Prader-Willi Syndrome: Advances in Genetics, Pathophysiology and Treatment

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 Bartholomews 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 16 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,
obsessivecompulsive 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 ([email protected]).

http://tem.trends.com 1043-2760/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2003.11.003
Review
13
Table 1. Specific treatment options in Prader-Willi syndromea,b

Treatment used currently
Benefits
Mechanism
Special feeding
GH in children
Improve infantile nutrition

" Growth velocity and final height
# Total body fat, " lean body mass
" Physical and respiratory muscle
strength
" Bone mineral density
" Lipolysis and resting energy
expenditure
Prevent testicular carcinoma
Special teats, 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.g. 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, compulsivity
# Depression, 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
[8,5,1]
[85]
Intervention difficult
Impact on family
" Energy expenditure

Reduce nocturnal hypoxia and
hypercapnia
[41 43,86]
[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
[41,43]
Dopamine and 5-HT

antagonists
[43]
" Bone mineral density

# Fracture rated
Improve body compositiond
" Muscle strength (androgens)d
Anabolic actions on bone, fat

and muscle
Oestrogen: " thrombosis risk,

menstruation
Testosterone: " aggressive behaviour,
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
[91,92]
Ghrelin antagonists
# Food intake and obesityd
Block orexigenic GHS-R in

hypothalamus ^ vagal
afferents
Anorexigenic gut hormones

e.g. PYY3 36, pancreatic
polypeptide
CNS acting anorexigenic
drugs
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
Delivery method
Stimulate anorexigenic and

inhibit orexigenic CNS
pathways

Side-effect profile
[73,93]
Potential use
GH in infants
GH in adults
Topiramate
Theoretical use
Somatostatin analogues
[63 66]
[72 76]
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

silenced. In 75% of cases, there is paternal deletion of
15q11-q13, maternal uniparental disomy (UPD) in 22%,
imprinting errors in 3% because of either a sporadic or
inherited microdeletion in the imprinting centre (IC), and
there is a paternal chromosomal translocation in , 1% of
cases. Imprinting occurs partly through parent-of-origin
allele-specific methylation of CpG residues, which is
http://tem.trends.com
established either during or after gametogenesis and

maintained throughout embryogenesis [5]. The IC has a
role in both establishing the paternal imprint, by erasing
the grandmaternal imprint during spermatogenesis, and
in its postzygotic maintenance [4,6].
The spectrum of neuroendocrine disturbances in PWS
indicates developmental abnormalities of the hypothalamus
[7,8]. Paternally expressed genes are particularly important
Review
14
(a)
(b)
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- 7
43
8A
HBII-85
(27copies)
X X
BP1 BP2
GABR
UBE3A
MK
cen
RN
3
M
AG
EL
ND
2
N
snoRNAs
3 5 3
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. 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. Purple 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 hypothalamic accumulation of androgenetic (duplicated paternal

genome) cells in chimeric mouse embryos [9].
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, see supplementary
information Table 2 http://archive.bmn.com/supp/tem/
Goldstone_Table2.pdf) [4]. Although expression is more
widespread and occurs outside the brain in humans
compared with mice, it is absent in lymphocytes, fibroblasts or brain tissue from PWS subjects. 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 [10,11]. SNURF-SNRPN is an extremely complex
gene locus that spans ,465 kb, with . 148 possible exons
that undergo alternative splicing [12]. This locus also
encodes the novel, small nucleolar RNAs (snoRNAs) that
do not encode proteins (human homologues are prefixed
HBII- and mouse homologues MBII-) [12 16].
With the exception of NDN and MAGEL2, the detailed
neuroanatomical location of RNA and proteins, including
their hypothalamic localization, have not been reported
[17 19]. Furthermore, with the exception of the role of
NDN in neural differentiation and survival, the function of
these genes is poorly understood [20]. Potential roles for
NDN and MAGEL2 genes in other PWS phenotypes, such
as small hands and feet, growth retardation, hypotonia,
articulation defects, dysmorphic mouth, 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.bmn.com/supp/tem/Goldstone_Table2.
pdf) [4,19]. Although the position of balanced translocations and submicroscopic deletions that involve the PWS
region indicates the relative importance of the snoRNAs,
especially the HBII-85 cluster, in the development of PWS
phenotypes, their function is unknown at present (see

supplementary information Table 2 http://archive.bmn.
com/supp/tem/Goldstone_Table2.pdf) [4,13]. Mutations
and deletions of individual genes have not yet been
reported in PWS or in patients with specific PWS
phenotypes [4].
Mouse models of PWS
A consistent phenotype of failure-to-thrive, hypotonia,
neonatal lethality and growth retardation in survivors is
seen in several mouse models of PWS. These include:
(i) maternal duplication of chromosome 7 (UPD); (ii) PWS
deletion, in which a transgene is inserted into the whole
PWS syngenic region in the paternal chromosome 7C;
(iii) deletion of the IC and Snurf-Snrpn exons 1 6; and
(iv) a more specific deletion between exon 2 of Snurf-Snrpn
and Ube3a that does not involve the IC [4,11,21,22].
Studies in mice have not reported any phenotype with
smaller deletions of individual exons of Snurf-Snrpn [11,22],
MBII-52 snoRNAs, Zfp127 and Ipw [4] (see supplementary
information Table 2 http://archive.bmn.com/supp/tem/
Goldstone_Table2.pdf). There are strain-dependent
variations in survival rates, but Ndn-deficient neonates
die from respiratory distress, with an abnormal respiratory
rhythm-generating centre in the medulla, and survivors
have increased skin-scraping activity, improved spatial
learning and structural abnormalities of the hypothalamus
[18,23,24]. This mimics recognized PWS phenotypes, including respiratory problems, infantile sudden death, skinpicking and unusual skill with jigsaws [25 27].
However, although mice that survive neonatal failureto-thrive can be small, no mouse model of PWS is obese or
infertile. The reasons why the phenotype is limited
remains unclear. Possibilities include species differences
in gene structure, function, copy variants, tissue- and
cell-expression patterns, neuroendocrine and metabolic
pathways, and imprinting leakage, and species- and
strain-specific modifier genes. It is also possible that the
Review
mice that would have developed such phenotypes die during

