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Prader-Willi syndrome: advances in genetics, pathophysiology ...
Prader-Willi syndrome: advances in genetics, pathophysiology ...
Prader-Willi syndrome: advances in genetics, pathophysiology ...
Prader-Willi syndrome: advances in genetics, pathophysiology ...
Prader-Willi syndrome: advances in genetics, pathophysiology ...
Prader-Willi syndrome: advances in genetics, pathophysiology ...
Prader-Willi syndrome: advances in genetics, pathophysiology ...
Prader-Willi syndrome: advances in genetics, pathophysiology ...
Prader-Willi syndrome: advances in genetics, pathophysiology ...
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Prader-Willi syndrome: advances in genetics, pathophysiology ...

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  • 1. 12 Review TRENDS in Endocrinology and Metabolism Vol.15 No.1 January/February 2004 Prader-Willi syndrome: advances in genetics, pathophysiology and treatment Anthony P. Goldstone1,2 1 Department of Endocrinology, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK 2 Present address: Department of Pediatric Genetics, Box 100296, University of Florida College of Medicine, Gainesville, FL 32610-0296, USA Prader-Willi syndrome (PWS) is a complex human Prader-Willi syndrome (PWS) is a genetic human obesity genetic disease that arises from lack of expression of syndrome (Figure 1a) with characteristic phenotypes, paternally inherited imprinted genes on chromosome including gross hyperphagia, hypogonadism and GH 15q11-q13. Identification of the imprinting control deficiency, that indicate hypothalamic dysfunction (Box 1) centre, novel imprinted genes and distinct phenotypes [1,2]. A recent epidemiological study estimates an inci- in PWS patients and mouse models has increased inter- dence of , 1 in 25 000 births, and a population prevalence est in this human obesity syndrome. In this review I of ,1 in 50 000 [3]. In this article, I review current focus on: (i) the chromosomal region and candidate knowledge of the genes involved in PWS, their possible genes associated with PWS, and the possible links with links with individual PWS phenotypes and current and individual PWS phenotypes identified using mouse potential treatment strategies (Table 1). models; (ii) the metabolic and hormonal phenotypes in PWS; (iii) postmortem studies of human PWS hypo- PWS genetics thalami; and (iv) current and potential advances in the PWS arises from the lack of expression of genes on the management of PWS and its complications. This could paternally derived chromosome 15q11-q13 (Figure 1b) [4]. have benefits for a wide spectrum of endocrine, paedia- Candidiate genes for PWS in this region are imprinted and tric and neuropsychiatric diseases. silenced on the maternally inherited chromosome. PWS Box 1. Diagnostic criteria for Prader-Willi syndrome [2] Major criteria † Hypopigmentation. † Neonatal and infantile hypotonia, with poor suck and subsequent † Small hands and feet for height and age. improvement with age. † Narrow hands with straight ulnar border. † Feeding problems and poor weight gain in infancy, needing gavage or † Eye abnormalities, including esotropis and myopia. other special feeding techniques. † Thick viscous saliva. † Weight gain (rapid onset at 1–6 years old), which leads to central † Speech articulation defect. obesity. † Skin picking. † Characteristic facial features, including narrow bifrontal diameter, almond-shaped palpebral fissures and down-turned mouth. Additional features † Hypogonadism/hypogenitalism: genital hypoplasia (small labia min- † High pain threshold. ora and clitoris in females, and hypoplastic scrotum in males); † Decreased vomiting. incomplete and delayed puberty, and infertility. † Altered temperature sensitivity. † Developmental delay/mild-to-moderate mental retardation/multiple † Scoliosis or kyphosis. learning disabilities. † Early adrenarche. † Hyperphagia/obsession with food. † Osteoporosis. † Chromosome 15q11-q13 abnormality. † Unusual skill with jigsaw puzzles. † Normal neuromuscular studies (e.g. muscle biopsy and electromyo- Minor criteria graphy). † Reduced foetal movement and infantile lethargy, which improves with age. Major criteria are weighted at one point each and minor criteria at one- † Characteristic behavioural problems, including temper tantrums, half point each. For children , 3 years of age, five points are required for obsessive–compulsive behaviour, stubbornnesss, rigidity, stealing diagnosis, four of which must be major criteria. For individuals . 3 years and lying. of age, eight points are required for diagnosis, five of which must be † Sleep disturbance or apnoea. major criteria. Supportive findings only increase or decrease the level of † Short stature for family by 15 years of age. suspicion of the diagnosis. Corresponding author: A.P. Goldstone (tgoldstone@yahoo.com). http://tem.trends.com 1043-2760/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2003.11.003
