1. 12 Review TRENDS in Endocrinology and Metabolism Vol.15 No.1 January/February 2004
Prader-Willi syndrome: advances in
genetics, pathophysiology and
Anthony P. Goldstone1,2
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
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 . 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) .
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 
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 (email@example.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
" Bone mineral density
" Lipolysis and resting energy
Orchidopexy/orchidectomy Prevent testicular carcinoma Repositioning or removal of 
Dietary and behavioural Prevent obesity and complications Reduced caloric intake Intervention difﬁcult [41– 43,86]
modiﬁcation Control maladaptive behavioural Behavioural adaptation Impact on family
Exercise Prevent obesity and complications " Energy expenditure 
" Muscle strength and agility
Noninvasive intermittent # Respiratory failure and cor Reduce nocturnal hypoxia and Tolerability 
positive pressure ventilation pulmonale hypercapnia
(NIPPV) # Daytime somnolence
Continuous positive airway # Cardiorespiratory and sudden deathd
Speech therapy Improve articulation and pragmatic 
Scoliosis surgery # Orthopaedic complications Correct spinal deformity " Morbidity and mortality 
" 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 
(phenothiazines or atypical # Aggressive behaviour antagonists Weight gaind
Sex steroidsc " Bone mineral density Anabolic actions on bone, fat Oestrogen: " thrombosis risk, 
# Fracture rated and muscle menstruation
Improve body compositiond Testosterone: " aggressive behaviour,
" Muscle strength (androgens)d prostatic hypertrophyd
GH in infants " Muscle strengthd Developmental and anabolic Glucose intolerance 
" Brain development and IQd actions of GH
GH in adults Improve body composition Anabolic and CNS actions of Glucose intolerance 
" Muscle strengthd GH Arthralgia and oedema
" Psychological well beingd
Topiramate # Skin picking " GABA activity Neurological side effects 
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
Effect of hyperghrelinaemia in PWS
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
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
CNS acting anorexigenic # Food intake and obesityd Stimulate anorexigenic and CNS developmental defects prevent actiond [73,93]
drugs inhibit orexigenic CNS Side-effect proﬁle
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.
Abbreviations: GABA, g-aminobutyric acid; GH, growth hormone; GHS-R, growth hormone secretagogue receptor; IGF-I, insulin-like growth factor-I.
Indicates therapies in routine use for which there is little or no published data on effectiveness, beneﬁts and risks.
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 . 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
3. 14 Review TRENDS in Endocrinology and Metabolism Vol.15 No.1 January/February 2004
(a) (b) PWS AS Non-imprinted
? Minimal critical region
β3 α5 γ3
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
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 . 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 .
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) . 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 . 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  (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 . 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
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 , 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 . 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 , 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 , 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 ,
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  and might have a similar increased metabolic rate relative to body size. This is related to the
predisposition to psychosis as UPD . Subjects with abnormal body composition and further contributes to the
deletions have a higher frequency of hypopigmentation of reduction in 24 h energy expenditure . 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 .
oculocutaneous albinism .
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 .
appropriate dietary and behavioural input, is sustained In PWS children, therapy with GH signiﬁcantly
into adulthood . 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 . 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 . Although increases in fasting insulin and
this behaviour involves early institution of a low-calorie, reduced glucose elimination rates have been seen during
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 , 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 . Orexin neurons in the
additional beneﬁts to starting GH therapy in early infancy lateral hypothalamic area have a primary role in control-
, 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 , but orexin neurons
death syndrome in PWS children . 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 , 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 . These hormones
talia, including micropenis, whereas girls have hypo- and neuropeptides also regulate the HP axis, sleep and
plastic labia minora . 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 . 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 . 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 .
ment with a selective 5-HT re-uptake inhibitor (SSRI) , 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 . However, because these mice pathways [64 –66], and is not related to GH deﬁciency .
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 . It has been suggested
Sex-hormone replacement therapy in PWS adults is that chronic overstimulation of the GHS-R in the
inconsistently prescribed . 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 , 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 . 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 . 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
, the beneﬁts of sex steroids and bisphosphonates have PWS patients , because with some operations ghrelin
yet to be examined in a controlled manner. The prescription secretion can be markedly reduced in nonPWS subjects .
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 . 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
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% , which is less than that reported in is, however, necessary to exclude relative differences in cell
control subjects . 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) . 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 . 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 . 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 , 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 . 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 , 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 . 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 .
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 . † Normal increase in the number of GHRH neurons in the INF during
† Long isoform leptin receptor mRNA expressed in lymphocytes . illness .
† 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 .
† Normal cholecystokinin secretion . † Reduced number of GHRH neurons in the INF in PWS children
† Normal distribution of neuropeptide Y (NPY), agouti-related receiving exogenous treatment with GH .
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) .
nucleus (INF) [77.78]. † Reduced number of total (38%) and oxytocin (42%)-containing
† Normal colocalization of NPY and AGRP in INF neurons . neurons in the PVN .
† Normal increase in NPY, measured by either immunocytochemical † Normal number of vasopressin-containing neurons in the PVN .
(ICC) staining or mRNA expression, or AGRP (ICC staining) in INF † Normal distribution of neurons that contain cocaine- and amphet-
during illness . amine-regulated transcript (CART) in the INF, PVN and lateral
† Reduced NPY (either ICC staining or mRNA expression) in INF, hypothalamic area (LHA) .
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 . 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 . neurons in the PVN in Ndn-knockout mice .
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
† What is the link between individual genes for PWS and speciﬁc † Are defects in the autonomic nervous system important in PWS
† 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?
† 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 ; ﬁnancial support from Merck Research
monoamine metabolites in the CSF  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
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