Review

12

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
Present address: Department of Pediatric Genetics, Box 100296, University of Florida College of Medicine, Gainesville,
FL 32610-0296, USA
2

Prader-Willi syndrome (PWS) is a complex human
genetic disease that arises from lack of expression of
paternally inherited imprinted genes on chromosome
15q11-q13. Identification of the imprinting control
centre, novel imprinted genes and distinct phenotypes
in PWS patients and mouse models has increased interest in this human obesity syndrome. In this review I
focus on: (i) the chromosomal region and candidate
genes associated with PWS, and the possible links with
individual PWS phenotypes identified using mouse
models; (ii) the metabolic and hormonal phenotypes in
PWS; (iii) postmortem studies of human PWS hypothalami; and (iv) current and potential advances in the
management of PWS and its complications. This could
have benefits for a wide spectrum of endocrine, paediatric and neuropsychiatric diseases.

Prader-Willi syndrome (PWS) is a genetic human obesity
syndrome (Figure 1a) with characteristic phenotypes,
including gross hyperphagia, hypogonadism and GH
deficiency, that indicate hypothalamic dysfunction (Box 1)
[1,2]. A recent epidemiological study estimates an incidence of , 1 in 25 000 births, and a population prevalence
of ,1 in 50 000 [3]. In this article, I review current
knowledge of the genes involved in PWS, their possible
links with individual PWS phenotypes and current and
potential treatment strategies (Table 1).
PWS genetics
PWS arises from the lack of expression of genes on the
paternally derived chromosome 15q11-q13 (Figure 1b) [4].
Candidiate genes for PWS in this region are imprinted and
silenced on the maternally inherited chromosome. PWS

Box 1. Diagnostic criteria for Prader-Willi syndrome [2]
Major criteria
† Neonatal and infantile hypotonia, with poor suck and subsequent
improvement with age.
† Feeding problems and poor weight gain in infancy, needing gavage or
other special feeding techniques.
† Weight gain (rapid onset at 1–6 years old), which leads to central
obesity.
† Characteristic facial features, including narrow bifrontal diameter,
almond-shaped palpebral fissures and down-turned mouth.
† Hypogonadism/hypogenitalism: genital hypoplasia (small labia minora and clitoris in females, and hypoplastic scrotum in males);
incomplete and delayed puberty, and infertility.
† Developmental delay/mild-to-moderate mental retardation/multiple
learning disabilities.
† Hyperphagia/obsession with food.
† Chromosome 15q11-q13 abnormality.

† Hypopigmentation.
† Small hands and feet for height and age.
† Narrow hands with straight ulnar border.
† Eye abnormalities, including esotropis and myopia.
† Thick viscous saliva.
† Speech articulation defect.
† Skin picking.

Additional features

Minor criteria

† High pain threshold.
† Decreased vomiting.
† Altered temperature sensitivity.
† Scoliosis or kyphosis.
† Early adrenarche.
† Osteoporosis.
† Unusual skill with jigsaw puzzles.
† Normal neuromuscular studies (e.g. muscle biopsy and electromyography).

† Reduced foetal movement and infantile lethargy, which improves
with age.
† Characteristic behavioural problems, including temper tantrums,
obsessive–compulsive behaviour, stubbornnesss, rigidity, stealing
and lying.
† Sleep disturbance or apnoea.
† Short stature for family by 15 years of age.

Major criteria are weighted at one point each and minor criteria at onehalf point each. For children , 3 years of age, five points are required for
diagnosis, four of which must be major criteria. For individuals . 3 years
of age, eight points are required for diagnosis, five of which must be
major criteria. Supportive findings only increase or decrease the level of
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