  • 2. Review TRENDS in Endocrinology and Metabolism Vol.15 No.1 January/February 2004 13 Table 1. Specific treatment options in Prader-Willi syndromea,b Treatment used currently Benefits Mechanism Difficulties and potential adverse effects Refs Special feeding Improve infantile nutrition Special teats, nasogastric tube GH in children " Growth velocity and final height Anabolic actions of GH Glucose intolerance [8,5,1] # Total body fat, " lean body mass Worsening scoliosisd " Physical and respiratory muscle strength " Bone mineral density " Lipolysis and resting energy expenditure Orchidopexy/orchidectomy Prevent testicular carcinoma Repositioning or removal of [85] testes Dietary and behavioural Prevent obesity and complications Reduced caloric intake Intervention difficult [41– 43,86] modification Control maladaptive behavioural Behavioural adaptation Impact on family problems Exercise Prevent obesity and complications " Energy expenditure [50] " Muscle strength and agility Noninvasive intermittent # Respiratory failure and cor Reduce nocturnal hypoxia and Tolerability [87] positive pressure ventilation pulmonale hypercapnia (NIPPV) # Daytime somnolence Continuous positive airway # Cardiorespiratory and sudden deathd pressure (CPAP) Speech therapy Improve articulation and pragmatic [88] skills Scoliosis surgery # Orthopaedic complications Correct spinal deformity " Morbidity and mortality [89] " Lung capacity Selective serotonin re- # Skin-picking, compulsivity Inhibit 5-HT re-uptake Side-effect profile [41,43] uptake inhibitors (SSRI)b # Depression, aggressive behaviour Return of menses and pregnancy riskd Antipsychotics Acute control of psychotic episodes Dopamine and 5-HT Side-effect profile [43] (phenothiazines or atypical # Aggressive behaviour antagonists Weight gaind e.g. risperidone)c Sex steroidsc " Bone mineral density Anabolic actions on bone, fat Oestrogen: " thrombosis risk, [85] # Fracture rated and muscle menstruation Improve body compositiond Testosterone: " aggressive behaviour, " Muscle strength (androgens)d prostatic hypertrophyd Potential use GH in infants " Muscle strengthd Developmental and anabolic Glucose intolerance [69] " Brain development and IQd actions of GH GH in adults Improve body composition Anabolic and CNS actions of Glucose intolerance [52] " Muscle strengthd GH Arthralgia and oedema " Psychological well beingd Topiramate # Skin picking " GABA activity Neurological side effects [83] Theoretical use Somatostatin analogues # Obesityd(benefit in paediatric # Hyperinsulinaemia Glucose intolerance [91,92] hypothalamic obesity from tumours) # Ghrelin secretiond Gallstones Suppression of GH/IGF-I axis Already relative # hyperinsulinaemia in PWSd Effect of hyperghrelinaemia in PWS unknown Ghrelin antagonists # Food intake and obesityd Block orexigenic GHS-R in Suppression of GH/IGF-I axisd [63– 66] hypothalamus ^ vagal CNS developmental defects prevent actiond afferents Drug availability Effect of hyperghrelinaemia in PWS unknown Anorexigenic gut hormones # Food intake and obesityd Anorexigenic actions in CNS developmental defects prevent actiond [72– 76] e.g. PYY3 –36, pancreatic hypothalamus and brainstem Delivery method polypeptide CNS acting anorexigenic # Food intake and obesityd Stimulate anorexigenic and CNS developmental defects prevent actiond [73,93] drugs inhibit orexigenic CNS Side-effect profile pathways a Treatments for diabetes mellitus, hypertension, hyperlipidaemia and osteoporosis are not included. There is no data indicating whether the choice of agent in PWS should be different to the general population and particularly those with obesity. b Abbreviations: GABA, g-aminobutyric acid; GH, growth hormone; GHS-R, growth hormone secretagogue receptor; IGF-I, insulin-like growth factor-I. c Indicates therapies in routine use for which there is little or no published data on effectiveness, benefits and risks. d Indicates unclear or uncertain effects. develops if the paternal alleles are defective, missing or established either during or after gametogenesis and silenced. In 75% of cases, there is paternal deletion of maintained throughout embryogenesis [5]. The IC has a 15q11-q13, maternal uniparental disomy (UPD) in 22%, role in both establishing the paternal imprint, by erasing imprinting errors in 3% because of either a sporadic or the grandmaternal imprint during spermatogenesis, and inherited microdeletion in the imprinting centre (IC), and in its postzygotic maintenance [4,6]. there is a paternal chromosomal translocation in , 1% of The spectrum of neuroendocrine disturbances in PWS cases. Imprinting occurs partly through parent-of-origin indicates developmental abnormalities of the hypothalamus allele-specific methylation of CpG residues, which is [7,8]. Paternally expressed genes are particularly important http://tem.trends.com
  • 3. 14 Review TRENDS in Endocrinology and Metabolism Vol.15 No.1 January/February 2004 (a) (b) PWS AS Non-imprinted ? Minimal critical region snoRNAs 8B 8A HBII-1 6 II- 7 43 HB I-43 II 3 HB -43 43 HBII-85 HBII-52 II- GABR 2 I (27copies) (47copies) HB HB 3 P EL RN UBE3A AG N β3 α5 γ3 MK ND cen M X X X tel exons 1-3 4-10 13-20 21 52 62 63 142 144 148 ATP10C BP1 BP2 BP3 SNURF SmN PAR-5 PAR-7 IPW PAR-1 PAR-4 UBE3A-AS PWCR1 SNURF-SNRPN PWS imprinting centre TRENDS in Endocrinology & Metabolism Figure 1. Prader-Willi syndrome (PWS): from genes to phenotype. (a) A 17-year-old female with PWS. (b) PWS chromosomal region on 15q11-q13 (not to scale) showing the genetic map of the 2 Mb PWS region. Imprinted genes are in blue (paternal allele expressed) and red (maternal allele expressed). Nonimprinted genes are in green. Pur- ple arrows indicate the area of regional imprint control through the imprinting centre at the 50 end of the bicistronic SNURF-SNRPN locus. Vertical bars indicate snoRNA transcripts and horizontal bars, the relative positions of identified exons and other transcripts within the SNURF-SNRPN locus. Also indicated are the overlapping sense and antisense transcripts of the Angelman syndrome (AS) gene, UBE3A, that is located adjacent to the PWS locus. The black crosses indicate common breakpoint (BP) regions for deletions. in hypothalamic development, as indicated by the hypo- phenotypes, their function is unknown at present (see thalamic accumulation of androgenetic (duplicated paternal supplementary information Table 2 http://archive.bmn. genome) cells in chimeric mouse embryos [9]. com/supp/tem/Goldstone_Table2.pdf) [4,13]. Mutations and deletions of individual genes have not yet been Imprinted genes in the PWS chromosomal region reported in PWS or in patients with specific PWS Several candidate genes in the human 15q11-q13 region phenotypes [4]. and syntenic mouse chromosome 7C display monoallelic paternal expression (Figure 1b, see supplementary Mouse models of PWS information Table 2 http://archive.bmn.com/supp/tem/ A consistent phenotype of failure-to-thrive, hypotonia, Goldstone_Table2.pdf) [4]. Although expression is more neonatal lethality and growth retardation in survivors is widespread and occurs outside the brain in humans seen in several mouse models of PWS. These include: compared with mice, it is absent in lymphocytes, fibro- (i) maternal duplication of chromosome 7 (UPD); (ii) PWS blasts or brain tissue from PWS subjects. The promotor deletion, in which a transgene is inserted into the whole and first exon of the SNURF-SNRPN gene locus appears to PWS syngenic region in the paternal chromosome 7C; be an integral part of the IC in the PWS chromosomal (iii) deletion of the IC and Snurf-Snrpn exons 1 – 6; and region [10,11]. SNURF-SNRPN is an extremely complex (iv) a more specific deletion between exon 2 of Snurf-Snrpn gene locus that spans ,465 kb, with . 148 possible exons and Ube3a that does not involve the IC [4,11,21,22]. that undergo alternative splicing [12]. This locus also Studies in mice have not reported any phenotype with encodes the novel, small nucleolar RNAs (snoRNAs) that smaller deletions of individual exons of Snurf-Snrpn [11,22], do not encode proteins (human homologues are prefixed MBII-52 snoRNAs, Zfp127 and Ipw [4] (see supplementary HBII- and mouse homologues MBII-) [12 – 16]. information Table 2 http://archive.bmn.com/supp/tem/ With the exception of NDN and MAGEL2, the detailed Goldstone_Table2.pdf). There are strain-dependent neuroanatomical location of RNA and proteins, including variations in survival rates, but Ndn-deficient neonates their hypothalamic localization, have not been reported die from respiratory distress, with an abnormal respiratory [17 – 19]. Furthermore, with the exception of the role of rhythm-generating centre in the medulla, and survivors NDN in neural differentiation and survival, the function of have increased skin-scraping activity, improved spatial these genes is poorly understood [20]. Potential roles for learning and structural abnormalities of the hypothalamus NDN and MAGEL2 genes in other PWS phenotypes, such [18,23,24]. This mimics recognized PWS phenotypes, includ- as small hands and feet, growth retardation, hypotonia, ing respiratory problems, infantile sudden death, skin- articulation defects, dysmorphic mouth, viscous saliva and picking and unusual skill with jigsaws [25– 27]. genital hypoplasia are also indicated by the embryonic and However, although mice that survive neonatal failure- postnatal expression of the mouse homologues Ndn and to-thrive can be small, no mouse model of PWS is obese or Magel2 outside the brain (see supplementary information infertile. The reasons why the phenotype is limited Table 2 http://archive.bmn.com/supp/tem/Goldstone_Table2. remains unclear. Possibilities include species differences pdf) [4,19]. Although the position of balanced transloca- in gene structure, function, copy variants, tissue- and tions and submicroscopic deletions that involve the PWS cell-expression patterns, neuroendocrine and metabolic region indicates the relative importance of the snoRNAs, pathways, and imprinting leakage, and species- and especially the HBII-85 cluster, in the development of PWS strain-specific modifier genes. It is also possible that the http://tem.trends.com
  • 4. Review TRENDS in Endocrinology and Metabolism Vol.15 No.1 January/February 2004 15 mice that would have developed such phenotypes die during well-balanced diet, with regular exercise, rigorous super- the postnatal period. This is being addressed by the develop- vision, restriction of access to food and money, and ment of further gene-specific knockout mice, Cre/lox appropriate psychological and behavioural counselling of knockout systems (which allow temporal-, tissue- and the patient and family [41– 43]. Pharmacological treat- neuron-specific gene modulation), transgenic rescue of ment, including anorexigenic agents that act through phenotypes and the use of different mouse strains. central monoamine and 5-hydroxytryptamine (5-HT) pathways, is not benefial in treating hyperphagia and Relevance to non-PWS phenotypes obesity, although there are few published control studies Identifying neuroendocrine abnormalities in PWS could [41,43]. Group homes specifically designed for individuals provide information on the important hypothalamic path- with PWS are particularly succesful in managing these ways and peripheral inputs that are involved in the problems during adulthood. The choice and use of specific regulation of body weight, as with mutations that lead antidiabetic (particularly metformin, thiazolidinediones to rare monogenic cases of obesity [28], and might and alternative