8th
International PWS Organisation Conference
Jackie Waters
REVIEW
With grateful thanks to Dr Suzanne B Cassidy for
checking and amending the original draft and to Dr June-Anne Gold for her
additional comments
PWSA UK had been preparing for three years
to host the 8th International PWS Organisation Conference. It was not an easy process, not least when
the venue we had booked to host the Celebration Supper/Gala Dinner was burned
to the ground by arsonists just a year before the conference was due to take
place.
The conference was, however, voted a great
success by those who attended. It was split into three programmes: scientific,
caregivers (for those working in residential care and supported living), and
parents. The parents programme was then split into three for parents of
children under 5, 6-16 and 16+.
The following report gives some of the main
highlights from the scientific programme (many of the talks in the parent
programme were on similar subjects) but it is impossible to cover all the talks
and poster presentations within the context of this article. If you would like to
know more, some of the presentations and the abstract book are available to
view online at www.pwsa.co.uk – click on
the link on the home page.
You can also order a hard copy of the
abstract/programme book (while stocks last) for the cost of postage (£2 in the
UK). If you’d like a copy, please contact Maggie Rowley at our office address,
or email mrowley@pwsa.co.uk
PWS in the wider context
Guest
speaker, Stephen O’Rahilly, Professor of Clinical Biochemistry and Medicine at
the University of Cambridge Metabolic Research Laboratories, put PWS into the
wider context of obesity research, in that much can be learned about how bodies
control fat stores and nutrient levels through studying those where these
processes have gone awry, such as people with PWS. He highlighted the fact that, for the first
time in human evolution, humanity is consuming surplus energy to that which it
is expending, hence the “obesity epidemic”. However, recent studies have shown
that up to 70% of the difference between lean and obese people can be traced to
genetic or hereditary factors. Most of the genes which have been identified in
“normal” obese people are expressed in the hypothalamus.
Prevalence, birth incidence and mortality rates
There
have been many estimates over the years as to the prevalence and birth
incidence of PWS. Tess Lionti and her team from Murdoch Children’s Research
Institute in Australia looked at 156 Australians with PWS and found a birth
incidence of 1:14,000 and a prevalence of between 1:25,000 and 1:29,000. They
found that at 35 years of age, 87% of people with PWS were still living,
compared with 98% in the general population. They also reported that generally
obesity increased with age, and this remains the major cause of early death.
Non-obese people had better survival.
Changing clinical perspectives
Daniel J Driscoll, from the University of
Florida, USA, spoke about interventions and changing clinical perspectives in
PWS. He commented that PWS was the first recognized human disorder related to
genomic imprinting (differences in gene expression depending on the parent from
whom the gene was inherited). He went on to say that the previous two-stage
model of PWS (pre- and post-hyperphagia) had now been replaced by a model,
based on longitudinal studies, of 7 distinct nutritional phases (described by
Miller at al, Journal of Medical Genetics, 2011), indicating that PWS is more
complex than originally thought.
Dr Miller’s published article describes
these phases thus:
“Phase 0
occurs in utero, with decreased fetal movements
and growth restriction compared to unaffected siblings.
Phase 1
the infant is hypotonic and not obese, with sub-phase 1a characterized by
difficulty feeding with or without failure
to thrive (ages birth—15 months; median
age at completion: 9 months). This phase is followed by sub-phase 1b when the
infant grows steadily along a growth curve and weight is increasing at a normal
rate (median age of onset: 9 months; age quartiles 5–15 months).
Phase 2
is associated with weight gain—in sub-phase 2a the weight increases without a
significant change in appetite or caloric intake (median age of onset 2.08
years; age quartiles 20–31 months;), while in sub-phase 2b the weight gain is
associated with a concomitant increased interest in food (median age of onset:
4.5 years; quartiles 3–5.25 years).
Phase 3
is characterized by hyperphagia, typically accompanied by food-seeking and lack
of satiety (median age of onset: 8 years; quartiles 5–13 years). Some adults
progress to:
Phase 4
which is when an individual who was previously in phase 3 no longer has an
insatiable appetite and is able to feel full.”