the postnatal period. This is being addressed by the development of further gene-specific knockout mice, Cre/lox
knockout systems (which allow temporal-, tissue- and
neuron-specific gene modulation), transgenic rescue of
phenotypes and the use of different mouse strains.
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, as with mutations that lead
to rare monogenic cases of obesity [28], and might
indicate potential therapies for both PWS and nonsyndromal obesity.
The PWS chromosomal region was not linked with
obesity in earlier sibling studies, and no association
between NDN polymorphisms and obesity in children
and adolescents has been identified [29]. 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], but
finer mapping has not been reported. Although PWS is a
pleiotropic syndromal condition, it is possible that polymorphisms in genes in the PWS region could play a role in
nonPWS obesity, especially if different genes are involved
in different phenotypes of PWS.
Interestingly, psychosis is almost exclusively restricted
to PWS adults with UPD rather than deletions [31], and
some genotype phenotype correlations in PWS indicate
other differences [32 35]. This hints that the dosages of
genes in the PWS region that do not display monoallelic
paternal expression might have phenotypic consequences.
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]. Subjects with
deletions have a higher frequency of hypopigmentation of
skin, hair and eyes [33,34,38], which is caused by loss of
expression of the nonimprinted P gene that is involved in
oculocutaneous albinism [39].
Neuroendocrine and metabolic abnormalities
Hyperphagia and obesity
In babies with PWS, postnatal hypotonia, poor suck and
feeding difficulties mean that special feeding strategies are
usually required for weeks to months to prevent failure-tothrive. This has usually improved significantly by 6
months of age. There is a rapid onset of hyperphagia and
obesity between the ages of 1 6 years, which, without
appropriate dietary and behavioural input, is sustained
into adulthood [40].
Without adequate dietary control, the extreme hyperphagia in PWS leads to obesity-related morbidity, such
as cardiopulmonary disease, type 2 diabetes mellitus,
thrombophlebitis, chronic leg oedema and mortality at
,35 years [40]. The abnormal feeding behaviour includes
a morbid obsession with food, food stealing, stealing money
to buy food, hording and foraging, pica behaviour, reduced
satiety, and earlier return of hunger after eating. Managing
this behaviour involves early institution of a low-calorie,
15
well-balanced diet, with regular exercise, rigorous supervision, restriction of access to food and money, and
appropriate psychological and behavioural counselling of
the patient and family [41 43]. Pharmacological treatment, including anorexigenic agents that act through
central monoamine and 5-hydroxytryptamine (5-HT)
pathways, is not benefial in treating hyperphagia and
obesity, although there are few published control studies
[41,43]. Group homes specifically designed for individuals
with PWS are particularly succesful in managing these
problems during adulthood. The choice and use of specific
antidiabetic (particularly metformin, thiazolidinediones
and alternative insulin regimes), antihypertensive and
lipid-lowering agents will be guided by those used in the
general population with obesity, but possible differences in
PWS have not been addressed systematically. Potential
novel therapies to control hyperphagia in PWS are
outlined in Table 1.
Body composition and energy expenditure
Body-composition studies show both increased body fat
and reduced muscle in PWS [44,45]. Magnetic resonance
imaging has found a selective relative reduction in visceral
adiposity in PWS adults, which protects against the
metabolic consequences of obesity, such as insulin resistance and hypertriglyceridaemia [46,47]. This unusual
situation occurs despite the presence of many phenotypes
that should increase visceral adiposity. Reduced parasympathetic innervation of visceral adipocytes or absent
expression of PWS genes in these cells, or even childhoodonset GH deficiency, might be responsible [46,48].
Physical activity is significantly reduced in PWS [49],
which is related to obesity, hypersomnolence and persistent, poor muscle strength. There is a reduced resting
metabolic rate relative to body size. This is related to the
abnormal body composition and further contributes to the
reduction in 24 h energy expenditure [45]. Increased
physical activity and exercise programs are beneficial in
improving body composition in PWS [50].
Growth retardation and growth hormone (GH) deficiency
Mild prenatal growth retardation is common, with a birth
weight of ,2.5 kg in 41% of cases, and an increased
prematurity rate reaching 34% in a recent study [*]. Short
stature is almost always present, because of both
GH deficiency and the lack of a pubertal growth spurt.
Spontaneous and pharmacologically stimulated secretion
of GH and the concentration of insulin-like growth factor I
are reduced in both children and adults, and GH deficiency
is independent of obesity [8].
In PWS children, therapy with GH significantly
improves the rate of growth and final height. Long-term
studies show that the final height is in the average range
for age [8,51], and GH is now licensed for use in PWS.
Studies also show that GH significantly decreases total
body fat. It also increases lean body mass, lipolysis and
resting energy expenditure, and improves physical
strength, agility, respiratory muscle hypotonia and the
reduced peripheral chemoreceptor sensitivity to carbon
dioxide [8]. Although increases in fasting insulin and
reduced glucose elimination rates have been seen during
16
Review
GH therapy, the development of glucose intolerance and