insulin regimes), antihypertensive and indicate potential therapies for both PWS and nonsyn- lipid-lowering agents will be guided by those used in the dromal obesity. general population with obesity, but possible differences in The PWS chromosomal region was not linked with PWS have not been addressed systematically. Potential obesity in earlier sibling studies, and no association novel therapies to control hyperphagia in PWS are between NDN polymorphisms and obesity in children outlined in Table 1. and adolescents has been identified [29]. A recent genome- wide scan found linkage between childhood-onset severe Body composition and energy expenditure obesity in French Caucasian families and an area on Body-composition studies show both increased body fat chromosome 15q that includes the PWS region [30], but and reduced muscle in PWS [44,45]. Magnetic resonance finer mapping has not been reported. Although PWS is a imaging has found a selective relative reduction in visceral pleiotropic syndromal condition, it is possible that poly- adiposity in PWS adults, which protects against the morphisms in genes in the PWS region could play a role in metabolic consequences of obesity, such as insulin resist- nonPWS obesity, especially if different genes are involved ance and hypertriglyceridaemia [46,47]. This unusual in different phenotypes of PWS. situation occurs despite the presence of many phenotypes Interestingly, psychosis is almost exclusively restricted that should increase visceral adiposity. Reduced para- to PWS adults with UPD rather than deletions [31], and sympathetic innervation of visceral adipocytes or absent some genotype– phenotype correlations in PWS indicate expression of PWS genes in these cells, or even childhood- other differences [32– 35]. This hints that the dosages of onset GH deficiency, might be responsible [46,48]. genes in the PWS region that do not display monoallelic Physical activity is significantly reduced in PWS [49], paternal expression might have phenotypic consequences. which is related to obesity, hypersomnolence and persist- PWS subjects with IC mutations appear to have a classical ent, poor muscle strength. There is a reduced resting PWS phenotype [36] and might have a similar increased metabolic rate relative to body size. This is related to the predisposition to psychosis as UPD [37]. Subjects with abnormal body composition and further contributes to the deletions have a higher frequency of hypopigmentation of reduction in 24 h energy expenditure [45]. Increased skin, hair and eyes [33,34,38], which is caused by loss of physical activity and exercise programs are beneficial in expression of the nonimprinted P gene that is involved in improving body composition in PWS [50]. oculocutaneous albinism [39]. Growth retardation and growth hormone (GH) deficiency Neuroendocrine and metabolic abnormalities Mild prenatal growth retardation is common, with a birth weight of ,2.5 kg in 41% of cases, and an increased Hyperphagia and obesity prematurity rate reaching 34% in a recent study [*]. Short In babies with PWS, postnatal hypotonia, poor suck and stature is almost always present, because of both feeding difficulties mean that special feeding strategies are GH deficiency and the lack of a pubertal growth spurt. usually required for weeks to months to prevent failure-to- Spontaneous and pharmacologically stimulated secretion thrive. This has usually improved significantly by 6 of GH and the concentration of insulin-like growth factor I months of age. There is a rapid onset of hyperphagia and are reduced in both children and adults, and GH deficiency obesity between the ages of 1 – 6 years, which, without is independent of obesity [8]. appropriate dietary and behavioural input, is sustained In PWS children, therapy with GH significantly into adulthood [40]. improves the rate of growth and final height. Long-term Without adequate dietary control, the extreme hyper- studies show that the final height is in the average range phagia in PWS leads to obesity-related morbidity, such for age [8,51], and GH is now licensed for use in PWS. as cardiopulmonary disease, type 2 diabetes mellitus, Studies also show that GH significantly decreases total thrombophlebitis, chronic leg oedema and mortality at body fat. It also increases lean body mass, lipolysis and ,35 years [40]. The abnormal feeding behaviour includes resting energy expenditure, and improves physical a morbid obsession with food, food stealing, stealing money strength, agility, respiratory muscle hypotonia and the to buy food, hording and foraging, pica behaviour, reduced reduced peripheral chemoreceptor sensitivity to carbon satiety, and earlier return of hunger after eating. Managing dioxide [8]. Although increases in fasting insulin and this behaviour involves early institution of a low-calorie, reduced glucose elimination rates have been seen during http://tem.trends.com
