among the main affected population group (Bideau et al., 1992), while the study of genealogical networks provided clues about the history of HHT in the region (Heyer, 1991; Brunet, 1998). In association with a genealogical study of families recruited across the Rhône-Alpes region, the medical specialists of the team pursued their in-depth clinical study (Plauchu et al., 1989) to determine the chromosomal location of one of the two major genes whose mutations cause the disease (Vincent et al., 1995). Further key contributions by our team include the description of the gene mutations present in the affected French families (Lesca et al., 2004; Lesca et al., 2006), and the discovery of the mutation affecting the patient cluster in the Ain and Jura départements.

Armed with this new information, we have revised some of our provisional research findings and partially reinterpreted the data, notably regarding the genealogical relationships between affected families and the history of the observed mutations. We will begin by outlining the initial research questions and describing the resources deployed before presenting the key findings of three decades of investigation in this field.

I. Using epidemiology to identify a population

At the beginning of this research project, the frequency of HHT in the French population was unknown. The only available estimate, based on studies in specialized journals, was published by an American physician, Dr McKusick, in a catalogue of human hereditary diseases (McKusick, 1966, 1978 and 1983). According to this source, HHT was a rare pathology, with an estimated frequency of 1 case per 100,000 population.(1) The existence of 37 affected families in the Lyon region, ten of whom lived in a zone straddling the Ain and Jura départements (delimited by the towns of Saint-Claude, Oyonnax and Bellegarde-sur-Valserine), suggested that its frequency in France was higher (Manipoud, 1962). To verify this hypothesis, two epidemiological surveys were launched using different methodologies, one at national level and the other at regional level. …

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