diabetes mellitus does not appear to be a problem, at least
if dietary control is maintained. There might also be
additional benefits to starting GH therapy in early infancy
[69], and prospective studies are ongoing. However, there
have been recent concerns about a possible unproven
involvement of GH therapy in anecdotal cases of sudden
death syndrome in PWS children [25]. This emphasizes
that such treatment, including the GH dosage regime and
IGF-I levels, should be carefully monitored in specialized
centers (D. Driscoll and J. Miller, pers. commun.). Studies
are also investigating whether there might be a worsening
of sleep apnoea in a subset of patients. A potential benefit
of lower doses of GH to improve body composition in PWS
adults has been reported [52], and further studies are
proceeding.
Hypothalamic pituitary (HP) gonadal axis
Boys with PWS usually have hypoplastic external genitalia, including micropenis, whereas girls have hypoplastic labia minora [53]. Adrenarche can occur early, but
gonadal maturation is usually either delayed or incomplete, with frequent delay in menarche, primary amenorrhoea and oligomenorrhoea [8,40,85]. Male adults usually
have low testosterone levels, although estradiol levels in
females can be in the early follicular range, possibly because
of increased aromatization by excess adipose tissue.
What causes impairment of the HP gonadal axis is
unknown. It has components of hypogonadotrophic hypogonadism, because of hypothalamic defects, and obesityrelated polycystic ovarian syndrome in women, as well as
primary gonadal failure, which is probably related to
frequent cryptorchidism in males [40,53]. Recently, two
fertile females with PWS have been reported [54,55]. In one
case, regular menstruation and pregnancy followed treatment with a selective 5-HT re-uptake inhibitor (SSRI) [54],
which indicates that underactivity of 5-HT pathways might
be part of the mechanism of HP-gonadal suppression.
Ndn-knockout mice have a 25% reduction in neurons
that contain luteinising hormone releasing hormone in the
medial pre-optic area [18]. However, because these mice
are not infertile, the effect on reproductive function is
unclear. Gonadotrophin releasing hormone neurons have
not yet examined in postmortem hypothalami from
humans with PWS.
Sex-hormone replacement therapy in PWS adults is
inconsistently prescribed [40]. Patients with PWS have
reduced bone-mineral density (BMD) and content [44,56],
which results from the lack of bone-maturating effects of
puberty, sex steroids and GH [8]. This puts patients at
increased risk of osteoporosis; a recent study of 58 patients
reported that 22% had had more than one fracture [57].
Although treatment of children with GH improves BMD
[51], the benefits of sex steroids and bisphosphonates have
yet to be examined in a controlled manner. The prescription
of testosterone therapy to PWS males has been complicated
by anecdotal reports of increased aggressive behaviour.
Sleep and respiratory problems
Daytime hypersomnolence occurs in 70 95% of PWS
subjects. As well as obesity-related sleep apnoea, which
responds to weight loss [58], PWS subjects have defective

central respiratory drive [24,59] and abnormalities in
rapid-eye-movement sleep [60]. Orexin neurons in the
lateral hypothalamic area have a primary role in controlling sleep and arousal. Orexin concentrations in the
cerebro spinal fluid (CSF) are low in a single reported
case of PWS with hypersomnia [61], but orexin neurons
have not been examined in PWS hypothalami. Noninvasive ventilatory support can help to reverse hypercapnoeic respiratory failure (Table 1).
Hyperphagia, peripheral signals and the brain
Plasma leptin, ghrelin and other gastrointestinal
hormones
The hypothalamic neuropeptide pathways that regulate
feeding and energy expenditure are targets for leptin, the
anorexigenic, adipocyte-derived hormone, and ghrelin, the
orexigenic, stomach-derived hormone [62]. These hormones
and neuropeptides also regulate the HP axis, sleep and
arousal, and mediate endocrine changes during starvation
and illness. There is no evidence of either absolute or
relative deficiency of leptin in PWS, and the fully functional long isoform of the leptin receptor (OBRb) is present
in PWS lymphocytes [45]. However, expression of OBRb in
human PWS hypothalami has not been reported.
Ghrelin is an endogenous ligand of the GH-secretagogue
receptor (GHS-R), which is located in the hypothalamus
and pituitary, and stimulates secretion of GH releasing
hormone (GHRH) and GH [63]. Ghrelin is secreted
primarily by the stomach, and plasma levels peak when
fasting and before starting a meal, and fall after meals. It
is also found in hypothalamic neurons and the pituitary.
Ghrelin stimulates food intake acutely in humans, and
chronic administration to rodents causes obesity [63].
Recent studies have found fasting levels of ghrelin in the
plasma are grossly elevated in adults and children with
PWS [64 66], which could contribute to their hyperphagia. This does not occur with other causes of obesity,
including monogenic defects in leptin and melanocortin
pathways [64 66], and is not related to GH deficiency [67].
Its cause and organ source are unknown, but one possibility is abnormal parasympathetic vagal innervation of
the stomach resulting from abnormalities in either the
hypothalamus or brainstem [68]. It has been suggested
that chronic overstimulation of the GHS-R in the
hypothalamus and/or pituitary by elevated circulating
ghrelin, leads to reduced GH secretion [65], perhaps through
densensitization of GHS-R or a reduction in receptor
number. The development of ghrelin antagonists and
drugs that lower plasma ghrelin, such as somatostatin
analogues, will help clarify its role in PWS phenotypes
(Table 1), as might revisiting the effects of gastric bypass in
PWS patients [70], because with some operations ghrelin
secretion can be markedly reduced in nonPWS subjects [90].
Post-prandial secretion of the anorexigenic pancreatic
polypeptide (PP) from the gastrointestinal tract is reduced
markedly in PWS subjects [71]. This might also result from
abnormal parasympathetic vagal tone. Although cholecystokinin secretion appears normal, it is important to
examine whether there is reduced post-prandial secretion
Review
of other anorexigenic gut hormones, such as PYY3 36