  • 5. 16 Review TRENDS in Endocrinology and Metabolism Vol.15 No.1 January/February 2004 GH therapy, the development of glucose intolerance and responds to weight loss [58], PWS subjects have defective diabetes mellitus does not appear to be a problem, at least central respiratory drive [24,59] and abnormalities in if dietary control is maintained. There might also be rapid-eye-movement sleep [60]. Orexin neurons in the additional benefits to starting GH therapy in early infancy lateral hypothalamic area have a primary role in control- [69], and prospective studies are ongoing. However, there ling sleep and arousal. Orexin concentrations in the have been recent concerns about a possible unproven cerebro– spinal fluid (CSF) are low in a single reported involvement of GH therapy in anecdotal cases of sudden case of PWS with hypersomnia [61], but orexin neurons death syndrome in PWS children [25]. This emphasizes have not been examined in PWS hypothalami. Non- that such treatment, including the GH dosage regime and invasive ventilatory support can help to reverse hyper- IGF-I levels, should be carefully monitored in specialized capnoeic respiratory failure (Table 1). centers (D. Driscoll and J. Miller, pers. commun.). Studies are also investigating whether there might be a worsening Hyperphagia, peripheral signals and the brain of sleep apnoea in a subset of patients. A potential benefit of lower doses of GH to improve body composition in PWS Plasma leptin, ghrelin and other gastrointestinal adults has been reported [52], and further studies are hormones proceeding. The hypothalamic neuropeptide pathways that regulate feeding and energy expenditure are targets for leptin, the Hypothalamic –pituitary (HP)– gonadal axis anorexigenic, adipocyte-derived hormone, and ghrelin, the Boys with PWS usually have hypoplastic external geni- orexigenic, stomach-derived hormone [62]. These hormones talia, including micropenis, whereas girls have hypo- and neuropeptides also regulate the HP axis, sleep and plastic labia minora [53]. Adrenarche can occur early, but arousal, and mediate endocrine changes during starvation gonadal maturation is usually either delayed or incom- and illness. There is no evidence of either absolute or plete, with frequent delay in menarche, primary amenor- relative deficiency of leptin in PWS, and the fully func- rhoea and oligomenorrhoea [8,40,85]. Male adults usually tional long isoform of the leptin receptor (OBRb) is present have low testosterone levels, although estradiol levels in in PWS lymphocytes [45]. However, expression of OBRb in females can be in the early follicular range, possibly because human PWS hypothalami has not been reported. of increased aromatization by excess adipose tissue. Ghrelin is an endogenous ligand of the GH-secretagogue What causes impairment of the HP – gonadal axis is receptor (GHS-R), which is located in the hypothalamus unknown. It has components of hypogonadotrophic hypo- and pituitary, and stimulates secretion of GH releasing gonadism, because of hypothalamic defects, and obesity- hormone (GHRH) and GH [63]. Ghrelin is secreted related polycystic ovarian syndrome in women, as well as primarily by the stomach, and plasma levels peak when primary gonadal failure, which is probably related to fasting and before starting a meal, and fall after meals. It frequent cryptorchidism in males [40,53]. Recently, two is also found in hypothalamic neurons and the pituitary. fertile females with PWS have been reported [54,55]. In one Ghrelin stimulates food intake acutely in humans, and case, regular menstruation and pregnancy followed treat- chronic administration to rodents causes obesity [63]. ment with a selective 5-HT re-uptake inhibitor (SSRI) [54], Recent studies have found fasting levels of ghrelin in the which indicates that underactivity of 5-HT pathways might plasma are grossly elevated in adults and children with be part of the mechanism of HP-gonadal suppression. PWS [64– 66], which could contribute to their hyper- Ndn-knockout mice have a 25% reduction in neurons phagia. This does not occur with other causes of obesity, that contain luteinising hormone releasing hormone in the including monogenic defects in leptin and melanocortin medial pre-optic area [18]. However, because these mice pathways [64 –66], and is not related to GH deficiency [67]. are not infertile, the effect on reproductive function is Its cause and organ source are unknown, but one possi- unclear. Gonadotrophin releasing hormone neurons have bility is abnormal parasympathetic vagal innervation of not yet examined in postmortem hypothalami from the stomach resulting from abnormalities in either the humans with PWS. hypothalamus or brainstem [68]. It has been suggested Sex-hormone replacement therapy in PWS adults is that chronic overstimulation of the GHS-R in the inconsistently prescribed [40]. Patients with PWS have hypothalamus and/or pituitary by elevated circulating reduced bone-mineral density (BMD) and content [44,56], ghrelin, leads to reduced GH secretion [65], perhaps through which results from the lack of bone-maturating effects of densensitization of GHS-R or a reduction in receptor puberty, sex steroids and GH [8]. This puts patients at number. The development of ghrelin antagonists and increased risk of osteoporosis; a recent study of 58 patients drugs that lower plasma ghrelin, such as somatostatin reported that 22% had had more than one fracture [57]. analogues, will help clarify its role in PWS phenotypes Although treatment of children with GH improves BMD (Table 1), as might revisiting the effects of gastric bypass in [51], the benefits of sex steroids and bisphosphonates have PWS patients [70], because with some operations ghrelin yet to be examined in a controlled manner. The prescription secretion can be markedly reduced in nonPWS subjects [90]. of testosterone therapy to PWS males has been complicated Post-prandial secretion of the anorexigenic pancreatic by anecdotal reports of increased aggressive behaviour. polypeptide (PP) from the gastrointestinal tract is reduced markedly in PWS subjects [71]. This might also result from Sleep and respiratory problems abnormal parasympathetic vagal tone. Although chole- Daytime hypersomnolence occurs in 70 –95% of PWS cystokinin secretion appears normal, it is important to subjects. As well as obesity-related sleep apnoea, which examine whether there is reduced post-prandial secretion http://tem.trends.com
