Recent UK Research - The Under Fives Project
From the Cambridge team:
This research project was designed to investigate infancy and the transition from the early characteristics (phenotype) of PWS – floppy (hypotonic) baby with no interest in feeding – to the later phenotype – obsessive interest in food as expressed in conversation, play, reading matter, or by active foraging. Previous research, based on retrospective data about people with PWS ranging in age from a few months to 47 years, had found that a high proportion of mothers had had problems in pregnancy and/or in the birth process and there had been difficulties with the newborn babies.
There were also indications that, in some cases, the weight of the babies with PWS may have increased abnormally before an interest in food had obviously developed. Also, the variability of age when food became a dominant interest and the inevitability of this occurrence suggested that, as is the case with normal puberty in later life, this change in weight and in eating behaviour was triggered by hormonal changes. The aim of this particular study was therefore to investigate the relationship between weight changes, eating behaviour, and the levels of specific hormones circulating in the blood (e.g. growth hormone, ghrelin). The fundamental question we were seeking to answer was what was responsible for this switch from one phenotype to another?
We recruited 46 under-fives and their mothers to try to answer the following questions: Would we find high levels of pregnancy and birth problems in a modern cohort of mothers (all of whom had given birth in the previous 5 years)? Would the babies’ growth records show abnormal weight gains before the mothers noticed an increased interest in food? Was there a difference in any circulating hormone related to appetite or eating behaviour, between those children who were clearly showing the early phenotype and those who had made the transition to the later phenotype and, if so, was this normal or abnormal when compared to changes that may normally occur with age? This latter question necessitated recruiting a non-PWS control group of similar ages to measure the same hormones – this was children 5 years and under having minor surgery such as tonsillectomy.
Findings
An initial surprise was the finding that about half the babies recruited had the mUPD1 (maternal uniparental disomy) genetic form of PWS. Previous research suggested that it is usually approximately 25%. However, as the probability of mUPD increases with maternal age a calculation based on expected rates of mUPD for the mother’s age at conception showed that this proportion was to be expected, given the ages at conception of our sample of mothers. This increase over time in maternal age appears to be representative of mothers in the UK today. There is a similar trend in France.
Problems in pregnancy and at birth2 were similar to those found in our earlier work and also similar to those found in a study of people with PWS of all ages in France. All babies showed some degree of floppiness (hypotonia), from mild to severe, and almost all were tube fed.
The lengths of the babies with PWS were normal at birth but growth was very slow and length centiles fell for a few months to eventually stabilise at a low level3 (i.e. the babies did not grow at the rate expected for children without PWS). In contrast, the babies’ weight tended to be low at birth but weight centiles exceeded height centiles by the end of the first year, on average. The gain in weight relative to height occurred on average earlier than the babies’ reported increase in interest in food.
Finally, when the normal changes with age were taken into account (as observed in the comparison group) there was no association between any of the hormonal levels and the presence or not of the early or later phenotype as measured by eating behaviour/food interest observations4. As expected mean leptin levels were higher, mean growth hormone levels lower and mean pancreatic polypeptide (PP) levels lower in the PWS group. Mean ghrelin levels were not significantly different between the PWS and the comparison group and in both groups, ghrelin levels were lower the older the child. This reduction in levels with age was however less marked in the PWS group.
Conclusions
Studies of the early phenotype of PWS and of the switch to the later phenotype are limited in number and methodologically difficult to undertake. This study has confirmed that the presence of a baby in-utero with PWS increases the risk of complications during pregnancy and at birth. We have also found that, in infancy, weight may begin to increase before there is any discernable change in eating behaviour. The absence of any significant differences between the PWS and a comparison group in terms of blood levels of specific hormones suggests that the mechanism that results in the switch from one phenotype to the other is central (perhaps in the hypothalamus) rather than being mediate by peripheral changes that can be measured in the blood. Other than the need to be vigilant about weight gain in infancy there are no specific implications from these findings in terms of the care of an infant with PWS. However, along with other studies this study has added to our knowledge about PWS and specifically the eating disorder and, in doing so, helps to build up a picture that we hope will ultimately lead to the possibility of treatment.
Acknowledgements
We are very grateful to all the mothers and babies who participated in this project and to the PWSA for all the help it gave us identifying and recruiting families with young children with PWS. If you would like copies of the papers listed below please contact Joyce Whittington by This e-mail address is being protected from spambots. You need JavaScript enabled to view it.
1 Whittington JE, Butler JV, Holland AJ. Changing rates of genetic subtypes of Prader-Willi syndrome in the UK. Eur J Hum Genet. 2007, 15:127-30.
2 Whittington JE, Butler JV, Holland AJ. Pre- Peri- and Post- Natal Complications in Prader-Willi syndrome in a UK sample. Early Human
Development 2008 84:331-6
3 Butler JV, Whittington JE, Holland AJ, McAllister CJ, Goldstone AP. The Transition between the Phenotypes of Prader-Willi Syndrome during Infancy
and Early Childhood. Dev Med Child Neurol. 2009 e-published Dec 23
4 Whittington JE, Holland AJ, Butler JV, Goldstone AP. What triggers the over-eating phase in PWS? (Not yet published)
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