Dr.
Driscoll also described a number of ongoing PWS clinical research and drug
trials.
Genetics
In his talk Bernhard Horsthemke, from the
Institut für Humagenetik in Germamy, described how finding a microdeletion
affecting the SNORD116 snoRNA gene cluster in a few patients pointed to a major
role of this gene in PWS. This is one of the genes located in the region of
chromosome 15 relevant to the cause of PWS. But he also warned that, despite
many years research, it is still unclear how or what roles this gene actually
plays in causing the features of PWS. Although mouse models have been used
extensively in trying to understand PWS, they are not an exact or ideal match.
For instance, human lipid metabolism and obesity is not replicated in mouse models,
their immune system is different, and they do not have cholesterol. There is
still no mouse model of PWS which is obese.
SNORD116 and the regulation of energy
homeostasis in PWS
More research into SNORD116 was included in
a poster presentation by a team at the Garvan Institute of Medical Research in
Australia. They generated mouse models which were lacking in the SNORD116 gene and
investigated their metabolic physiology. They found that these mice suffered
growth deficiency from birth, with reduced body weight, bone mass and length,
compared with healthy mice. They also showed increased food intake and an
impairment in the growth hormone pathway.
Marc Lalande, from University of Connecticut,
presented work on the development and use of pluripotent stem cells to study
the mechanism of silencing and re-activating of the maternally inherited genes
related to PWS, especially SNORD116. Once this is understood, there is the
potential for future treatments by reactivating these genes.
Françoise Muscatelli presented work from
researchers in France that showed a small amount of residual expression from
imprinted genes, especially NDN, in the PWS region, and they were able to show
better outcomes in mice with higher residual function. Re-activating imprinted
genes to improve outcomes in PWS may be able to be exploited.
Endocrinology and hyperphagia
A talk by Anthony Goldstone, of Imperial
College London, outlined the extensive role that neuroendocrine factors have in
PWS. These include underdeveloped genitalia, childhood development of obesity
and hyperphagia (excessive eating), growth hormone deficiency, delayed puberty
and infertility (in most), developmental delay and learning disabilities, and
abnormal sleep patterns. Dr Goldstone reported that people with PWS have normal
fasting and post-prandial (after meal) plasma levels of several anorexigenic (appetite
suppressing) hormones (leptin, PYY, GLP-1 and CCK). However, fasting and
post-prandial levels of the anorexigenic hormone pancreatic polypeptide (PP)
are reduced in PWS, and this appears to be present from early childhood. As
with genetics, there is still much research to be done. The cause for the
delayed development of hyperphagia remains unknown and, in addition to hormonal
abnormalities, there are likely to be overriding hypothalamic brain defects
which also contribute to the appetite problems.
Indian cactus caralluma fimbriata – effect on hyperphagia
A small
scale study of the use of caralluma fimbriata extract (CFE), a cactus extract, was
performed by Joanne Griggs and her team at the Victoria University College of
Health Biomedicine in Australia. Nine children and adolescents aged between 5
and 17 years were given powdered CFE or a placebo. Interim results suggested
that supplementation with CFE decreases appetite behaviour in some children and
adolescents with PWS and some decrease in behaviours relating to distraction
and distress. They are now hoping to extend their research into a worldwide
population to see if these results are replicated in a larger sample of
patients. CFE is licensed for use as “Slimaluma”. There was no monitoring of
liver function tests during this study.
Vagus nerve stimulation in PWS: effects on eating and
behaviour
A team from the Department of Psychiatry
at the University of Cambridge presented a poster about three individuals with
PWS who underwent surgery to implant a vagus nerve stimulation (VNS) device.
This device is used to control epilepsy, but it had been noted that these
patients with epilepsy also lost weight.
The team wanted to test the theory that this would also occur with PWS
patients. Effects on weight were
equivocal, with one person putting on weight and others showing some
improvement in eating behaviour.
