The load of genetic and partially genetic disease in man. IV. Severe visual handicaps and profound childhood deafness in Hungarian school-age children

In Hungary, the school-age prevalences of severe visual handicaps and of profound childhood deafness have been estimated to be about 6/10⁴ and 10/10⁴, respectively. Most of these conditions have onset at birth or in early childhood and are aetiologically heterogeneous.

Severe visual handicaps are grouped under 11 aetiological categories, their relative contributions to the prevalence being: perinatal damage syndrome (20%; half of this is due to retinopathy of premature infants), cataracts (15%), choroidoretinal degenerations (15%), congenital abnormalities of the eye (15%), syndromes (10%), high myopia ± retinal detachment (7%), postnatal causes (5%), nystagmus (5%), optic atrophy (4%), bilateral retinoblastoma (2%) and prenatal causes (2%). Overall, Mendelian conditions (included under many of the above) account for about 50% with relatively more autosomal dominant than autosomal recessive and sex-linked entities, and acquired causes account for about 40% of the cases studied. No actiology could be assigned in 10% of the cases.

For profound childhood deafness, the rank order of the aetiological categories is: autosomal recessive entities (34%), postnatal causes (22%), perinatal causes (19%), autosomal dominant entities (17%), prenatal causes (5%) and unknown causes (3%).

Severe childhood visual handicaps are responsible for about 60 years of loss of life per 10⁴ live births and about 400 years of impaired life per 10⁴ live births. Genetic causes account for one-quarter of lost life years and three-quarters of impaired life years. The comparable estimates for profound childhood deafness are: about 240 years of life loss per 10⁴ live births (again, about one-quarter due to genetic causes) and about 640 years of impaired life per 10⁴ live births (about one-half due to genetic causes). In all these calculations, it has been assumed that the average life expectancy at birth for an individual in the population is 70 years.     

Exposure fractionation effects for X-ray-induced dominant lethals in immature (stage-7) oocytes of Drosophila melanogaster: A re-analysis

Young (0—4-h-old) Drosophila melanogaster females were X-irradiated with single or fractioned exposured over a range up to 6000 R and the induction of dominant lethals in immatuer (stage-7) oocytes was studied. The results show that (i) the frequencies of dominant lethals are higher after single than after fractionated exposures; (ii) at any given exposure level, the higher the number of fractions, the lower is the frequency of dominant lethals; (iii) conserquently, the reduction in dominant lethality relative to single exposures increases with increasing number of fractions; and (iv) this relative reduction in dominant lethality approaches a maximum value when the magnitude of the single X-ray exposure approaches zero (i.e., when tha egg survival after single X-ray exposure approaches 100%); the maximum, however, are different for the different fractionation regimes, being higher with increasing number of fractions.These findings are consistent with the assumed kinetics of X-ray induction of dominant lethality in stage-7 oocytes. It is shown that it is possible to predict the expected relative reduction in dominant lethality after fractionation, from appropriate dominant lethal data from single unfractioned exposures.     

Spectroscopical identification of residues of subunit G of the yeast V-ATPase in its connection with subunit E

A critical point in the V₁ sector and entire V₁V_O complex is the interaction of stalk subunits G (Vma10p) and E (Vma4p). Previous work, using precipitation assays, has shown that both subunits form a complex. In this work, we have analysed the N-terminal segment of subunit G (G_1–59) of the V₁V_O ATPase from Saccharomyces cerevisiae by using nuclear magnetic resonance (NMR) spectroscopy. Analyses of ¹H-¹⁵N heteronuclear single quantum coherence (HSQC) spectra of G_1–59 in the absence and presence of the N-terminal peptides E_1–18 and E_18–38 as well as the produced and purified C-terminal segment (E_39–233) shows specific interactions only with the peptide fragment E_18–38. The binding of this peptide occurs via the residues M₁, V₂, S₃, and K₅ as well for V₂₂, S₂₃, K₂₄, A₂₅ and R₂₆ of G_1–59. The specific E_18–38/G_1–59 binding has been confirmed by fluorescence correlation spectroscopy data. The E_18–38 peptide has been studied by CD spectroscopy and NMR. The 3D structure of this peptide adopts a stable helix-hinge-helix formation in solution. A model structure of the E_18–38/G_1–59 complex reveals the orientation of E_18–38 relative to G_1–59 via salt-bridges of the polar residues and van der Waals forces at the very N-terminus of both segments.     

In vivo and in vitro radioprotective effects of the prostaglandin E1 analogue misoprostol in DNA repair-proficient and -deficient rodent cell systems.

The radioprotective effect of a stable prostaglandin E(1) analogue, misoprostol, was studied in cells from mice with severe combined immunodeficiency (SCID) and in normal cells using X-ray-induced chromosomal aberrations and/or cell killing as the end points. The results clearly show misoprostol-induced radioprotective effects in spermatocytes of the first meiotic division when analyzed for X-ray-induced chromosomal aberrations. The protective effect was independent of Trp53 (formerly known as p53) status. Since spermatocytes are relatively easy to isolate, this appears to be a suitable in vivo model that will allow biochemical studies of the mechanisms involved in radioprotection mediated by misoprostol. Using transfected CHO-K1 cells that stably express a PGE(2) receptor (CPE cells), significant radioprotection mediated by misoprostol from both chromosome breakage and cell death could be demonstrated under in vitro conditions. In addition, evidence was obtained indicating that the degree of radioprotection was dependent on the cell cycle and that S-phase cells were less responsive to misoprostol-mediated radioprotection. These results suggest that CPE cells may be a suitable in vitro model for further studies on the cellular pathways involved in radioprotection by misoprostol in particular and prostaglandins in general.     

The load of genetic and partially genetic diseases in man. III. Mental retardation

This paper summarizes estimates of detriment associated with different etiologic categories of mental retardation (MR) in Hungary. The basic data derive from an earlier study carried out in Budapest on 1276 school-age mentally retarded children (with some etiologic reclassification based on recent studies). Detriment associated with these different categories of MR is expressed in terms of years of lost and impaired life. About 30 per 10(3) school-age children in Hungary are mentally retarded (mild + severe MR), one-tenth of whom have severe MR (IQ less than or equal to 50); 50% of the latter are institutionalized. The breakdown on the basis of etiology is as follows: gene mutations and chromosomal abnormalities, about 4 per 10(3); 'familial' (multifactorial) causes, 12 per 10(3); adverse pre-, peri- and post-natal causes, 11 per 10(3); and 'causes as yet unknown', the remainder. The estimates of mean number of years of lost life range from 42 to 68 (depending on the etiologic category), with an overall mean of 58. The total number of years of lost life is about 36,000 per 10(4) live births of which over 70% is due to pre-, peri- and post-natal causes, 18% due to 'familial' causes and the remainder due to Mendelian 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 admittedly approximate, these estimates suggest that detriment associated with MR-related causes is not inconsiderable. Additionally, they provide some indication of causes of MR which are minimizable.