missing or silenced.8].com established either during or after gametogenesis and maintained throughout embryogenesis [5]. d Indicates unclear or uncertain effects. The spectrum of neuroendocrine disturbances in PWS indicates developmental abnormalities of the hypothalamus [7.86] [50] Tolerability [87] [88] Correct spinal deformity " Morbidity and mortality [89] Inhibit 5-HT re-uptake Side-effect profile Return of menses and pregnancy riskd Side-effect profile Weight gaind [41. b Abbreviations: GABA.93] Potential use GH in infants GH in adults Topiramate Theoretical use Somatostatin analogues [63– 66] [72– 76] a Treatments for diabetes mellitus.g. There is no data indicating whether the choice of agent in PWS should be different to the general population and particularly those with obesity.15 No. menstruation Testosterone: " aggressive behaviour.92] Ghrelin antagonists # Food intake and obesityd Block orexigenic GHS-R in hypothalamus ^ vagal afferents Anorexigenic gut hormones e. compulsivity # Depression. Paternally expressed genes are particularly important .trends.6]. c Indicates therapies in routine use for which there is little or no published data on effectiveness. g-aminobutyric acid.b Treatment used currently Benefits Mechanism Special feeding GH in children Improve infantile nutrition " Growth velocity and final height # Total body fat. pancreatic polypeptide CNS acting anorexigenic drugs # Food intake and obesityd Anorexigenic actions in hypothalamus and brainstem Glucose intolerance Gallstones Suppression of GH/IGF-I axis Already relative # hyperinsulinaemia in PWSd Effect of hyperghrelinaemia in PWS unknown Suppression of GH/IGF-I axisd CNS developmental defects prevent actiond Drug availability Effect of hyperghrelinaemia in PWS unknown CNS developmental defects prevent actiond Delivery method # Food intake and obesityd Stimulate anorexigenic and inhibit orexigenic CNS pathways CNS developmental defects prevent actiond Side-effect profile [73. growth hormone secretagogue receptor. PYY3 –36.1 January/February 2004 Table 1. prostatic hypertrophyd [85] " Muscle strengthd " Brain development and IQd Improve body composition " Muscle strengthd " Psychological well beingd # Skin picking Developmental and anabolic actions of GH Anabolic and CNS actions of GH Glucose intolerance [69] Glucose intolerance Arthralgia and oedema [52] " GABA activity Neurological side effects [83] # Obesityd(benefit in paediatric hypothalamic obesity from tumours) # Hyperinsulinaemia # Ghrelin secretiond [91. 1% of cases. maternal uniparental disomy (UPD) in 22%. benefits and risks. and in its postzygotic maintenance [4. Imprinting occurs partly through parent-of-origin allele-specific methylation of CpG residues. IGF-I.5. aggressive behaviour Acute control of psychotic episodes # Aggressive behaviour Repositioning or removal of testes Reduced caloric intake Behavioural adaptation Difficulties and potential adverse effects Refs Glucose intolerance Worsening scoliosisd [8.43] Dopamine and 5-HT antagonists [43] " Bone mineral density # Fracture rated Improve body compositiond " Muscle strength (androgens)d Anabolic actions on bone. GHS-R. risperidone)c Sex steroidsc Prevent obesity and complications Control maladaptive behavioural problems Prevent obesity and complications " Muscle strength and agility # Respiratory failure and cor pulmonale # Daytime somnolence # Cardiorespiratory and sudden deathd Improve articulation and pragmatic skills # Orthopaedic complications " Lung capacity # Skin-picking. nasogastric tube Anabolic actions of GH Orchidopexy/orchidectomy Dietary and behavioural modification Exercise Noninvasive intermittent positive pressure ventilation (NIPPV) Continuous positive airway pressure (CPAP) Speech therapy Scoliosis surgery Selective serotonin reuptake inhibitors (SSRI)b Antipsychotics (phenothiazines or atypical e. and there is a paternal chromosomal translocation in .g. there is paternal deletion of 15q11-q13. growth hormone. insulin-like growth factor-I. Specific treatment options in Prader-Willi syndromea. fat and muscle Oestrogen: " thrombosis risk. GH. imprinting errors in 3% because of either a sporadic or inherited microdeletion in the imprinting centre (IC).1] [85] Intervention difficult Impact on family " Energy expenditure Reduce nocturnal hypoxia and hypercapnia [41– 43. The IC has a role in both establishing the paternal imprint. by erasing the grandmaternal imprint during spermatogenesis. In 75% of cases.Review TRENDS in Endocrinology and Metabolism 13 Vol. " lean body mass " Physical and respiratory muscle strength " Bone mineral density " Lipolysis and resting energy expenditure Prevent testicular carcinoma Special teats. which is http://tem. develops if the paternal alleles are defective. hypertension. hyperlipidaemia and osteoporosis are not included.