However, unexpectedly, two of the three participants reported marked
improvements in their behaviour and asked for the VNS to continue at the end of
the study.
Thyroid function in children and
adolescents with PWS
In a poster presentation, a team from Italy
had conducted thyroid function tests on 299 children and adolescents with
genetically confirmed PWS, and found thyroid axis dysfunction in 10.7% of their
patients – more than is in the general population. They conclude that thyroid
function should be carefully evaluated in PWS patients to identify those who
may require hormonal replacement therapy.
Assessment of adrenal function
A poster
presentation by a Japanese team from Dokkyo Medical University set out to
assess adrenal function in 36 children and adolescents with PWS by insulin
tolerance test. Central adrenal insufficiency (CAI) due to hypothalamic
dysfunction had previously been suggested as a possible cause of death by other
researchers, particularly in association with infection-related stress. This
study results suggest that basal and peak levels of cortisol are within the
normal range in PWS patients, while peak responses of cortisol to insulin
stimulation are delayed in most patients. The researchers state that it is
likely that hypothalamic dysfunction alters secretion patterns of cortisol in
PWS, but say that further studies are necessary to clarify the possible
association between the altered response of cortisol to hypoglycaemia and
unexplained deaths in PWS.
Oxytocin
In her
talk on New Perspectives for Prader-Willi Syndrome, Maithé Tauber, of the
Centre de Référence du Syndrome de Prader-Willi in France, acknowledged that
the cure for PWS remains the foremost issue for persons with PWS and their
families and carers. She described how her team’s research into oxytocin administered
to 24 adult patients with PWS showed a positive effect on trust in others and
on disruptive behaviour, with a trend towards decreased food intake. In PWS mouse
models, they demonstrated that a single injection of oxytocin in the first five
hours of life completely rescued the newborn mice from early death by
recovering normal suckling abilities. They are now testing this treatment with
5 babies with PWS, and long term effects are currently being analysed, with the
hope that this may offer positive treatment early in life.
However,
a different result of treatment with oxytocin was reported by Ellie Smith,
University of Sydney, Australia, who described her team’s research in
administering oxytocin or a placebo as a nasal spray to 31 people with PWS aged
between 12 and 30 years. Behaviours such as hyperphagia, temper outbursts,
skin-picking, obsessive behaviours, and under-reaction to pain were evaluated
daily by primary carers. The outcomes were disappointing in that there were no
significant differences between those who received oxytocin and those who
received the placebo.
Growth hormone treatment in children
Nienke
Bakker, from the Dutch Growth Research Foundation in Rotterdam, reported on 8
years of growth hormone (GH) treatment in 60 children with PWS. The Dutch team
found that during this time lean body mass improved, fat percentage and body
mass index remained stable, while height and head circumference had completely
normalised. They conclude that GH is a potent force for counteracting the
clinical course of obesity in PWS.
Growth hormone and face shape
Using
dense surface modelling and shape signature techniques, Peter Hammond and teams
from University College London and the University of Catania, Italy,
demonstrated that growth hormone therapy in PWS has a corrective effect on
vertical facial growth, but not more generally on face shape.
Effect of growth hormone on bone fragility and effect on BMI
and adipose tissue of stopping growth hormone
In a
poster presentation, a team from the Dokkyo Medical University, Japan,
investigated 148 patients (112 treated with GH and 36 untreated) between 2 and
47 years of age to assess bone mineral density (BMD) in the lumbar spine (L2-4).
They also looked at scoliosis, which was present in 45 treated and 19 untreated
patients. They found that 33.8% of the patients had BMD below the normal range
(osteoporosis), and 27.7% had low normal BMD (osteopenia). The difference in
BMD between those with and without scoliosis did not reach statistical
significance. Treatment with GH did improve
BMD. They suggest that GH may be a useful treatment for reducing the frequency
of bone fractures and surgical complications caused by osteoporosis.
