Natural selection at the MJD locus: phenotypic diversity, survival and fertility among Machado-Joseph Disease patients from the Azores.

Machado-Joseph Disease (MJD) is an autosomal dominant neurodegenerative disorder of adult onset, associated with the expansion of a (CAG)n tract in the coding region of the causative gene, localized on 14q32.1. Machado-Joseph Disease shows non-Mendelian features typical of other triplet repeat disorders, including clinical heterogeneity, variable age at onset and anticipation. Three phenotypes have been proposed (clinical types 1, 2 and 3). Type 1 is associated with early age at onset and a high repeat number of the CAG sequence, and Types 2 and 3 have later onset and lower numbers of CAG repeats. This paper investigates whether there is selection against the MJD gene, acting through differential survival. nuptiality and fertility associated with clinical type and age at onset. The study sample comprised 40 MJD patients from the Azores (Portugal) having fully documented reproductive histories and known dates of death. The proportion of married patients of each clinical type increased from 0.22 among Type 1 patients, to 0.40 in Type 2 and 0.95 in Type 3. Age at onset and length of survival were also associated with marital status, with the married cases having later mean age at onset and longer mean survival time. In the whole sample, clinical type was associated with fertility, with significantly fewer children born to Type 1 patients. Among married patients clinical type was not associated with age at marriage, reproductive span or number of children. No reduction of fertility was detected among married patients in whom the onset of MJD was below the age of 50. The authors' interpretation of these results is that the high-repeat CAG haplotypes associated with early age at onset and clinical Type 1 are selected against through reduced survival and fertility. The fertility component of selection is mediated by nuptiality rather than marital fertility.

Origins of a mutation: population genetics of Machado-Joseph disease in the Azores (Portugal).

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder of adult onset. In the islands of the Azores (Portugal), MJD reaches the highest prevalence reported worldwide. It has been postulated that it is highly represented in the Azorean population as a result of a founder effect. To test this hypothesis, we reconstructed the ascending genealogies of the 32 Azorean families presently identified as harboring the disease (103 patients), using parish records as the main source of data. These patients were originally from the islands of São Miguel, Terceira, Graciosa, and Flores. The genealogies of the two main Azorean American families (Machado and Joseph) were also reconstructed. To identify the links between the MJD families, we calculated the kinship coefficient between the proponents of these genealogies. The family from Terceira was linked to three different MJD families from Flores through common ancestors. No kinship was observed between the MJD families from São Miguel and families from any other island. Links between the two Azorean American families and Azorean MJD families were found. The founders present in more than one ascendance were identified. Their chronological and geographic distribution indicates that more than one MJD mutation was introduced in the Azores, probably by settlers coming from the Portuguese mainland. The molecular evidence to date corroborates these results, because two distinct haplotypes have been established, one on the island of São Miguel and the other on Flores. Therefore molecular biology studies confirm the accuracy of the conclusions drawn from the genealogical evidence supporting the absence of a founder effect for MJD in the Azorean population.

Causes of death in Machado-Joseph disease: a case-control study in the Azores (Portugal).

BACKGROUND: Machado-Joseph disease (MJD) is an autosomal dominant cerebellar ataxia of adult onset with a high prevalence in the islands of Azores (Portugal). The genetic epidemiological studies presently under way in these islands are based on the genealogical reconstruction of the affected families, thus partially depending on the reference of patients using family history. A considerable effort has been made to obtain genealogies that are as complete as possible, making use of different types of data. The utility of the death causes contained in the death registers of the patients with MJD was determined in this study. OBJECTIVES: To estimate the extent to which the cause of death reported in the death register can confirm other reports of an individual's status for the disease (ie, oral information), and to determine the accuracy of the death certificates in listing MJD in patients whose disease was clinically diagnosed. DESIGN: Case-control study. METHODS: The death registers of 113 patients with MJD (82 whose disease was identified by history and 31 whose disease was clinically diagnosed) were examined and compared with those of controls matched by sex and date and place of death. RESULTS: There were significant differences in the causes of death between cases and controls, both for those whose disease was identified by history (chi(2) = 51.69, P < .001) and for those whose disease was identified by examination (chi(2) = 27.78, P = .004). However, the cause of death was in accord with the presence of the disease in only 40% of the cases reported as being identified only by family history. In the cases in which the disease was clinically diagnosed, only nearly 38% of the registers provided reliable information as to MJD being the direct cause of death. CONCLUSIONS: The fact that only nearly 40% of the patients with clinically confirmed MJD had a cause of death compatible with MJD precludes the use of cause of death as a means of identifying affected individuals in the Azorean MJD pedigrees.

