A chiasma-hormonal hypothesis relating Down's syndrome and maternal age [25]

THE incidence of the human congenital abnormality known as Down's syndrome (or mongolism) has been observed to increase with maternal age¹. The trend of sharply increased incidence beyond the age of 30 has been well documented², and various hypotheses have been formulated to explain it. These include cumulative ovum or uterine dysfunction (radiation³, chemicals⁴, disease⁵), acute effects of radiation and chemicals, hormonal effects⁶, the 'production line' hypothesis ^7,8 and changes in sexual behaviour⁹. We describe here our hypothesis that there is an interaction between the hormonally governed rate of meiosis and the timing of chiasma terminalisation. We propose that changing hormone levels during the menstrual cycle not only trigger resumption of meiosis in the ovum¹⁰, but also control the rate of meiosis through the availability of a limiting substance¹¹. As hormone levels and the length of the cycle change with advancing age of the mother, meiosis slows down, and chiasma frequencies decline^7,12. Meiotic chromosome bivalents are held together by their chiasmata against strong mutual repulsion during late dictyotene and diakinesis¹³, making smaller bivalents with fewer chiasmata, such as 21, the most vulnerable to premature separation during terminalisation^14,15; premature separation can lead to trisomy 21, by far the most frequent cytological manifestation of Down's syndrome ¹⁶.