from the intestinal L-cells in PWS because this might
suggest potential therapeutic avenues [72 74]. However,
as with all gut homones that alter appetite, it is conceivable that their target CNS pathways do not respond
normally in PWS. For example infusing supraphysiological amounts of PP in PWS subjects reduces acute food
intake by 12% [75], which is less than that reported in
control subjects [76].
Hypothalamic feeding and growth neuropeptides
Ghrelin stimulates feeding by activating neurons in the
hypothalamic arcuate nucleus [called the infundibular
nucleus (INF) in humans], that contains orexigenic neuropeptide Y (NPY) and agouti-related protein (AGRP)
neurons, which are inhibited by leptin [62,63,77]. The
INF also includes anorexigenic pro-opiomelanocortin
(POMC)-containing neurons that project to similar areas
as the NPY- and AGRP-containing neurons, including the
paraventricular nucleus (PVN). AGRP antagonizes the
effect of a-melanocyte stimulating hormone (a product of
POMC) at melanocortin-4 (MC4) receptors, and mutations
in genes that encode POMC and MC4 receptors lead to
childhood-onset obesity in humans [28]. Hypothalamic
overactivity of NPY and AGRP in rodents leads to
hyperphagia and obesity, and NPYoveractivity also causes
hypogonadism and GH deficiency [62].
Quantitative neuroanatomical studies of postmortem human tissue from the Netherlands Brain Bank
[7,27,47,77,78] failed to find any abnormalities of
NPY-, AGRP- and GHRH-containing neurons in the INF of
PWS hypothalami (Box 2). Although this indicates that
these neurons might not be involved in the pathogenesis of
hyperphagia, GH deficiency and hypogonadism [77,78],
interpretation is complicated by the small number of
samples and the effects of premorbid illness. However,
NPY-, AGRP- and GHRH-containing neurons respond
appropriately to illness, obesity and exogenous GH
therapy in PWS subjects (Box 2), which indicates that
17
these neurons respond normally to alterations in peripheral signals. Preliminary studies also found no evidence of
a lack of anorexigenic POMC-containing neurons and
neurons that contain cocaine- and amphetamine-regulated transcript, and no obvious excess of neurons that
contain orexigenic melanin-concentrating hormone in
PWS hypothalami (Box 2) [47,77]. Quantitative analysis
is, however, necessary to exclude relative differences in cell
number.
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]. This might have a primary role in the
hyperphagia associated with PWS because oxytocin has
anorexigenic actions in rodents. Haploinsufficiency for
SIM1 on chromosome 6q16.2 also leads to obesity in
humans [79]. SIM1 encodes a transcription factor involved
in neurogenesis, and obesity probably results from a
nonselective loss of PVN neurons [80]. Interestingly, a
29% reduction in PVN oxytocin neurons is also seen in
Ndn-knockout mice [18], although these mice are not
obese. These abnormalities might also contribute to
peripheral hormonal abnormalities in PWS through projections from the PVN to the brainstem and vagus nerve.
Given the importance of the INF projections to the PVN in
the control of feeding [62], it remains to be seen whether
the PVN, and other brain regions, can respond normally to
hyperghrelinaemia in PWS.
The lack of obesity in mouse models of PWS limits their
usefulness in studying the causes of hyperphagia. However, 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].
5-HT and monoaminergic neurons
The pathways involved in hyperphagia in PWS could lie in
reward and addiction circuits, such as the limbic system,
amygdala, and ascending 5-HT-, noradrenaline- and
dopamine-containing pathways from the brainstem.
Box 2. Hypothalamic neuropeptides and their signalling inputs in Prader-Willi syndrome (PWS)
Normal leptin secretion [45].

Long isoform leptin receptor mRNA expressed in lymphocytes [45].
Increased fasting plasma ghrelin [64 66].
Reduced post-prandial secretion of pancreatic polypeptide [71,74].
Reduced fasting and post-prandial insulin secretion [46,84].
Normal cholecystokinin secretion [74].
Normal distribution of neuropeptide Y (NPY), agouti-related
protein (AGRP), pro-opiomelamocortin (POMC) and growth
hormone releasing hormone (GHRH) neurons in infundibular
nucleus (INF) [77.78].
Normal colocalization of NPY and AGRP in INF neurons [77].
Normal increase in NPY, measured by either immunocytochemical
(ICC) staining or mRNA expression, or AGRP (ICC staining) in INF
during illness [77].
Reduced NPY (either ICC staining or mRNA expression) in INF,
compared with control, but not nonPWS obese adults, corrected for
the duration of premorbid illness [77].
Normal AGRP (ICC staining) in INF, compared to control and
nonPWS obese adults, corrected for the duration of premorbid
illness [77].
Normal increase in the number of GHRH neurons in the INF during

illness [78].
Normal number of GHRH neurons in the INF compared to control
and nonPWS obese adults, corrected for the duration of premorbid
illness and gender [78].
Reduced number of GHRH neurons in the INF in PWS children
receiving exogenous treatment with GH [78].
Normal distribution of oxytocin and vasopressin neurons in the
paraventricular nucleus (PVN) [27].
Reduced number of total (38%) and oxytocin (42%)-containing
neurons in the PVN [27].
Normal number of vasopressin-containing neurons in the PVN [27].
Normal distribution of neurons that contain cocaine- and amphetamine-regulated transcript (CART) in the INF, PVN and lateral
hypothalamic area (LHA) [47].
Deficiency of POMC-containing neurons in INF, and CART neurons
in INF, PVN and LHA is not complete [47,77].
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].
18
Review
Box 3. Important outstanding questions in Prader-Willi syndrome (PWS)