hypotonia.bmn. infantile sudden death. neonatal lethality and growth retardation in survivors is seen in several mouse models of PWS. although mice that survive neonatal failureto-thrive can be small. Imprinted genes in the PWS chromosomal region Several candidate genes in the human 15q11-q13 region and syntenic mouse chromosome 7C display monoallelic paternal expression (Figure 1b. in the development of PWS http://tem.and mouse homologues MBII-) [12 – 16]. fibroblasts or brain tissue from PWS subjects. hypotonia. such as small hands and feet. have not been reported [17 – 19].1 January/February 2004 PWS AS Non-imprinted ? Minimal critical region 43 8B HBII-52 (47copies) HB II- HB I HB I-43 HBII-1 6 II 3 HB -43 II. including respiratory problems. the relative positions of identified exons and other transcripts within the SNURF-SNRPN locus. With the exception of NDN and MAGEL2.bmn. These include: (i) maternal duplication of chromosome 7 (UPD). (iii) deletion of the IC and Snurf-Snrpn exons 1 – 6. Imprinted genes are in blue (paternal allele expressed) and red (maternal allele expressed). Although the position of balanced translocations and submicroscopic deletions that involve the PWS region indicates the relative importance of the snoRNAs.com/supp/tem/ Goldstone_Table2. SNURF-SNRPN is an extremely complex gene locus that spans . but Ndn-deficient neonates die from respiratory distress. Nonimprinted genes are in green. This mimics recognized PWS phenotypes. and imprinting leakage. it is absent in lymphocytes. MBII-52 snoRNAs. Studies in mice have not reported any phenotype with smaller deletions of individual exons of Snurf-Snrpn [11.bmn.com phenotypes.pdf).22]. (a) A 17-year-old female with PWS.7 43 8A HBII-85 (27copies) X X BP1 BP2 GABR UBE3A MK cen RN 3 M AG EL ND 2 N snoRNAs P β3 α5 γ3 X exons 1-3 4-10 13-20 SNURF SmN PAR-5 21 52 62 PAR-7 IPW PAR-1 63 142 144 PAR-4 148 ATP10C tel BP3 UBE3A-AS PWCR1 SNURF-SNRPN PWS imprinting centre TRENDS in Endocrinology & Metabolism Figure 1. and survivors have increased skin-scraping activity. growth retardation.Review 14 (a) TRENDS in Endocrinology and Metabolism (b) Vol. and (iv) a more specific deletion between exon 2 of Snurf-Snrpn and Ube3a that does not involve the IC [4.22]. tissue. Prader-Willi syndrome (PWS): from genes to phenotype. This locus also encodes the novel.24]. no mouse model of PWS is obese or infertile. Possibilities include species differences in gene structure. their function is unknown at present (see supplementary information Table 2 http://archive. as indicated by the hypothalamic accumulation of androgenetic (duplicated paternal genome) cells in chimeric mouse embryos [9]. pdf) [4. The reasons why the phenotype is limited remains unclear. com/supp/tem/Goldstone_Table2.23.465 kb. The black crosses indicate common breakpoint (BP) regions for deletions. the detailed neuroanatomical location of RNA and proteins. with . small nucleolar RNAs (snoRNAs) that do not encode proteins (human homologues are prefixed HBII. Mutations and deletions of individual genes have not yet been reported in PWS or in patients with specific PWS phenotypes [4]. The promotor and first exon of the SNURF-SNRPN gene locus appears to be an integral part of the IC in the PWS chromosomal region [10. However. in hypothalamic development. viscous saliva and genital hypoplasia are also indicated by the embryonic and postnatal expression of the mouse homologues Ndn and Magel2 outside the brain (see supplementary information Table 2 http://archive.and cell-expression patterns. Vertical bars indicate snoRNA transcripts and horizontal bars.and strain-specific modifier genes. copy variants. Potential roles for NDN and MAGEL2 genes in other PWS phenotypes. dysmorphic mouth. with an abnormal respiratory rhythm-generating centre in the medulla. articulation defects.com/supp/tem/ Goldstone_Table2. that is located adjacent to the PWS locus. in which a transgene is inserted into the whole PWS syngenic region in the paternal chromosome 7C. 148 possible exons that undergo alternative splicing [12].bmn.pdf) [4. including their hypothalamic localization. (b) PWS chromosomal region on 15q11-q13 (not to scale) showing the genetic map of the 2 Mb PWS region. It is also possible that the . (ii) PWS deletion.15 No.21. There are strain-dependent variations in survival rates.11].13]. skinpicking and unusual skill with jigsaws [25– 27]. with the exception of the role of NDN in neural differentiation and survival. Although expression is more widespread and occurs outside the brain in humans compared with mice.pdf) [4]. Purple arrows indicate the area of regional imprint control through the imprinting centre at the 50 end of the bicistronic SNURF-SNRPN locus. Mouse models of PWS A consistent phenotype of failure-to-thrive. neuroendocrine and metabolic pathways. Also indicated are the overlapping sense and antisense transcripts of the Angelman syndrome (AS) gene. see supplementary information Table 2 http://archive.11. especially the HBII-85 cluster. the function of these genes is poorly understood [20]. Furthermore. function. UBE3A.com/supp/tem/Goldstone_Table2. Zfp127 and Ipw [4] (see supplementary information Table 2 http://archive.trends. and species.19]. improved spatial learning and structural abnormalities of the hypothalamus [18.

