Joyce Whittington

Population prevalence and estimated birth incidence and mortality rate for people with Prader-Willi syndrome in one UK Health Region

Editor—Prader-Willi syndrome (PWS) is a genetically determined disorder in which the absence of expression of one or more maternally imprinted gene(s) in the chromosomal region 15q11-13 results in a characteristic facial appearance, learning disabilities (mental retardation), and severe overeating behaviour owing to an abnormal satiety response to food intake, together with a range of other behaviours. Initially, as reported by Prader et al ,1 PWS was conceived as a syndrome of obesity, short growth, cryptorchidism, and mental retardation following hypotonia in the neonatal period. As more and more people with PWS were reported and research into the syndrome began, behavioural characteristics and other clinical features were added, culminating in the consensus diagnostic criteria.2Concurrently, the genetics of the disorder were receiving attention. First was the discovery that for many there was a visible chromosomal deletion in the proximal part of the long arm of chromosome 15 (15q11-13). Reports of an apparently similar deletion being associated with a phenotypically very different syndrome (Angelman syndrome, AS),3 and the observation that PWS was the result of a deletion on the chromosome 15 of paternal origin, and AS the chromosome 15 of maternal origin, led to the recognition that gender specific imprinting of genes at that locus accounted for two diverse syndromes being associated with apparently similar chromosomal deletions.4 Maternal chromosome 15 disomies, mutations of an imprinting centre, and chromosomal translocations accounted for non-deletion cases of PWS.5 In published reports on Prader-Willi syndrome (PWS), prevalence has been variously quoted as “about 1 in 25 000 live births”,6 “between one in 25 000 and one in 10 000 live born children”,7 “[estimates] vary 6-fold from 1 in 5000 to 10 000; 1 in 10 000; 1 in 15 000; 1 in 25 000; to 1 in 10 000 to 30 000”.8 Only two estimates …

Evidence for the independence of positive and negative well-being: implications for quality of life assessment.

OBJECTIVES Evidence is accumulating that positive mental states are more than the absence of symptoms, and may play an independent role in health outcomes. The aim of this study is to compare the characteristics and determinants of positive and negative mental states in a population sample. DESIGN A novel analysis of data was undertaken from the General Health Questionnaire (GHQ-30) which was completed by 6,317 participants in the Health and Lifestyle Survey at Time 1 and 3,778 at Time 2, 7 years later. METHODS We derived a positive well-being scale (POS-GHQ) based on positive responses to the positive items of the GHQ-30, and compared it to a standard symptom measure (CGHQ). Discriminant function analyses were performed to establish which demographic, health and social variables best accounted for scores on each scale. RESULTS The distributional properties of the two scales, together with the results of the discriminant analyses, demonstrate a degree of independence between positive and negative well-being. Over one third of the sample obtained either low scores on both positive and negative well-being measures or high scores on both measures. Disability and lack of social roles were important determinants of psychological symptoms, but had less influence on positive well-being. Having paid employment was an important determinant of positive well-being but had less influence on psychological symptoms. We also found that 7-year mortality was predicted more strongly by the absence of positive well-being than by the presence of psychological symptoms. CONCLUSIONS These findings point to the need to include measures of positive well-being in studies of health outcomes and quality of life assessment.

Psychotic illness in people with Prader Willi syndrome due to chromosome 15 maternal uniparental disomy

In a population-based study of Prader Willi syndrome (PWS), we investigated the relation between genetic subtypes of the syndrome and psychiatric morbidity. Of 25 patients aged 18 years or older, seven (28%) had severe affective disorder with psychotic features, with a mean age of onset of 26 years (SD 5.9). The seven people affected, all aged 28 years or older, included all five with disomies of chromosome 15, one with a deletion in this chromosome, and one with an imprinting centre mutation in the same chromosome. We postulate that in PWS, an abnormal pattern of expression of a sex-specific imprinted gene on chromosome 15 is associated with psychotic illness in early adult life.