What are the function and expression profiles of candidate genes for
PWS, 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, as indicated by abnormalities in
monoamine metabolites in the CSF [82] and the use of
SSRIs to help skin-picking, depression, compulsivity and
aggressive episodes (but not obesity) in some patients with
PWS [41,43]. Mood stabilizers such as lithium and
antiepileptic drugs have also been used, but formal drug
trials have yet to be performed. Anecdotally, atypical
antipsychotics, such as risperidone, benefit some individuals with psychotic features and extreme aggression
[41,43]. Topiramate, an anti-epileptic drug that increases
GABA activity, also reduces skin-picking behaviour, but
has not been shown to help obesity [83].
Future studies
Many outstanding questions remain in our understanding
of this fascinating disease (Box 3). The genetic complexity
of the PWS chromosomal region, with multiple imprinted
genes, alternative splice variants, gene duplications and
variant copies, and the mechanisms of imprinting itself,
are matched by the wide variety of phenotypes that involve
multiple organ systems and the complexity of peripheral
brain circuits. 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, postmortem PWS material and larger
cohorts of PWS patients. This will benefit patients with
PWS and, potentially, many other diseases, through
identification of pathways involved in appetite control,
body composition, growth, reproduction, learning disability, psychosis and other behavioural problems.
Note added in proof
A recent paper has now described in detail the brain, and
particularly hypothalamic, expression patterns of the
Mkrn3, Magel2, Ndn, Snrpn, Ipw and MBII-85 snoRNA
transcripts in the mouse embryo [94].
Acknowledgements
I thank D.F. Swaab, U.A. Unmehopa, staff of Netherlands Brain Bank and
Institute for Brain Research, Amsterdam, A.E. Brynes, E.L. Thomas,
J.D. Bell, G. Frost, M.A. Ghatei, A.J. Holland, S.R. Bloom, for their
Is there a delay in the onset of hyperphagia in PWS beyond

improvement in neonatal hypotonia?
What is the cause and consequence of hyperghrelinaemia in
PWS?
Are defects in the autonomic nervous system important in PWS
phenotypes?
At what age should growth hormone (GH)-treatment be started in
children with PWS?
Is there a role for GH treatment in adults with PWS?
What is the role of sex-steroid replacement in adults with PWS?
Do we manage diabetes mellitus, hypertension, cardiorespiratory
disease and osteoporosis appropriately in PWS?
Are there novel therapeutic avenues for treating hyperphagia in PWS
(e.g. ghrelin antagonists and somatostatin analogues)?
What causes the psychiatric and behavioural phenotypes in PWS,
and how are they best treated?
research contributions; S. Chamberlain for helpful comments; collaborators worldwide for provision of brain material and clinical information
from PWS subjects [74]; financial support from Merck Research
Laboratories, Rahway, USA, Pharmacia and Upjohn, the UK Medical
Research Council, the Royal Society of London, the Royal College of
Physicians (London), PAD 9607; and PWS patients, their families and
carers for their participation in research studies and the inspiration
behind this work.
References
1 Prader, A. et al. (1956) Ein syndrome von adipositas, kleinwuchs,
kryptorchismus und oligophrenie nach myotonieartigem zustand im
neugeborenenalter. Schweiz. Med. Wochenschr. 86, 1260 1261
2 Holm, V.A. et al. (1993) Prader-Willi syndrome: consensus diagnostic
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
syndrome in one UK Health Region. J. Med. Genet. 38, 792 798
4 Nicholls, R.D. and Knepper, J.L. (2002) Genome organization,
function, and imprinting in Prader-Willi and Angelman syndromes.
Annu. Rev. Genomics Hum. Genet. 2, 153 175
5 Guens, E. et al. (2003) Methylation imprints of the imprint control
region of the SRNPN-gene in human gametes and preimplantation
embryos. Hum. Mol. Genet. 12, 2873 2879
6 El-Maarri, O. et al. (2001) Maternal methylation imprints on human
chromosome 15 are established during or after fertilization. Nat.
Genet. 27, 341 344
7 Swaab, D.F. (1997) Prader-Willi syndrome and the hypothalamus. Acta
Paediatr. Suppl. 423, 50 54
8 Burman, P. et al. (2001) Endocrine dysfunction in Prader-Willi
syndrome: a review with special reference to GH. Endocr. Rev. 22,
787 799
9 Keverne, E.B. (1997) Genomic imprinting in the brain. Curr. Opin.
Neurobiol. 7, 463 468
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
switch. Nat. Genet. 25, 74 78
11 Yang, T. et al. (1998) A mouse model for Prader-Willi syndrome
imprinting-centre mutations. Nat. Genet. 19, 25 31
12 Runte, M. et al. (2001) The IC-SNURF-SNRPN transcript serves as a
host for multiple small nucleolar RNA species and as an antisense
RNA for UBE3A. Hum. Mol. Genet. 10, 2687 2700
13 Gallagher, R.C. et al. (2002) Evidence for the role of PWCR1/HBII-85
C/D box small nucleolar RNAs in Prader-Willi syndrome. Am. J. Hum.
Genet. 71, 669 678
14 Cavaille, J. et al. (2000) Identification of brain-specific and imprinted
small nucleolar RNA genes exhibiting an unusual genomic organization. Proc. Natl. Acad. Sci. U. S. A. 97, 14311 14316
15 De Los Santos, T. et al. (2000) Small evolutionarily conserved RNA,
Review
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
resembling C/D box small nucleolar RNA, is transcribed from PWCR1,