food stealing. and earlier return of hunger after eating. Body composition and energy expenditure Body-composition studies show both increased body fat and reduced muscle in PWS [44. This is being addressed by the development of further gene-specific knockout mice.com Vol. and some genotype– phenotype correlations in PWS indicate other differences [32– 35]. is not benefial in treating hyperphagia and obesity. psychosis is almost exclusively restricted to PWS adults with UPD rather than deletions [31]. and might indicate potential therapies for both PWS and nonsyndromal obesity. PWS subjects with IC mutations appear to have a classical PWS phenotype [36] and might have a similar increased predisposition to psychosis as UPD [37]. Interestingly. Magnetic resonance imaging has found a selective relative reduction in visceral adiposity in PWS adults. and an increased prematurity rate reaching 34% in a recent study [*]. without appropriate dietary and behavioural input.Review TRENDS in Endocrinology and Metabolism mice that would have developed such phenotypes die during the postnatal period. This has usually improved significantly by 6 months of age. Growth retardation and growth hormone (GH) deficiency Mild prenatal growth retardation is common. There is a rapid onset of hyperphagia and obesity between the ages of 1 – 6 years. which protects against the metabolic consequences of obesity. http://tem. tissue. as with mutations that lead to rare monogenic cases of obesity [28]. Spontaneous and pharmacologically stimulated secretion of GH and the concentration of insulin-like growth factor I are reduced in both children and adults. rigorous supervision. and appropriate psychological and behavioural counselling of the patient and family [41– 43]. Short stature is almost always present. with a birth weight of . Although increases in fasting insulin and reduced glucose elimination rates have been seen during . There is a reduced resting metabolic rate relative to body size. thiazolidinediones and alternative insulin regimes). which is related to obesity.38]. Reduced parasympathetic innervation of visceral adipocytes or absent expression of PWS genes in these cells. but possible differences in PWS have not been addressed systematically. restriction of access to food and money. such as cardiopulmonary disease. Physical activity is significantly reduced in PWS [49]. although there are few published control studies [41. In PWS children. is sustained into adulthood [40]. but finer mapping has not been reported. Managing this behaviour involves early institution of a low-calorie. antihypertensive and lipid-lowering agents will be guided by those used in the general population with obesity. Long-term studies show that the final height is in the average range for age [8.47].15 No. such as insulin resistance and hypertriglyceridaemia [46.34. This unusual situation occurs despite the presence of many phenotypes that should increase visceral adiposity. Increased physical activity and exercise programs are beneficial in improving body composition in PWS [50]. type 2 diabetes mellitus.48]. Without adequate dietary control.35 years [40]. or even childhoodonset GH deficiency. A recent genomewide scan found linkage between childhood-onset severe obesity in French Caucasian families and an area on chromosome 15q that includes the PWS region [30]. Although PWS is a pleiotropic syndromal condition. which is caused by loss of expression of the nonimprinted P gene that is involved in oculocutaneous albinism [39].5 kg in 41% of cases. transgenic rescue of phenotypes and the use of different mouse strains. Neuroendocrine and metabolic abnormalities Hyperphagia and obesity In babies with PWS. the extreme hyperphagia in PWS leads to obesity-related morbidity. hypersomnolence and persistent. Pharmacological treatment. including anorexigenic agents that act through central monoamine and 5-hydroxytryptamine (5-HT) pathways. The choice and use of specific antidiabetic (particularly metformin. Potential novel therapies to control hyperphagia in PWS are outlined in Table 1. respiratory muscle hypotonia and the reduced peripheral chemoreceptor sensitivity to carbon dioxide [8]. Subjects with deletions have a higher frequency of hypopigmentation of skin. This hints that the dosages of genes in the PWS region that do not display monoallelic paternal expression might have phenotypic consequences. lipolysis and resting energy expenditure. and improves physical strength. chronic leg oedema and mortality at . especially if different genes are involved in different phenotypes of PWS. stealing money to buy food. The abnormal feeding behaviour includes a morbid obsession with food. which. therapy with GH significantly improves the rate of growth and final height. and no association between NDN polymorphisms and obesity in children and adolescents has been identified [29].2.51]. poor muscle strength.and neuron-specific gene modulation). Studies also show that GH significantly decreases total body fat. poor suck and feeding difficulties mean that special feeding strategies are usually required for weeks to months to prevent failure-tothrive. Group homes specifically designed for individuals with PWS are particularly succesful in managing these problems during adulthood.45].1 January/February 2004 15 well-balanced diet. Relevance to non-PWS phenotypes Identifying neuroendocrine abnormalities in PWS could provide information on the important hypothalamic pathways and peripheral inputs that are involved in the regulation of body weight. Cre/lox knockout systems (which allow temporal-. postnatal hypotonia. This is related to the abnormal body composition and further contributes to the reduction in 24 h energy expenditure [45]. The PWS chromosomal region was not linked with obesity in earlier sibling studies.trends.43]. it is possible that polymorphisms in genes in the PWS region could play a role in nonPWS obesity. hording and foraging. pica behaviour. thrombophlebitis. reduced satiety. with regular exercise. hair and eyes [33. agility. and GH is now licensed for use in PWS. It also increases lean body mass. might be responsible [46. because of both GH deficiency and the lack of a pubertal growth spurt. and GH deficiency is independent of obesity [8].