Clinical reassessment of malignant hyperthermia in Abitibi-Témiscamingue.

PURPOSE: In 1992, 1812 individuals (1.2% of the population) were labelled at risk for malignant hyperthermia (MH) in seven families from Abitibi-Témiscamingue. To evaluate the effective risk in this population, a multidisciplinary study was undertaken which included clinical, genealogical and molecular aspects. This paper presents the clinical aspects of the study. METHOD: For each of the 1546 individuals reached, all anesthetic exposures were screened for elements relevant to MH. Malignant hyperthermia events were analyzed with "the clinical grading scale." All 44 reports of caffeine halothane contracture tests were reappraised. Finally, genealogical study was done to complete each family tree up to the initial French settlers in order to identify links between these seven families through common ancestors. RESULTS: Following this reassessment, the families were compared and classified into four groups. Two families (1097 individuals) are not considered to be at a higher risk for MH than the population in general. Two families are still considered possibly at risk. Finally, one family (402 individuals) is highly at risk and two other families are probably at risk. Family trees did not show any link up to the colonization of Abitibi-Témiscamingue in the beginning of this Century but common ancestors were found around the 9th generation. CONCLUSION: This clinical reassessment will help to focus education and prevention on a much smaller group of individuals still considered potentially at risk for MH. By adequate evaluation of phenotypes, combined with the use of a genealogical approach, it will be possible to target families for molecular research.

[A model for analyzing ascending genealogies]. / Un modele d'analyse de genealogie ascendante.

"This paper presents a model of ascending genealogies, with the definition and investigation of the functions allowing for the study of these genealogies as well as with the main algorithms used in operationalizing the model on a micro-computer. Examples of the type of results one may obtain with this model are provided; they concern file outputs as well as the computation of consanguinity and completeness coefficients." The examples provided concern the island of Saint Barthelemy, Guadeloupe. (SUMMARY IN ENG AND SPA)

[A program of research on biocultural dynamics]. / Un programme de recherches sur la dynamique bioculturelle.

"The objective of the research program presented in this note is to analyse the interrelations between biological and social factors in the process of demographic renewal. Population registers of various communities, among them those of Saint-Barthelemy (French Antilles) and Ile-aux-Coudres (Quebec), are used. The genealogies which were obtained from these registers contribute to the study of genetical epidemiology. The research program also includes the identification of social factors which may have contributed to the biological structure of the communities under study." (SUMMARY IN ENG AND SPA)

Studies on an isolated West Indies population. III. Epidemiologic study of sensorineural hearing loss.

An epidemiologic study of hearing loss was undertaken on a small Caribbean island and revealed a high frequency of abnormal audiograms among the population of French origin. Since there is no clear-cut discrimination between hypoacusis and normal hearing, but rather a continuous spectrum, the degree of hearing loss was quantified by an audiometric index, using the results of audiograms performed on 70% of the inhabitants. No environmental factors could be identified, although the effect of such factors is highly suggested by several observations of deafness aggravated by, or appearing after, a small dose of ototoxic antibiotics, and also by a strong residual age effect after correction for physiological presbyacusis. Hearing loss was found to be sparsed all over the island. Familial aggregation was noticed for several severe cases.

[Study of an isolated West Indies population. II. Estimation of the inbreeding value (author's transl)]. / Etude d'un isolat des Antilles. II. Estimation de la consanguinité.

Saint-Barthélémy, a small island near Guadeloupe, has been isolated since the 18th century. A first estimation of genetic size at each generation gives an estimation of the present inbreeding value due to random genetic drift. It is of the order of half a per cent. A census of matings between closely related persons (first or second cousins), during the three last generation may provide an estimation of the inbreeding value related to choice of mates based on relatedness using Sutter's equation of apparent consanguinity. This estimation is of the same order (0.8%) but is restricted to the cumulative effect of random genetic drift and non-random mating between relatives during these three last generations. A full estimation of remote consanguinity at present time requires a detailed analysis of genealogies.

[Demographic history and its biological implications in two Quebec villages]. / Histoire demographique et destin biologique de deux villages quebecois

PIP: A comparison between two rural Quebec communities is presented. One has experienced extensive in- and out-migration, and the other has remained relatively isolated. The impact of migration or the lack of it on the genetic and biological characteristics of these populations is analyzed. The data for the study are taken from parish registers.^ieng