Prevalence of, and risk factors for, physical ill‐health in people with Prader‐Willi syndrome: a population‐based study

The medical findings from a population-based study of Prader-Willi syndrome (PWS) are discussed (in which birth incidence of PWS was estimated at 1:22,000 and death rate at over 3% per annum). In this study the prevalence of specific medical disorders that might account for a shortened life expectancy were investigated. Of all people with a possible diagnosis of PWS, only those meeting clinical criteria and/or with a confirmed genetic diagnosis were included in the study. Sixty-six individuals, 40 males and 26 females with a mean age of 19 years (range of 0 to 46 years) agreed to participate in the population-based study group. A prevalence rate of 25% for non-insulin dependent diabetes mellitus (NIDDM) was found in adults. Mean age at onset was 20 years. Those with NIDDM had a higher past maximum body weight and a greater likelihood of positive family history. Nearly 50% across the age groups reported a history of recurrent respiratory infections. High rates of fractures (29%), leg ulceration (22% in adults), sleep disorders (20%), and severe scoliosis (15% in childhood) were also reported. It is postulated that hypotonia is a possible contributory factor to the risk of strabismus, scoliosis, and respiratory infections. Other causes of morbidity, in particular the high rates of NIDDM, may be due to a failure to manage over-eating resulting in severe obesity. Early diagnosis and clear guidance to families about these risks and how they might be prevented is recommended. It is hypothesized that the high pain threshold may result in the presence of some illness not being apparent.

Symptoms of psychological distress predict 7-year mortality

As part of the Health and Lifestyle Survey (HALS), 6096 adults from a representative sample of community residents completed a standardized questionnaire which elicited psychiatric symptoms--the General Health Questionnaire (GHQ-30) of Goldberg (1972). Their survival status at 7 years was determined, and 474 had died. Respondents whose GHQ score was above the conventional threshold (4/5), used when screening for psychiatric disorder, were 60% more likely to die over the 7-year interval than respondents whose GHQ score was below threshold (risk ratio 1.64 for men and 1.58 for women). The differences were statistically significant for both sexes when the effects of age, physical disorder, social class and smoking behaviour were taken into account. Personality traits (neuroticism, extraversion) were not related to mortality, neither was self-reported difficulty in sleeping. However, a low subjective rating of ones general health was associated with increased mortality. We explored a range of cut-points and found reliable effects for both sexes at all cut-points from 3/4 to 6/7. Possible differences related to natural versus unnatural causes of death were explored and found not to explain the results. The findings from this general population study confirm that is is not only psychiatric disorders, but also psychiatric symptoms, which are associated with subsequent mortality, and thereby reinforce the importance of appropriate intervention to alleviate these symptoms.

The paradox of Prader-Willi syndrome: a genetic model of starvation.

The neurodevelopmental disorder, Prader-Willi syndrome, is generally regarded as a genetic model of obesity. Although the values of some hypothalamic neuropeptides are as expected in obesity, and should result in satiety, we propose that abnormal hypothalamic pathways mean that these are ineffective. We postulate that the body incorrectly interprets the absence of satiation as starvation, and therefore, paradoxically, this syndrome should be redefined as one of starvation that manifests as obesity in a food-rich environment. Also, this syndrome is generally believed to be a contiguous gene disorder, which results from the absence of expression of the paternally derived alleles of maternally imprinted genes on chromosome 15 (15q11-13). We argue, however, that the whole phenotype can be explained by one mechanism and, by implication, the failure of expression of the paternal allele of a single maternally imprinted gene that controls energy balance. We suggest clinical and laboratory approaches to test our hypotheses.

