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STUDIES ON SPONTANEOUSLY-ARISING GENETIC AND PARTIALLY GENETIC DISORDERS IN MAN WITHIN THE FRAMEWORK OF THE EVA- LUATION OF GENETIC RADIATION HAZARDS

Objective

The overall goals of this research project are:
to make a detailed analysis of the prevalence of, and detriment associated with, spontaneously arising diseases of complex aetiology (congenital abnormalities and common chronic diseases in adults) and of Mendelian (autosomal dominant, XAlinked and autosomal recessive) diseases to examine the validity of the currently used prevalence estimates;
to develop methods to estimate the risk of multifactorial diseases in populations exposed to ionizing radiation;
to reassess the conceptual basis and assumptions used in genetic risk estimation in the light of advances in molecular and radiation genetics.
Detailed analysis has been carried out of the population prevalence of naturally occurring multifactorial diseases, of mendelian diseases and chromosomal diseases in order to examine the validity of the estimates of prevalence currently used in the context of the evaluation of genetic radiation hazards in man. These data and those that bear on the severity of these diseases are used to arrive at estimates of detriment.

With the exception of epilepsy (mostly childhood epilepsy cases), these common multifactorial diseases (CMD) are not associated with mortality between ages 0 and 19, but are among the leading causes of death between ages 20 and 69 and thereafter. Overall about 16% of deaths that occur in Hungary every year (all age groups) can be attributed to these diseases.

The mean number of years life lost (YLL) is substantial only for 5 of the diseases (epilepsy, 30 years; affective psychoses, multiple sclerosis and systemic lupus erythematosus, 18 to 20 years; schizophrenia, 13 years). At the population level, the total YLL is about 2700 per 10{4} individuals; those with acute myocardial infarction and subacute myocardial infarction account for about a half of this total. Years of potentially imparied life (PIL) and actually impaired life have been estimated. The mean PIL was calculated by subtrating the mean age at onset from the mean age at death. This covers a wide range (about 20 to 40 years, 12 to 70 years and 40 to 60 years for the very severe, moderately severe and milder disease respectively), the overall mean being about 24 years. However, the nature and degree of impairment and the impact on life quality of those afflicted differ for the different diseases. The mean AIL was estimated as the difference between the mean age at death and the mean age at premature retirement. This encompasses again, a wide range from 16 to 45 years, but the overall averages for the diseases included in each of the 3 groups are roughly the same, being about 20 years. At the population level, the diseases considered herein cause about 96,000 years of PIL and about 5800 years of AIL per 10{4} individuals in the population.

The prevalence of mental retardation (MR) among school age children was estimated. The data made available show that about 30 per 10{3} school age children (7 to 14 years; about 35,000 chidlren) are mentally retarded (mild plus severe; intelligence quotient (IQ) of 70 or less) and this figure is essentially the same over the school years 1974/1975 to 1986/1987. One tenth of these children have severe MR (IQ of less than 50) about half of whom are institutionalized. The estimates of mean number of years of lost life range from 42 to 68 (depending on the aetiological category) with an overall mean of 58 years. The total number of years of lost life is about 36,000 per 10{4} livebirths of which over 70% is due to prenatal, perinatal and post natal causes, 18% due to familial causes and the remainder due to mendelian diseases and chromosomal diseases. The total number of years of impaired life is about 7300 per 10{4} livebirths, 50% of which is due to familial causes. While these figures are admittedly approximate, they do suggest that detriment associated with MR related causes is not inconsiderable. Additionally, they provide some indication of causes of MR which are minimizable.

A reexamination was undertaken of the concepts and assumptions used in genetic risk estimation and analysis of the impact of knowledge on the nature of mutations to the estimation of the risk of Mendelian disease. The principal conclusions are the following:
about 50% of naturally occurring Mendelian diseases are due to point mutations and the remainder due to deoxyribonucleic acid (DNA) deletions;
point mutations do not appear to be distributed at random throughout the gene; likewise, the breakpoints of deletions are also nonrandomly distributed;
in mouse germ cells most radiation induced mutations are DNA deletions and this is true in general of radiation induced mutaions in mammalian somatic cells.
On the basis of chromatin and DNA orgnaization in cells and the biophysical and microdosimetric properties of ionizing radiation, one can qualitatively explain the predominance of deletions; for spontaneously arising and radiation induced point mutations there may be common elements in mechanisms, but for spontaneously arising and induced deletions the extent of overlap in mechanisms is difficult to discern at present.
On the basis of these and other findings, arguments are advanced to support the thesis that:
ionizing radiation is probalby not efficient in inducing the very specific molecular changes that are known to underlie spontaneous mutations which cause naturally occurring dominant genetic diseases;
the doubling dose estimate of 1 Gy that is used to estimate risk for autosomal dominant and X-linked diseases is conservative;
the 1% prevalence figure for these diseases that is used for this purpose may be too high;
the current estimate of risk of dominant and X-linked diseases may need to be revised downwards;
the choice of an overall doubling dose for genetic risk estimation (which take into account the numerically very large class of multifactorial disorders and for which there is no simple relationship between mutation and disease) depends on what indicators are perceived to be relevant in the human context and is largely judgemental and since among radiation induced mutations recessives predominate, adverse genetic effects of radiation exposure are primarily those associated with induced recessive mutations in the heterozygous condition.

The recorded prevalence of severe visual handicaps (blindness and severe vision defects) is about 0.42 per 10{3} school age children in Hungary. For ascertaining the relative proportions of the different aetiological categories, school age children from 2 schools were evaluated.

On the basis of data on onset, mortality and other epidemio logical parameters, it is estimated that of those with these vision defects the average years of LL is of the order of 12 years and the average life expectancy is about 58 years. At the population level the total number of years of LL is about 100 per 10{4} livebirths and the total number of years of impaired life is about 500 per 10{4} livebirths.
The epidemiological aspects of this work are carried out in collaboration with Dr. A. Czeizel (Dept of Human Genetics and Teratology, National Institute of Hygiene, Budapest, Hungary); current focus is on blindness, deafAmutism and cancers. Mathematical modelling for multifactorial diseases is being carried out in collaboration with Dr. G. Tusnady (Mathematical Institute of the Hungarian Academy of Sciences, Budapest) and Dr. N. Yasuda (National Institute of Radiological Sciences, Chiba, Japan). The reassessment of the conceptual basis of genetic risk estimation has been, in part, necessitated by the recent findings in genetic studies of the atom bomb survivors in Japan which suggest lower genetic risks than those arrived at in the 1988 report of the United Nations Scientific Committee on the Effects of Atomic Radiation and in the 1990 report of the US National Academy of Sciences.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

RIJKSUNIVERSITEIT LEIDEN
Address
Stationsweg 46
2300 RA Leiden
Netherlands