  • 6. Review TRENDS in Endocrinology and Metabolism Vol.15 No.1 January/February 2004 17 of other anorexigenic gut hormones, such as PYY3 – 36 these neurons respond normally to alterations in periph- from the intestinal L-cells in PWS because this might eral signals. Preliminary studies also found no evidence of suggest potential therapeutic avenues [72– 74]. However, a lack of anorexigenic POMC-containing neurons and as with all gut homones that alter appetite, it is con- neurons that contain cocaine- and amphetamine-regu- ceivable that their target CNS pathways do not respond lated transcript, and no obvious excess of neurons that normally in PWS. For example infusing supraphysiologi- contain orexigenic melanin-concentrating hormone in cal amounts of PP in PWS subjects reduces acute food PWS hypothalami (Box 2) [47,77]. Quantitative analysis intake by 12% [75], which is less than that reported in is, however, necessary to exclude relative differences in cell control subjects [76]. number. There is a reduction in both the total number of cells and Hypothalamic feeding and growth neuropeptides of oxytocin-containing cells in the PVN of PWS adults Ghrelin stimulates feeding by activating neurons in the (Box 2) [27]. This might have a primary role in the hypothalamic arcuate nucleus [called the infundibular hyperphagia associated with PWS because oxytocin has nucleus (INF) in humans], that contains orexigenic neuro- anorexigenic actions in rodents. Haploinsufficiency for peptide Y (NPY) and agouti-related protein (AGRP) SIM1 on chromosome 6q16.2 also leads to obesity in neurons, which are inhibited by leptin [62,63,77]. The humans [79]. SIM1 encodes a transcription factor involved INF also includes anorexigenic pro-opiomelanocortin in neurogenesis, and obesity probably results from a (POMC)-containing neurons that project to similar areas nonselective loss of PVN neurons [80]. Interestingly, a as the NPY- and AGRP-containing neurons, including the 29% reduction in PVN oxytocin neurons is also seen in paraventricular nucleus (PVN). AGRP antagonizes the Ndn-knockout mice [18], although these mice are not effect of a-melanocyte stimulating hormone (a product of obese. These abnormalities might also contribute to POMC) at melanocortin-4 (MC4) receptors, and mutations peripheral hormonal abnormalities in PWS through pro- in genes that encode POMC and MC4 receptors lead to jections from the PVN to the brainstem and vagus nerve. childhood-onset obesity in humans [28]. Hypothalamic Given the importance of the INF projections to the PVN in overactivity of NPY and AGRP in rodents leads to the control of feeding [62], it remains to be seen whether hyperphagia and obesity, and NPYoveractivity also causes the PVN, and other brain regions, can respond normally to hypogonadism and GH deficiency [62]. hyperghrelinaemia in PWS. Quantitative neuroanatomical studies of post- The lack of obesity in mouse models of PWS limits their mortem human tissue from the Netherlands Brain Bank usefulness in studying the causes of hyperphagia. How- [7,27,47,77,78] failed to find any abnormalities of ever, neonatal mice with a PWS deletion have reduced NPY-, AGRP- and GHRH-containing neurons in the INF of concentrations of AGRP mRNA and increased concen- PWS hypothalami (Box 2). Although this indicates that trations of POMC mRNA that could contribute to their these neurons might not be involved in the pathogenesis of failure to thrive [81]. hyperphagia, GH deficiency and hypogonadism [77,78], interpretation is complicated by the small number of 5-HT and monoaminergic neurons samples and the effects of premorbid illness. However, The pathways involved in hyperphagia in PWS could lie in NPY-, AGRP- and GHRH-containing neurons respond reward and addiction circuits, such as the limbic system, appropriately to illness, obesity and exogenous GH amygdala, and ascending 5-HT-, noradrenaline- and therapy in PWS subjects (Box 2), which indicates that dopamine-containing pathways from the brainstem. Box 2. Hypothalamic neuropeptides and their signalling inputs in Prader-Willi syndrome (PWS) † Normal leptin secretion [45]. † Normal increase in the number of GHRH neurons in the INF during † Long isoform leptin receptor mRNA expressed in lymphocytes [45]. illness [78]. † Increased fasting plasma ghrelin [64 –66]. † Normal number of GHRH neurons in the INF compared to control † Reduced post-prandial secretion of pancreatic polypeptide [71,74]. and nonPWS obese adults, corrected for the duration of premorbid † Reduced fasting and post-prandial insulin secretion [46,84]. illness and gender [78]. † Normal cholecystokinin secretion [74]. † Reduced number of GHRH neurons in the INF in PWS children † Normal distribution of neuropeptide Y (NPY), agouti-related receiving exogenous treatment with GH [78]. protein (AGRP), pro-opiomelamocortin (POMC) and growth † Normal distribution of oxytocin and vasopressin neurons in the hormone releasing hormone (GHRH) neurons in infundibular paraventricular nucleus (PVN) [27]. nucleus (INF) [77.78]. † Reduced number of total (38%) and oxytocin (42%)-containing † Normal colocalization of NPY and AGRP in INF neurons [77]. neurons in the PVN [27]. † Normal increase in NPY, measured by either immunocytochemical † Normal number of vasopressin-containing neurons in the PVN [27]. (ICC) staining or mRNA expression, or AGRP (ICC staining) in INF † Normal distribution of neurons that contain cocaine- and amphet- during illness [77]. amine-regulated transcript (CART) in the INF, PVN and lateral † Reduced NPY (either ICC staining or mRNA expression) in INF, hypothalamic area (LHA) [47]. compared with control, but not nonPWS obese adults, corrected for † Deficiency of POMC-containing neurons in INF, and CART neurons the duration of premorbid illness [77]. in INF, PVN and LHA is not complete [47,77]. † Normal AGRP (ICC staining) in INF, compared to control and † Reduced number of luteinising hormone releasing hormone- nonPWS obese adults, corrected for the duration of premorbid containing neurons in the pre-optic area and oxytocin-containing illness [77]. neurons in the PVN in Ndn-knockout mice [18]. http://tem.trends.com
  • 7. 18 Review TRENDS in Endocrinology and Metabolism Vol.15 No.1 January/February 2004 Box 3. Important outstanding questions in Prader-Willi syndrome (PWS) † What are the function and expression profiles of candidate genes for † Is there a delay in the onset of hyperphagia in PWS beyond PWS, especially snoRNAs? improvement in neonatal hypotonia? † How are genes that are implicated in PWS involved in brain † What is the cause and consequence of hyperghrelinaemia in development? PWS? † What is the link between individual genes for PWS and specific † Are defects in the autonomic nervous system important in PWS phenotypes? phenotypes? † What is the role of the expression of genes for PWS outside the brain? † At what age should growth hormone (GH)-treatment be started in † Why do mouse models of PWS have limited phenotypes and why are children with PWS? they not obese? † Is there a role for GH treatment in adults with PWS? † What is the explanation for phenotypic variation in PWS? † What is the role of sex-steroid replacement in adults with PWS? † Are there further genotype –phenotype correlations in PWS? † Do we manage diabetes mellitus, hypertension, cardiorespiratory † Are genes for PWS involved in similar phenotypes in the general disease and osteoporosis appropriately in PWS? population? † Are there novel therapeutic avenues for treating hyperphagia in PWS † What causes prenatal growth retardation and hypotonia in PWS? (e.g. ghrelin antagonists and somatostatin analogues)? † What are the causes of sudden death in PWS children? † What causes the psychiatric and behavioural phenotypes in PWS, † What are the causes of the hypothalamic abnormalities in PWS and and how are they best treated? why are they selective? These neurons might also be involved in the behavioural research contributions; S. Chamberlain for helpful comments; collabora- problems seen in PWS, as indicated by abnormalities in tors worldwide for provision of brain material and clinical information from PWS subjects [74]; financial support from Merck Research monoamine metabolites in the CSF [82] and the use of Laboratories, Rahway, USA, Pharmacia and Upjohn, the UK Medical SSRIs to help skin-picking, depression, compulsivity and Research Council, the Royal Society of London, the Royal College of aggressive episodes (but not obesity) in some patients with Physicians (London), PAD 9607; and PWS patients, their families and PWS [41,43]. Mood stabilizers such as lithium and carers for their participation in research studies and the inspiration antiepileptic drugs have also been used, but formal drug behind this work. trials have yet to be performed. Anecdotally, atypical antipsychotics, such as risperidone, benefit some indi- References 1 Prader, A. et al. (1956) Ein syndrome von adipositas, kleinwuchs, viduals with psychotic features and extreme aggression kryptorchismus und oligophrenie nach myotonieartigem zustand im [41,43]. Topiramate, an anti-epileptic drug that increases neugeborenenalter. Schweiz. Med. Wochenschr. 86, 1260 – 1261 GABA activity, also reduces skin-picking behaviour, but 2 Holm, V.A. et al. (1993) Prader-Willi syndrome: consensus diagnostic has not been shown to help obesity [83]. criteria. Pediatrics 91, 398 – 402 3 Whittington, J.E. et al. (2001) Population prevalence and estimated birth incidence and mortality rate for people with Prader-Willi Future studies syndrome in one UK Health Region. J. Med. Genet. 38, 792 – 798 Many outstanding questions remain in our understanding 4 Nicholls, R.D. and Knepper, J.L. (2002) Genome organization, of this fascinating disease (Box 3). The genetic complexity function, and imprinting in Prader-Willi and Angelman syndromes. of the PWS chromosomal region, with multiple imprinted Annu. Rev. Genomics Hum. Genet. 2, 153 – 175 genes, alternative splice variants, gene duplications and 5 Guens, E. et al. (2003) Methylation imprints of the imprint control region of the SRNPN-gene in human gametes and preimplantation variant copies, and the mechanisms of imprinting itself, embryos. Hum. Mol. Genet. 12, 2873 – 2879 are matched by the wide variety of phenotypes that involve 6 El-Maarri, O. et al. (2001) Maternal methylation imprints on human multiple organ systems and the complexity of peripheral – chromosome 15 are established during or after fertilization. Nat. brain circuits. The pathophysiological challenge in the Genet. 27, 341 – 344 coming years will be to link the genetic and phenotypic 7 Swaab, D.F. (1997) Prader-Willi syndrome and the hypothalamus. Acta aspects of the disease, using multidisciplinary studies of Paediatr. Suppl. 