a novel imprinted gene in the Prader-Willi deletion region, which is
highly expressed in brain. Am. J. Hum. Genet. 67, 1067 1082
Meguro, M. et al. (2001) Large-scale evaluation of imprinting status in
the Prader-Willi syndrome region: an imprinted direct repeat cluster
resembling small nucleolar RNA genes. Hum. Mol. Genet. 10, 383 394
Niinobe, M. et al. (2000) Cellular and subcellular localization of necdin
in fetal and adult mouse brain. Dev. Neurosci. 22, 310 319
Muscatelli, F. et al. (2000) Disruption of the mouse Necdin gene results
in hypothalamic and behavioral alterations reminiscent of the human
Prader-Willi syndrome. Hum. Mol. Genet. 9, 3101 3110
Lee, S. et al. (2000) Expression and imprinting of MAGEL2 suggest a
role in Prader-Willi syndrome and the homologous murine imprinting
phenotype. Hum. Mol. Genet. 9, 1813 1819
Yoshikawa, K. (2000) Cell cycle regulators in neural stem cells and
postmitotic neurons. Neurosci. Res. 37, 1 14
Gabriel, J.M. et al. (1999) A transgene insertion creating a heritable
chromosome deletion mouse model of Prader-Willi and Angelman
syndromes. Proc. Natl. Acad. Sci. U. S. A. 96, 9258 9263
Tsai, T.F. et al. (1999) Paternal deletion from Snrpn to Ube3a in the
mouse causes hypotonia, growth retardation and partial lethality and
provides evidence for a gene contributing to Prader-Willi syndrome.
Hum. Mol. Genet. 8, 1357 1364
Gerard, M. et al. (1999) Disruption of the mouse necdin gene results in
early post-natal lethality. Nat. Genet. 23, 199 202
Ren, J. et al. (2003) Absence of Ndn, encoding the Prader-Willi
syndrome-deleted gene necdin, results in congenital deficiency of
central respiratory drive in neonatal mice. J. Neurosci. 23, 1569 1573
Nordmann, Y. et al. (2002) Sudden death of an infant with Prader-Willi
syndrome - not a unique case? Biol. Neonate 82, 139 141
Dykens, E.M. (2002) Are jigsaw puzzle skills spared in persons with
Prader-Willi syndrome? J. Child Psychol. Psychiatry 43, 343 352
Swaab, D.F. et al. (1995) Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in
Prader-Willi syndrome: a study of five cases. J. Clin. Endocrinol.
Metab. 80, 573 579
Farooqi, I.S. and ORahilly, S. (2000) Recent advances in the genetics of
severe childhood obesity. Arch. Dis. Child. 83, 31 34
Chagnon, Y.C. et al. (2003) The human obesity gene map: the 2002
update. Obes. Res. 11, 313 367
Meyre, D. et al. (2002) First genome-wide search for young-onset
obesity susceptibility genes shows 3 loci on 6q, 15q and 16q. Diabetes
51 (Suppl. 2), 1062
Boer, H. et al. (2002) Psychotic illness in people with Prader Willi
syndrome due to chromosome 15 maternal uniparental disomy. Lancet
359, 135 136
Roof, E. et al. (2000) Intellectual characteristics of Prader-Willi
syndrome: comparison of genetic subtypes. J. Intellect. Disabil. Res.
44, 25 30
Cassidy, S.B. et al. (1997) Comparison of phenotype between patients
with Prader-Willi syndrome due to deletion 15q and uniparental
disomy 15. Am. J. Med. Genet. 68, 433 440
Gillessen-Kaesbach, G. et al. (1995) Genotype-phenotype correlation
in a series of 167 deletion and non-deletion patients with Prader-Willi
syndrome. Hum. Genet. 96, 638 643
Webb, T. et al. (2002) A study of the influence of different genotypes on
the physical and behavioral phenotypes of children and adults
ascertained clinically as having PWS. Clin. Genet. 62, 273 281
Saitoh, S. et al. (1997) Clinical spectrum and molecular diagnosis of
Angelman and Prader Willi syndrome patients with an imprinting
mutation. Am. J. Med. Genet. 68, 195 206
Vogels, A. et al. (2003) Chromosome 15 maternal uniparental disomy
and psychosis in Prader-Willi Syndrome. J. Med. Genet. 40, 72 73
Spritz, R.A. et al. (1997) Hypopigmentation in the Prader Willi
syndrome correlates with P gene deletion but not with haplotype of the
hemizygous P allele. Am. J. Med. Genet. 71, 57 62
Lee, S.T. et al. (1994) Mutations of the P gene in oculocutaneous
albinism, ocular albinism, and Prader-Willi syndrome plus albinism.
N. Engl. J. Med. 330, 529 534
Greenswag, L.R. (1987) Adults with Prader-Willi syndrome: a survey
of 232 cases. Dev. Med. Child Neurol. 29, 145 152
Dykens, E.M. et al. (1996) Prader-Willli syndrome: genetic, behavioral
and treatment issues. Child. Adolesc. Clin. N. Am. 5, 913 927
19
42 Eiholzer, U. (2003) A comprehensive approach to limiting weight gain

