Anthony J. Holland

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 …

Down's Syndrome and Alzheimer's disease: a review

Neuropathological change found in nearly all individuals with Downs Syndrome over the age of 35 years closely resembles that of Alzheimers disease. The extent to which dementia occurs as a result of this change is unclear, and the studies which have investigated presumed cognitive deficits are reviewed. The theories put forward to explain the association between these two disorders and their possible significance to the understanding of the aetiology of Alzheimers disease are discussed.

Recommendations for the diagnosis and management of Prader-Willi syndrome

OBJECTIVE The objective of the study was to provide recommendations for the diagnosis and management of Prader-Willi syndrome throughout the life span to guide clinical practice. PARTICIPANTS An open international multidisciplinary expert meeting was held in October 2006 in Toulouse, France, with 37 invited speakers and session chairs (see Acknowledgments) and 85 additional registered participants. The meeting was supported by an unrestricted educational grant from Pfizer. EVIDENCE Invited participants with particular expertise reviewed the published evidence base for their specialist topic and unpublished data from personal experience, previous national and international PWS conferences, and PWS Association clinical advisory groups. Sessions covered epidemiology, psychiatric, and behavioral disorders; breathing and sleep abnormalities; genetics; endocrinology; and management in infancy, childhood, transition, and adulthood. CONSENSUS PROCESS This included group meetings including open discussion after each session. The guidelines were written by the Scientific Committee (authors), using the conclusions provided by the sessions chairs and summary provided by each speaker, including incorporation of changes suggested after review by selected meeting participants (see Acknowledgments). CONCLUSIONS The diagnosis and management of this complex disorder requires a multidisciplinary approach with particular emphasis on the importance of early diagnosis using accredited genetic testing, use and monitoring of GH therapy from early childhood, control of the food environment and regular exercise, appropriate management of transition, consideration of group home placement in adulthood, and distinction of behavioral problems from psychiatric illness.

Changes in appetite, food preference, and eating habits in frontotemporal dementia and Alzheimer’s disease

Background: Despite numerous reports of changes in satiety, food preference, and eating habits in patients with frontotemporal dementia, there have been few systematic studies. Objectives: To investigate the frequency of changes in eating behaviours and the sequence of development of eating behaviours in frontotemporal dementia and Alzheimer’s disease, using a caregiver questionnaire. Methods: Three groups of patients were studied: frontal variant frontotemporal dementia (fv-FTD) (n = 23), semantic dementia (n = 25), and Alzheimer’s disease (n = 43). Level of education and dementia severity was similar in the three groups. The questionnaire consisted of 36 questions investigating five domains: swallowing problems, appetite change, food preference, eating habits, and other oral behaviours. Results: The frequencies of symptoms in all five domains, except swallowing problems, were higher in fv-FTD than in Alzheimer’s disease, and changes in food preference and eating habits were greater in semantic dementia than in Alzheimer’s disease. In semantic dementia, the developmental pattern was very clear: a change in food preference developed initially, followed by appetite increase and altered eating habits, other oral behaviours, and finally swallowing problems. In fv-FTD, the first symptom was altered eating habits or appetite increase. In Alzheimer’s disease, the pattern was not clear although swallowing problems developed in relatively early stages. Conclusions: Change in eating behaviour was significantly more common in both of the frontotemporal dementia groups than in Alzheimer’s disease. It is likely that the changing in eating behaviours reflects the involvement of a common network in both variants of frontotemporal dementia—namely, the ventral (orbitobasal) frontal lobe, temporal pole, and amygdala.

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.

Anorexia nervosa: Evidence for a genetic basis

This paper reports the preliminary results of a combined twin and family study of anorexia nervosa. Fifty-six per cent of the 25 female monozygotic (MZ) twin pairs and 5% of the 20 female dizygotic (DZ) twin pairs were concordant for anorexia nervosa. Nearly 5% of other female first degree relatives also had a history of anorexia nervosa. Analysis of data from the Eating Disorders Questionnaire (EDI) given to the twins and data as to weight loss, length of amenorrhoea and other characteristics of anorexia nervosa, together with the twin and family data, supports the hypothesis that genetic factors are very significant in the aetiology of anorexia nervosa. Analysis of this data using established techniques of psychiatric genetics suggested that up to 80% of the variance in liability to anorexia nervosa may be accounted for by genetic factors. The problems of this type of analysis are discussed as is the background to the genetics of weight and appetite control. A genetic/environmental model accounting for the features of anorexia nervosa is proposed.