423, 50 – 54 8 Burman, P. et al. (2001) Endocrine dysfunction in Prader-Willi PWS mouse models, postmortem PWS material and larger syndrome: a review with special reference to GH. Endocr. Rev. 22, cohorts of PWS patients. This will benefit patients with 787 – 799 PWS and, potentially, many other diseases, through 9 Keverne, E.B. (1997) Genomic imprinting in the brain. Curr. Opin. identification of pathways involved in appetite control, Neurobiol. 7, 463 – 468 body composition, growth, reproduction, learning disabil- 10 Bielinska, B. et al. (2000) De novo deletions of SNRPN exon 1 in early human and mouse embryos result in a paternal to maternal imprint ity, psychosis and other behavioural problems. switch. Nat. Genet. 25, 74 – 78 11 Yang, T. et al. (1998) A mouse model for Prader-Willi syndrome Note added in proof imprinting-centre mutations. Nat. Genet. 19, 25 – 31 A recent paper has now described in detail the brain, and 12 Runte, M. et al. (2001) The IC-SNURF-SNRPN transcript serves as a particularly hypothalamic, expression patterns of the host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A. Hum. Mol. Genet. 10, 2687– 2700 Mkrn3, Magel2, Ndn, Snrpn, Ipw and MBII-85 snoRNA 13 Gallagher, R.C. et al. (2002) Evidence for the role of PWCR1/HBII-85 transcripts in the mouse embryo [94]. C/D box small nucleolar RNAs in Prader-Willi syndrome. Am. J. Hum. Genet. 71, 669– 678 Acknowledgements 14 Cavaille, J. et al. (2000) Identification of brain-specific and imprinted I thank D.F. Swaab, U.A. Unmehopa, staff of Netherlands Brain Bank and small nucleolar RNA genes exhibiting an unusual genomic organiz- Institute for Brain Research, Amsterdam, A.E. Brynes, E.L. Thomas, ation. Proc. Natl. Acad. Sci. U. S. A. 97, 14311 – 14316 J.D. Bell, G. Frost, M.A. Ghatei, A.J. Holland, S.R. Bloom, for their 15 De Los Santos, T. et al. (2000) Small evolutionarily conserved RNA, http://tem.trends.com
  • 8. Review TRENDS in Endocrinology and Metabolism Vol.15 No.1 January/February 2004 19 resembling C/D box small nucleolar RNA, is transcribed from PWCR1, 42 Eiholzer, U. (2003) A comprehensive approach to limiting weight gain a novel imprinted gene in the Prader-Willi deletion region, which is and to normalising body composition in Prader-WIlli syndrome. In highly expressed in brain. Am. J. Hum. Genet. 67, 1067– 1082 Prader-Willi Syndrome as a Model for Obesity (Eiholzer, U. et al., eds), 16 Meguro, M. et al. (2001) Large-scale evaluation of imprinting status in pp. 211 – 221, Karger the Prader-Willi syndrome region: an imprinted direct repeat cluster 43 Dykens, E. and Shah, B. (2003) Psychiatric disorders in Prader-Willi resembling small nucleolar RNA genes. Hum. Mol. Genet. 10, 383– 394 syndrome: epidemiology and management. CNS Drugs 17, 167 – 178 17 Niinobe, M. et al. (2000) Cellular and subcellular localization of necdin 44 Brambilla, P. et al. (1997) Peculiar body composition in patients with in fetal and adult mouse brain. Dev. Neurosci. 22, 310 – 319 Prader-Labhart-Willi syndrome. Am. J. Clin. Nutr. 65, 1369– 1374 18 Muscatelli, F. et al. (2000) Disruption of the mouse Necdin gene results 45 Goldstone, A.P. et al. (2002) Resting metabolic rate, plasma leptin in hypothalamic and behavioral alterations reminiscent of the human concentrations, leptin receptor expression, and adipose tissue Prader-Willi syndrome. Hum. Mol. Genet. 9, 3101 – 3110 measured by whole-body magnetic resonance imaging in women 19 Lee, S. et al. (2000) Expression and imprinting of MAGEL2 suggest a with Prader-Willi syndrome. Am. J. Clin. Nutr. 75, 468 – 475 role in Prader-Willi syndrome and the homologous murine imprinting 46 Goldstone, A.P. et al. (2001) Visceral adipose tissue and metabolic phenotype. Hum. Mol. Genet. 9, 1813 – 1819 complications of obesity are reduced in Prader-Willi syndrome female 20 Yoshikawa, K. 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  • 9. 20 Review TRENDS in Endocrinology and Metabolism Vol.15 No.1 January/February 2004 children and are markedly increased in Prader-Willi syndrome. J. Clin. 81 Ge, Y.L. et al. (2002) Anorexigenic melanocortin signaling in the Endocrinol. Metab. 88, 174 – 178 hypothalamus is augmented in association with failure-to-thrive in a 67 Haqq, A.M. et al. (2003) Effects of growth hormone on pulmonary transgenic mouse model for Prader-Willi syndrome. Brain Res. 957, function, sleep quality, behavior, cognition, growth velocity, body 42 – 45 composition, and resting energy expenditure in Prader-Willi syn- 82 Akefeldt, A. et al. (1998) Cerebrospinal fluid monoamines in Prader- drome. J. Clin. Endocrinol. Metab. 88, 2206 – 2212 Willi syndrome. Biol. Psychiatry 44, 1321 – 1328 68 DiMario, F.J.J. et al. (1996) Respiratory sinus arrhythmia in patients 83 Shapira, N.A. et al. (2002) Topiramate attenuates self-injurious with Prader-Willi syndrome. J. 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Genet. 10, 1465 – 1473 Congress of Endocrinology, Lyon, France, p 358 Endeavour the quarterly magazine for the history and philosophy of science Sex glands, vasectomy and the quest for rejuvenation by C. Sengoopta Global science: the eruption of Krakatau by M. Doerries ¨ Two pills, two paths: a tale of gender bias by M. Potts Locate Endeavour in the BioMedNet Reviews collection. (http://reviews.bmn.com) or on ScienceDirect (http://www.sciencedirect.com) http://tem.trends.com

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