and to normalising body composition in Prader-WIlli syndrome. In
Prader-Willi Syndrome as a Model for Obesity (Eiholzer, U. et al., eds),
pp. 211 221, Karger
43 Dykens, E. and Shah, B. (2003) Psychiatric disorders in Prader-Willi
syndrome: epidemiology and management. CNS Drugs 17, 167 178
44 Brambilla, P. et al. (1997) Peculiar body composition in patients with
Prader-Labhart-Willi syndrome. Am. J. Clin. Nutr. 65, 1369 1374
45 Goldstone, A.P. et al. (2002) Resting metabolic rate, plasma leptin
concentrations, leptin receptor expression, and adipose tissue
measured by whole-body magnetic resonance imaging in women
with Prader-Willi syndrome. Am. J. Clin. Nutr. 75, 468 475
46 Goldstone, A.P. et al. (2001) Visceral adipose tissue and metabolic
complications of obesity are reduced in Prader-Willi syndrome female
adults: evidence for novel influences on body fat distribution. J. Clin.
Endocrinol. Metab. 86, 4330 4338
47 Goldstone, A.P. et al. (2003) Hypothalamic neuropeptides and
regulation of fat mass in Prader-Willi syndrome. In Prader-Willi
Syndrome as a Model for Obesity (Eiholzer, U. et al., eds), pp. 31 43,
Karger
48 Kreier, F. et al. (2002) Selective parasympathetic innervation of
subcutaneous and intra-abdominal fat - functional implications.
J. Clin. Invest. 110, 1243 1250
49 van Mil, E.A. et al. (2000) Activity related energy expenditure in
children and adolescents with Prader-Willi syndrome. Int. J. Obes. 24,
429 434
50 Silverthorn, K.H. and Hornak, J.E. (1993) Beneficial effects of exercise
on aerobic capacity and body composition in adults with Prader-Willi
syndrome. Am. J. Ment. Retard. 97, 654 658
51 Carrel, A.L. et al. (2002) Benefits of long-term GH therapy in PraderWilli syndrome: a 4-year study. J. Clin. Endocrinol. Metab. 87,
1581 1585
52 Hoybye, C. et al. (2003) Growth hormone treatment improves body
composition in adults with Prader-Willi syndrome. Clin. Endocrinol.
(Oxf.) 58, 653 661
53 Muller, J. (1997) Hypogonadism and endocrine metabolic disorders in
Prader-Willi syndrome. Acta Paediatr. 86 (Suppl. 423), 58 59
54 Akefeldt, A. et al. (1999) A woman with Prader-Willi syndrome gives
birth to a healthy baby girl. Dev. Med. Child Neurol. 41, 789 790
55 Schulze, A. et al. (2001) Fertility in Prader-Willi syndrome: a case
report with Angelman syndrome in the offspring. Acta Paediatr. 90,
455 459
56 Hoybye, C. et al. (2002) Metabolic profile and body composition in
adults with Prader-Willi syndrome and severe obesity. J. Clin.
57 Butler, J.V. et al. (2002) Prevalence of, and risk factors for, physical illhealth in people with Prader-Willi syndrome: a population-based
study. Dev. Med. Child Neurol. 44, 248 255
58 Harris, J.C. and Allen, R.P. (1996) Is excessive daytime sleepiness
characteristic of Prader-Willi syndrome? The effects of weight change.
Arch. Pediatr. Adolesc. Med. 150, 1288 1293
59 Schluter, B. (2003) Dysregulation of respiration and sleep in PraderWilli syndrome. In Prader-Willi Syndrome as a Model for Obesity
(Eiholzer, U. et al., eds), pp. 128 139, Karger
60 Manni, R. et al. (2001) Hypersomnia in the Prader Willi syndrome:
clinical-electrophysiological features and underlying factors. Clin.
Neurophysiol. 112, 800 805
61 Mignot, E. et al. (2002) The role of cerebrospinal fluid hypocretin
measurement in the diagnosis of narcolepsy and other hypersomnias.
Arch. Neurol. 59, 1553 1562
62 Kalra, S.P. et al. (1999) Interacting appetite-regulating pathways in
the hypothalamic regulation of body weight. Endocr. Rev. 20, 68 100
63 Kojima, M. and Kangawa, K. (2002) Ghrelin, an orexigenic signaling
molecule from the gastrointestinal tract. Curr. Opin. Pharmacol. 2,
665 668
64 Cummings, D.E. et al. (2002) Elevated plasma ghrelin levels in Prader
Willi syndrome. Nat. Med. 8, 643 644
65 Delparigi, A. et al. (2002) High circulating ghrelin: a potential cause for
hyperphagia and obesity in Prader-Willi syndrome. J. Clin. Endocrinol.
Metab. 87, 54615464
66 Haqq, A.M. et al. (2003) Serum ghrelin levels are inversely correlated
with body mass index, age, and insulin concentrations in normal
Review
20
67
68
69
70
71
72
73
74
75
76
77
78
79
80
children and are markedly increased in Prader-Willi syndrome. J. Clin.