Neural contributions to the motivational control of appetite in humans

The motivation to eat in humans is a complex process influenced by intrinsic mechanisms relating to the hunger and satiety cascade, and extrinsic mechanisms based on the appetitive incentive value of individual foods, which can themselves induce desire. This study was designed to investigate the neural basis of these two factors contributing to the control of motivation to eat within the same experimental design using positron emission tomography. Using a novel counterbalanced approach, participants were scanned in two separate sessions, once after fasting and once after food intake, in which they imagined themselves in a restaurant and considered a number of items on a menu, and were asked to choose their most preferred. All items were tailored to each individual and varied in their incentive value. No actual foods were presented. In response to a hungry state, increased activation was shown in the hypothalamus, amygdala and insula cortex as predicted, as well as the medulla, striatum and anterior cingulate cortex. Satiety, in contrast, was associated with increased activation in the lateral orbitofrontal and temporal cortex. Only activity in the vicinity of the amygdala and orbitofrontal cortex was observed in response to the processing of extrinsic appetitive incentive information. These results suggest that the contributions of intrinsic homeostatic influences, and extrinsic incentive factors to the motivation to eat, are somewhat dissociable neurally, with areas of convergence in the amygdala and orbitofrontal cortex. The findings of this study have implications for research into the underlying mechanisms of eating disorders.

A four year prospective study of age-related cognitive change in adults with Down's syndrome

BACKGROUND While neuropathological studies indicate a high risk for Alzheimers disease in adults with Downs syndrome, neuropsychological studies suggest a lower prevalence of dementia. In this study, cognitive deterioration in adults with Downs syndrome was examined prospectively over 4 years to establish rates and profiles of cognitive deterioration. METHODS Fifty-seven people with Downs syndrome aged 30 years or older were assessed using a battery of neuropsychological tests on five occasions across 50 months. Assessments of domains of cognitive function known to change with the onset of Alzheimer related dementia were employed. These included tests of learning, memory, orientation, agnosia, apraxia and aphasia. The individual growth trajectory methodology was used to analyse change over time. RESULTS Severe cognitive deterioration, such as acquired, apraxia and agnosia, was evident in 28.3% of those aged over 30 and a higher prevalence of these impairments was associated with older age. The rate of cognitive deterioration also increased with age and degree of pre-existing cognitive impairment. Additionally, deterioration in memory, learning and orientation preceded the acquisition of aphasia, agnosia and apraxia. CONCLUSIONS The prevalence of cognitive impairments consistent with the presence of Alzheimers disease is lower than that suggested by neuropathological studies. The pattern of the acquisition of cognitive impairments in adults with Downs syndrome is similar to that seen in individuals with Alzheimers disease who do not have Downs syndrome.

Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain

Abnormal phosphorylation of tau is a feature of Alzheimers disease (AD), which develops prematurely in Down syndrome (DS) patients. Cognitive impairment is also recognized as a clinical characteristic of schizophrenia, which does not appear to be associated with tau‐aggregate formation. Several kinases can phosphorylate tau in cell‐free assays. Here we show increased activity of mitogen‐activated protein kinases (MAPKs) (including ERK1/2, SAPKs and p38) in post mortem AD and DS brains, which could not be accounted for by expression changes. In contrast, glycogen synthase kinase‐3 activity (GSK‐3αβ) was reduced significantly. Examination of tau in AD and DS using antibodies selective for MAPK phosphorylation sites showed increased immunoreactivity. In addition, phosphorylation of S199, reportedly a selective substrate for cyclin‐dependent kinase‐5 (cdk5) or GSK‐3αβ was only observed in AD samples, which showed a concomitant increase in the expression of p25, the enhancing cofactor for cdk5 activity. However, in schizophrenia brain, MAPK‐phosphorylated tau was unchanged compared to matched controls, despite similar expression levels to those in AD. The activities of the MAPKs and GSK‐3αβ were also unchanged. These data demonstrate that in AD and DS, enhanced MAPK activity, which has an established role in regulating neuronal plasticity and survival, can account for irregular tau phosphorylation, and that the molecular processes involved in these neurodegenerative disorders are distinct from those in schizophrenia. These data also question the significance of GSK‐3αβ, as much previous work carried out in vitro has placed this kinase as a favoured candidate for involvement in the pathological phosphorylation of tau.