because of hypothalamic defects. Miller.). peripheral signals and the brain Plasma leptin. there have been recent concerns about a possible unproven involvement of GH therapy in anecdotal cases of sudden death syndrome in PWS children [25]. and obesityrelated polycystic ovarian syndrome in women. but one possibility is abnormal parasympathetic vagal innervation of the stomach resulting from abnormalities in either the hypothalamus or brainstem [68]. The prescription of testosterone therapy to PWS males has been complicated by anecdotal reports of increased aggressive behaviour. which http://tem. although estradiol levels in females can be in the early follicular range. adipocyte-derived hormone. Ghrelin is secreted primarily by the stomach.16 Review TRENDS in Endocrinology and Metabolism GH therapy. and prospective studies are ongoing. Recent studies have found fasting levels of ghrelin in the plasma are grossly elevated in adults and children with PWS [64– 66]. Orexin concentrations in the cerebro– spinal fluid (CSF) are low in a single reported case of PWS with hypersomnia [61]. sleep and arousal. which indicates that underactivity of 5-HT pathways might be part of the mechanism of HP-gonadal suppression. but orexin neurons have not been examined in PWS hypothalami. Gonadotrophin releasing hormone neurons have not yet examined in postmortem hypothalami from humans with PWS. There is no evidence of either absolute or relative deficiency of leptin in PWS. such as somatostatin analogues. perhaps through densensitization of GHS-R or a reduction in receptor number. This might also result from abnormal parasympathetic vagal tone. the effect on reproductive function is unclear. However. Orexin neurons in the lateral hypothalamic area have a primary role in controlling sleep and arousal. and ghrelin. Hypothalamic –pituitary (HP)– gonadal axis Boys with PWS usually have hypoplastic external genitalia. and stimulates secretion of GH releasing hormone (GHRH) and GH [63]. including the GH dosage regime and IGF-I levels.56]. at least if dietary control is maintained. because with some operations ghrelin secretion can be markedly reduced in nonPWS subjects [90]. It has been suggested that chronic overstimulation of the GHS-R in the hypothalamus and/or pituitary by elevated circulating ghrelin. and is not related to GH deficiency [67]. but gonadal maturation is usually either delayed or incomplete. Sex-hormone replacement therapy in PWS adults is inconsistently prescribed [40]. which could contribute to their hyperphagia. including monogenic defects in leptin and melanocortin pathways [64 –66]. sex steroids and GH [8]. Hyperphagia. A potential benefit of lower doses of GH to improve body composition in PWS adults has been reported [52]. two fertile females with PWS have been reported [54. it is important to examine whether there is reduced post-prandial secretion . What causes impairment of the HP – gonadal axis is unknown. which is located in the hypothalamus and pituitary. as well as primary gonadal failure. However. leads to reduced GH secretion [65]. The development of ghrelin antagonists and drugs that lower plasma ghrelin.40. It has components of hypogonadotrophic hypogonadism.1 January/February 2004 responds to weight loss [58]. possibly because of increased aromatization by excess adipose tissue. which is probably related to frequent cryptorchidism in males [40. will help clarify its role in PWS phenotypes (Table 1). the benefits of sex steroids and bisphosphonates have yet to be examined in a controlled manner. In one case. Driscoll and J. the orexigenic. Post-prandial secretion of the anorexigenic pancreatic polypeptide (PP) from the gastrointestinal tract is reduced markedly in PWS subjects [71]. which results from the lack of bone-maturating effects of puberty. with frequent delay in menarche. and fall after meals. It is also found in hypothalamic neurons and the pituitary. Although cholecystokinin secretion appears normal.15 No. the anorexigenic. ghrelin and other gastrointestinal hormones The hypothalamic neuropeptide pathways that regulate feeding and energy expenditure are targets for leptin. As well as obesity-related sleep apnoea. commun. as might revisiting the effects of gastric bypass in PWS patients [70]. regular menstruation and pregnancy followed treatment with a selective 5-HT re-uptake inhibitor (SSRI) [54].trends. because these mice are not infertile. PWS subjects have defective central respiratory drive [24. There might also be additional benefits to starting GH therapy in early infancy [69]. Its cause and organ source are unknown. should be carefully monitored in specialized centers (D. This does not occur with other causes of obesity. Ndn-knockout mice have a 25% reduction in neurons that contain luteinising hormone releasing hormone in the medial pre-optic area [18]. a recent study of 58 patients reported that 22% had had more than one fracture [57]. whereas girls have hypoplastic labia minora [53]. Male adults usually have low testosterone levels. Recently. and mediate endocrine changes during starvation and illness.59] and abnormalities in rapid-eye-movement sleep [60]. Noninvasive ventilatory support can help to reverse hypercapnoeic respiratory failure (Table 1). Patients with PWS have reduced bone-mineral density (BMD) and content [44.53]. Sleep and respiratory problems Daytime hypersomnolence occurs in 70 –95% of PWS subjects. Studies are also investigating whether there might be a worsening of sleep apnoea in a subset of patients. primary amenorrhoea and oligomenorrhoea [8. This puts patients at increased risk of osteoporosis. Ghrelin stimulates food intake acutely in humans. and chronic administration to rodents causes obesity [63]. and plasma levels peak when fasting and before starting a meal. This emphasizes that such treatment.com Vol.85]. and further studies are proceeding. expression of OBRb in human PWS hypothalami has not been reported.55]. These hormones and neuropeptides also regulate the HP axis. pers. including micropenis. Adrenarche can occur early. However. the development of glucose intolerance and diabetes mellitus does not appear to be a problem. and the fully functional long isoform of the leptin receptor (OBRb) is present in PWS lymphocytes [45]. Ghrelin is an endogenous ligand of the GH-secretagogue receptor (GHS-R). stomach-derived hormone [62]. Although treatment of children with GH improves BMD [51].