Haqq, A.M. et al. (2003) Effects of growth hormone on pulmonary
function, sleep quality, behavior, cognition, growth velocity, body
composition, and resting energy expenditure in Prader-Willi syndrome. J. Clin. Endocrinol. Metab. 88, 2206 2212
DiMario, F.J.J. et al. (1996) Respiratory sinus arrhythmia in patients
with Prader-Willi syndrome. J. Child Neurol. 11, 121 125
Eiholzer, U. et al. (2001) Early manifestations of Prader-Willi
Syndrome: influence of growth hormone. J. Pediatr. Endocrinol.
Metab. 14 (Suppl. 6), 1441 1444
Anderson, A.E. et al. (1980) Gastric bypass for morbid obesity in
children and adolescents. J. Pediatr. Surg. 15, 876 881
Zipf, W.B. et al. (1983) Pancreatic polypeptide responses to protein
meal challenges in obese but otherwise normal children and obese
children with Prader-Willi syndrome. J. Clin. Endocrinol. Metab. 57,
1074 1080
Batterham, R.L. et al. (2002) Gut hormone PYY(3-36) physiologically
inhibits food intake. Nature 418, 650 654
Neary, N.M. et al. Appetite regulation: from the gut to the
hypothalamus. Clin. Endocrinol. (in press)
Tomita, T. et al. (1989) Protein meal-stimulated pancreatic polypeptide
secretion in Prader-Willi syndrome of adults. Pancreas 4, 395 400
Berntson, G.G. et al. (1993) Pancreatic polypeptide infusions reduce
food intake in Prader-Willi syndrome. Peptides 14, 497 503
Batterham, R.L. et al. (2003) Pancreatic polypeptide reduces appetite
and food intake in humans. J. Clin. Endocrinol. Metab. 88, 3989 3992
Goldstone, A.P. et al. (2002) Hypothalamic NPY and agouti-related
protein are increased in human illness but not in Prader-Willi
syndrome and other obese subjects. J. Clin. Endocrinol. Metab. 87,
927 937
Goldstone, A.P. et al. (2003) Hypothalamic growth hormone-releasing
hormone (GHRH) cell number is increased in human illness, but is not
reduced in Prader-Willi syndrome or obesity. Clin. Endocrinol. 58,
743 755.erratum. Clin. Endocrinol. 59, 266
Holder, J.L.J. et al. (2000) Profound obesity associated with a balanced
translocation that disrupts the SIM1 gene. Hum. Mol. Genet. 9,
101 108
Michaud, J.L. et al. (2001) Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the
hypothalamus. Hum. Mol. Genet. 10, 1465 1473
81 Ge, Y.L. et al. (2002) Anorexigenic melanocortin signaling in the

hypothalamus is augmented in association with failure-to-thrive in a
transgenic mouse model for Prader-Willi syndrome. Brain Res. 957,
42 45
82 Akefeldt, A. et al. (1998) Cerebrospinal fluid monoamines in PraderWilli syndrome. Biol. Psychiatry 44, 1321 1328
83 Shapira, N.A. et al. (2002) Topiramate attenuates self-injurious
behaviour in Prader-Willi syndrome. Int. J. Neuropsychopharmacol.
5, 141 145
84 Schuster, D.P. et al. (1996) Characterization of alterations in glucose
and insulin metabolism in Prader-Willi subjects. Metabolism 45,
1514 1520
85 Crino, A. et al. (2003) Hypogonadism and pubertal development in
Prader-Willi syndrome. Eur. J. Pediatr. 162, 327 333
86 Hoffman, C.J. et al. (1992) A nutrition survey of and recommendations
for individuals with Prader-Willi syndrome who live in group homes.
J. Am. Diet. Assoc. 92, 823 830
87 Smith, I.E. et al. (1998) Treatment of ventilatory failure in the PraderWilli syndrome. Eur. Respir. ET J. 11, 1150 1152
88 Defloor, T. et al. (2001) Aerodynamic and acoustic characteristics of
voice in Prader-Willi syndrome. J. Voice 15, 284 290
89 Rees, D. et al. (1989) Scoliosis surgery in the Prader-Willi syndrome.
J. Bone Joint Surg. Br. 71, 685 688
90 Cummings, D.E. and Shannon, M.H. (2003) Ghrelin and gastric
bypass: is there a hormonal contribution to surgical weight loss?
J. Clin. Endocrinol. Metab. 88, 2999 3002
91 Lustig, R.H. et al. (2003) Octreotide therapy of pediatric hypothalamic
obesity: a double-blind, placebo-controlled trial. J. Clin. Endocrinol.
Metab. 88, 2586 2592
92 Haqq, A.M. et al. (2003) Circulating ghrelin levels are suppressed by
meals and octreotide therapy in children with Prader-Willi syndrome.
J. Clin. Endocrinol. Metab. 88, 3573 3576
93 Korner, J. and Aronne, L.J. (2003) The emerging science of body weight
regulation and its impact on obesity treatment. J. Clin. Invest. 111,
565 570
94 Lee, S. et al. (2003) Prader-Willi syndrome transcripts are expressed in
phenotypically significant regions of the developing mouse brain. Gene
Expr. Patterns 3, 599 609
* McGowan, R. et al. (2003) Increased incidence of prematurity and low
birth weight in Prader Willi syndrome. Abstracts 6th European
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. Do erries
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)

Prader-Willi Syndrome: Advances in Genetics, Pathophysiology and Treatment

Uploaded by

Copyright:

Available Formats

Prader-Willi Syndrome: Advances in Genetics, Pathophysiology and Treatment

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Prader-Willi Syndrome: Advances in Genetics, Pathophysiology and Treatment

Uploaded by

Copyright:

Available Formats

Review

TRENDS in Endocrinology and Metabolism

Vol.15 No.1 January/February 2004