Development of the eating behaviour in Prader–Willi Syndrome: advances in our understanding

Prader–Willi Syndrome (PWS) is a genetically determined neurodevelopmental disorder associated with mild to moderate intellectual disability, growth and sex-hormone deficiencies and a propensity to overeat that leads to severe obesity. The PWS phenotype changes from an early disinterest in food to an increasing pre-occupation with eating and a failure of the normal satiety response to food intake. The prevention of severe obesity is primarily through strict control of access to food and it is this aspect that most limits the independence of those with PWS. This review considers the eating disorder in PWS, specifically how the as yet uncertain genetics of the syndrome and the transition from the early to the later phenotype might account for the later hyperphagia. On the basis of behavioural and imaging studies, a failure of satiety and excessive activation of neural reward pathways have both been suggested. We speculate that the overeating behaviour, consequent upon one or other of the above, could either be due to a direct effect of the PWS genotype on the feeding pathways of the hypothalamus or a consequence of prenatal changes in the regulation of genes responsible for energy balance that sets a high satiation threshold. Understanding the overeating in PWS will lead to more focused and successful management and ultimately, treatment of this life-threatening behaviour.

Relationship between clinical and genetic diagnosis of Prader-Willi syndrome

A s part of a population based study of Prader-Willi syndrome (PWS), we have examined more closely the relationship between clinical and genetic diagnoses in a large number of people with established or suspected PWS. We report here on agreements and disagreements between clinical and genetic diagnoses. We consider whether a genetic diagnosis implies the presence of any one (or more) of the major, minor, or supportive diagnostic criteria, and also whether the presence of any one (or more) particular diagnostic criteria1 implies a positive genetic finding, and what minimal genetic findings correspond to a positive finding on the basis of the clinical diagnostic criteria. In this paper, we also report on four specific cases that illustrate diagnostic difficulties. An early diagnosis of PWS is of particular importance as the propensity to overeat can start as early as 2 years of age, and parental control of access to food can prevent the development of life threatening obesity. As part of this study, we have found high rates of physical morbidity and mortality that are likely to be preventable if weight is adequately controlled.2,3 Initially, as reported by Prader et al ,4 PWS was conceptualised as a syndrome of obesity, short stature, cryptorchidism, and mental retardation following severe hypotonia in the neonatal period (decreased activity in utero, “floppy” at birth, marked feeding difficulties). With increasing clinical experience and research studies, behavioural characteristics such as hyperphagia, outbursts of temper, obsessional traits, and stubbornness, and clinical features such as central adiposity, sleep disorders, abnormalities of temperature and pain perception were added, culminating in the Consensus Diagnostic Criteria.1 A weighted score of 8 or more for ages >3 (5 or more for ages <4), based on the presence of eight major (score 1) and 11 minor (score 0.5) symptoms, …

Changing rates of genetic subtypes of Prader-Willi syndrome in the UK.

The genetically determined neurodevelopmental disorder, Prader–Willi syndrome (PWS), has two main genetic subtypes: a 15q11–q13 deletion affecting the paternally inherited chromosome 15 and chromosome 15 maternal uniparental disomy (mUPD) in which two maternal copies of chromosome 15 are inherited but no paternal copy. It has been accepted that these subtypes occur in approximately 70 and 25% of cases, respectively. This is the first report of a greater proportion (50%) of those with PWS due to mUPD in children presently under 5 years living in the UK. Increasing maternal age at conception is likely to explain the changing proportions in this generation of mothers.

A study of the influence of different genotypes on the physical and behavioral phenotypes of children and adults ascertained clinically as having PWS

A population‐based cohort of people with a clinical diagnosis of Prader–Willi syndrome (PWS) was genetically assessed using molecular diagnostic methods and subsequently divided into the following genetic subtypes involving chromosome 15: ‘deletion’, ‘disomy’ and genetically negative (referred to as ‘PWS‐like’). The physical and behavioral characteristics of the three groups were compared in order to evaluate the unique characteristics of the phenotype resulting from loss of expression of imprinted genes at 15q11q13 (PWS vs. PWS‐like cases), the possible effect of either haploid insufficiency of non‐imprinted genes (deletion cases), or gain of function of imprinted genes (disomy cases) located within the PWS critical region at 15q11q13. In this study, the main differences between probands with either a deletion or disomy are considered, and the possible involvement of contributing genes discussed. The differences within the PWS group proved difficult to quantify. It would appear that haploid insufficiency or gain of function are more subtle contributors than gender‐specific genomic imprinting in the production of the PWS phenotype.