Hypothalamic neuropeptides and their signalling inputs in Prader-Willi syndrome (PWS) † † † † † † † † † † † Normal leptin secretion [45]. Interestingly. http://tem. neonatal mice with a PWS deletion have reduced concentrations of AGRP mRNA and increased concentrations of POMC mRNA that could contribute to their failure to thrive [81]. such as PYY3 – 36 from the intestinal L-cells in PWS because this might suggest potential therapeutic avenues [72– 74].47. † Normal distribution of neurons that contain cocaine. † Normal number of vasopressin-containing neurons in the PVN [27]. and no obvious excess of neurons that contain orexigenic melanin-concentrating hormone in PWS hypothalami (Box 2) [47.com † Normal increase in the number of GHRH neurons in the INF during illness [78]. but not nonPWS obese adults. compared with control. which are inhibited by leptin [62.77. † Reduced number of total (38%) and oxytocin (42%)-containing neurons in the PVN [27]. and other brain regions.78].77]. which is less than that reported in control subjects [76]. and NPYoveractivity also causes hypogonadism and GH deficiency [62]. and obesity probably results from a nonselective loss of PVN neurons [80]. PVN and LHA is not complete [47. However. amygdala. corrected for the duration of premorbid illness [77]. that contains orexigenic neuropeptide Y (NPY) and agouti-related protein (AGRP) neurons. NPY-. However. which indicates that Vol. Normal distribution of neuropeptide Y (NPY). interpretation is complicated by the small number of samples and the effects of premorbid illness. as with all gut homones that alter appetite. Reduced fasting and post-prandial insulin secretion [46. The lack of obesity in mouse models of PWS limits their usefulness in studying the causes of hyperphagia. PVN and lateral hypothalamic area (LHA) [47]. † Normal distribution of oxytocin and vasopressin neurons in the paraventricular nucleus (PVN) [27]. noradrenaline.and amphetamine-regulated transcript. However.1 January/February 2004 17 these neurons respond normally to alterations in peripheral signals. and mutations in genes that encode POMC and MC4 receptors lead to childhood-onset obesity in humans [28].27. Normal cholecystokinin secretion [74]. or AGRP (ICC staining) in INF during illness [77].77]. AGRP. AGRP antagonizes the effect of a-melanocyte stimulating hormone (a product of POMC) at melanocortin-4 (MC4) receptors. although these mice are not obese. Preliminary studies also found no evidence of a lack of anorexigenic POMC-containing neurons and neurons that contain cocaine. † Deficiency of POMC-containing neurons in INF.and GHRH-containing neurons respond appropriately to illness. however. Hypothalamic feeding and growth neuropeptides Ghrelin stimulates feeding by activating neurons in the hypothalamic arcuate nucleus [called the infundibular nucleus (INF) in humans]. Reduced post-prandial secretion of pancreatic polypeptide [71.15 No. corrected for the duration of premorbid illness and gender [78]. and CART neurons in INF. † Reduced number of luteinising hormone releasing