Mothers of children with phenylketonuria have a significantly lower miscarriage rate than a matched control population in Ireland and west Scotland. This protective effect of the gene against some factor causing foetal death would seem to constitute a heterozygote advantage which might account for the previously observed polymorphism for phenylketonuria. It is suggested that the decrease in foetal mortality is mediated by the higher concentration of phenylalanine in the heterozygous mother's blood, but that this is not a simple nutritional effect of an increased supply of an essential amino acid leading to increased protein deposition.

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Mice homozygous for d(l) have been suggested as models for phenylketonuria. We found: (1) the concentration of phenylalanine in the blood was normal at all ages examined; (2) phenylalanine hydroxylase activity in the liver in vitro equalled that in unaffected littermates; (3) the apparent K(m) values for phenylalanine and cofactor respectively in d(l)/d(l) mice were the same as in their normal littermates; (4) inhibition of the overall reaction by the particulate fraction, excess of substrate, excess of cofactor or phenylpyruvic acid showed no difference between d(l)/d(l) mice and their unaffected littermates; (5) phenylalanine injected in vivo had equal, small, effects on phenylalanine hydroxylase activity of the liver measured in vitro in the two groups of mice. An explanation of the findings of other workers, based on the natural history of the disease process, is tentatively put forward.

Abstract— The lipid composition of brains of mice homozygous for the gene‘dilute lethal’and aged 13‐26 days has been determined. This period covers the early stages of myelination up to the time of death. The brains of affected mice contained up to 8 per cent less total lipid than normal. The lipids increasing most rapidly at this age period were most affected; cerebroside, which normally increased six‐fold between the 14th and 24th days of life, was as much as 25 per cent below normal, but there was no significant reduction in non‐myelin lipids. Studies with [l‐14C]acetate suggested that the low levels of lipids reflected decreased rates of synthesis. In contrast to other reports, no myelin breakdown could be detected, either by TLC for cholesterol esters or histologically. The lowest levels of lipids and slowest rates of cerebroside synthesis occurred in the smallest affected mice; we suggest that the abnormalities in brain lipids reflect a reduced growth rate caused by poorer nutrition in the affected mice.

In the seminiferous tubules and interstitium of the viper there occur cyclical changes basically similar to those in birds and the pike. These involve the metamorphosis of unshed germinal material into cholesterol-positive Iipids, the rehabilitation of the interstitium after the seasonal depletion of its cytoplasmic Iipids and cholesterol shortly after the spring emergence from hibernation, and the completion of spermatogenesis after basking in the sun. The viper differs from birds in that its tubule Iipids contain much less cholesterol; also, the subsequent spermatogenesis begins almost immediately (as in poikilothermous pike and frog), and proceeds to the spermatid stage in the presence of such Iipids. Further, although in some individuals new Leydig cells rapidly mature, this resurgence is delayed in others. Thus, although the succeeding spermatogenesis always begins in still-lipoidal tubules, it may do so in the presence of a largely non-lipoidal interstitium. Mitoses were observed in mature Leydig cells. Fibroblasts occasionally alter to take on an apparently glandular function. By July most animals had regained a heavy lipoidal and cholesterol-positive interstitium, lost most of their tubule Iipids, and possessed either secondary spermatocytes or, sometimes, spermatids. This internal activity is probably partly responsible for autumnal sexual behaviour. Factors additional to temperature control spermatogenesis, for only a few spermatozoa are formed by the time of hibernation in October. No pronounced retrogressive changes occur during hibernation: the cycle merely halts, and begins without further delay on emergence. Thus spermatogenesis may be at its peak by the end of March. The expanded, glandular ‘sexual segment’ of the male renal tubule also exhibits cyclical changes involving the production and expenditure of cholesterol-positive Iipids, but such changes take place also in narrow parts of the tubule and, further, in the kidney of the female.