hormonecontaining neurons in the pre-optic area and oxytocin-containing neurons in the PVN in Ndn-knockout mice [18]. corrected for the duration of premorbid illness [77]. GH deficiency and hypogonadism [77. it is conceivable that their target CNS pathways do not respond normally in PWS. SIM1 encodes a transcription factor involved in neurogenesis.trends.77]. agouti-related protein (AGRP). † Normal number of GHRH neurons in the INF compared to control and nonPWS obese adults. compared to control and nonPWS obese adults. † Reduced number of GHRH neurons in the INF in PWS children receiving exogenous treatment with GH [78].84]. Quantitative neuroanatomical studies of postmortem human tissue from the Netherlands Brain Bank [7.78]. Increased fasting plasma ghrelin [64 –66]. Haploinsufficiency for SIM1 on chromosome 6q16.and GHRH-containing neurons in the INF of PWS hypothalami (Box 2).2 also leads to obesity in humans [79]. can respond normally to hyperghrelinaemia in PWS.74]. Hypothalamic overactivity of NPY and AGRP in rodents leads to hyperphagia and obesity. and ascending 5-HT-. such as the limbic system. Quantitative analysis is. Reduced NPY (either ICC staining or mRNA expression) in INF. . Normal AGRP (ICC staining) in INF. 5-HT and monoaminergic neurons The pathways involved in hyperphagia in PWS could lie in reward and addiction circuits. necessary to exclude relative differences in cell number. pro-opiomelamocortin (POMC) and growth hormone releasing hormone (GHRH) neurons in infundibular nucleus (INF) [77.78] failed to find any abnormalities of NPY-. measured by either immunocytochemical (ICC) staining or mRNA expression. Although this indicates that these neurons might not be involved in the pathogenesis of hyperphagia. Box 2. For example infusing supraphysiological amounts of PP in PWS subjects reduces acute food intake by 12% [75]. There is a reduction in both the total number of cells and of oxytocin-containing cells in the PVN of PWS adults (Box 2) [27].and dopamine-containing pathways from the brainstem. including the paraventricular nucleus (PVN). The INF also includes anorexigenic pro-opiomelanocortin (POMC)-containing neurons that project to similar areas as the NPY. a 29% reduction in PVN oxytocin neurons is also seen in Ndn-knockout mice [18]. These abnormalities might also contribute to peripheral hormonal abnormalities in PWS through projections from the PVN to the brainstem and vagus nerve. it remains to be seen whether the PVN. Normal increase in NPY.63. Given the importance of the INF projections to the PVN in the control of feeding [62].Review TRENDS in Endocrinology and Metabolism of other anorexigenic gut hormones. Long isoform leptin receptor mRNA expressed in lymphocytes [45]. Normal colocalization of NPY and AGRP in INF neurons [77].and amphetamine-regulated transcript (CART) in the INF. This might have a primary role in the hyperphagia associated with PWS because oxytocin has anorexigenic actions in rodents. obesity and exogenous GH therapy in PWS subjects (Box 2). AGRP.and AGRP-containing neurons.

C. S. J. Med. R. The pathophysiological challenge in the coming years will be to link the genetic and phenotypic aspects of the disease. using multidisciplinary studies of PWS mouse models. gene duplications and variant copies. hypertension. 71.1 January/February 2004 Box 3. S. atypical antipsychotics. through identification of pathways involved in appetite control. Genet. E. and how are they best treated? research contributions.F. Proc. Ndn. (2001) Endocrine dysfunction in Prader-Willi syndrome: a review with special reference to GH. Genet. E. with multiple imprinted genes. The genetic complexity of the PWS chromosomal region.L. 669– 678 14 Cavaille. and Knepper.D. Mol. for their http://tem. expression patterns of the Mkrn3. the Royal Society of London. Future studies Many outstanding questions remain in our understanding of this fascinating disease (Box 3). (1997) Prader-Willi syndrome and the hypothalamus. Rev. Topiramate. 2873 – 2879 6 El-Maarri. Frost. especially snoRNAs? † How are genes that are implicated in PWS involved in brain development? † What is the link between individual genes for PWS and specific phenotypes? † What is the role of the expression of genes for PWS outside the brain? † Why do mouse models of PWS have limited phenotypes and why are they not obese? † What is the explanation for phenotypic variation in PWS? † Are there further genotype –phenotype correlations in PWS? † Are genes for PWS involved in similar phenotypes in the general population? † What causes prenatal growth retardation and hypotonia in PWS? † What are the causes of sudden death in PWS children? † What are the causes of the hypothalamic abnormalities in PWS and why are they selective? These neurons might also be involved in the behavioural problems seen in PWS. 2687– 2700 13 Gallagher. Genet. Magel2. T. P. learning disability. potentially. A. This will benefit patients with PWS and. 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