In a
separate poster, this research team also looked at 14 patients with PWS before
and after the cessation of GH treatment. They discovered that body mass index
(BMI) significantly increased after cessation, though subcutaneous and visceral
adipose tissue was not significantly affected. They conclude that to maintain
good body composition and prevent complications of obesity, long-term use of GH
in adult patients with PWS may be advisable.
Growth hormone therapy and respiratory disorders: long-term
follow-up in PWS children
In another poster presentation, a team
from Italy looked at the effects of long-term growth hormone therapy on
sleep-disordered breathing and adenotonsillar hypertrophy in 50 children with
PWS. They observed an increase of apnoea
hypopnoea and a decrease of central apnoea events, leading to an overall
decrease of the respiratory disturbance index.
However, the percentage of patients with severe adenotonsillar
hypertrophy increased significantly after two and three years of growth hormone
treatment. They recommend annual overnight polysomnography checks and
adenotonsillar evaluation.
Another poster presentation on this topic
was from a Scandinavian collaborative group. These authors conducted a placebo
controlled study of GH in 46 adults with PWS that respiratory polysomnography
did not change over time with GH treatment, and therefore that GH in PWS is not
associated with increased risk of sleep apnea.
Sex hormone deficiency
The Hypothalamic-Pituitory –Gonadal (HPG) Axis is Active in
Prader-Willi syndrome infants
Harry
Hirsch, of The Hebrew University, Israel, reported on research his team had
conducted into hypogonadism (immature sexual development) in infants with PWS.
As nearly all adult men with PWS have abnormally low testosterone levels and
adult females have low Inhibin B levels (a hormone produced by ovarian
follicles), it might be expected to find abnormally low levels of these
reproductive hormones in infants with PWS. Normal infants have an increase in
the HPG axis from birth to 4 months often referred to as “minipuberty”. However,
of the 9 male and 6 female infants with PWS the Israeli team studied, all of
the boys and some of the girls had normal reproductive hormone levels for age.
These results show that most infants with PWS are not born with deficiencies in
sex hormone production, and that further studies are needed to determine why
gonadal function becomes abnormal in PWS adolescents and adults and why
genitalia are small starting at birth.
Pregnancy in PWS
Two new
cases of women with deletion-type PWS becoming pregnant were described by
Suzanne Cassidy, from the University of California. One case was a 27 year old
woman who had a normal son, delivered by Caesarean section. She had had no
psychotropic medications. The other case was a 31 year old woman who took
Citalopram for two years before pregnancy. Her daughter had Angelman syndrome. There
have been two previously reported cases of successful pregnancy to women with
PWS. Dr Cassidy concluded that fertility in a few women with PWS probably reflects
variability in hypogonadism and absence of opportunity in others who are
potentially fertile, and recommends that sex education and contraception should
be part of the management of women with PWS.
Treatment of Hypogonadism in Females
In a
poster, Talia Eldar-Geva presented the Israeli group’s approach to treating
hypogonadism in adolescent and adult females with PWS. Their approach is
individualized, using contraception and hormone replacement based on bone
density, hormonal profiles and personal and family wishes.
Scoliosis
The
topic of scoliosis and other spinal deformities in PWS was addressed by Harold
van Bosse, of the Shriners Hospital for Children, Pennsylvania. He said that
40-90% of children with PWS have spinal deformities, and that 15% of all
children will require treatment. There are two main peaks in incidence of
scoliosis 0-24 months representing initial hypotonia and the second being
idiopathic. His data did not support discontinuing growth hormone treatment,
and in fact indicated that its use correlated with decreased risk for spine
surgery.
In a poster
presentation, Dr van Bosse discussed the prevention of surgical complications
in PWS scoliosis surgery. Previous studies had reported frequent serious
complications after spinal procedures, with rates as high as 56%. He and his
team developed a protocol for pre-operative work-up and peri-operative care to
minimize complications. The pre-operative protocol included pulmonary function
tests, sleep studies, and assessments for behavioural risks. Surgical planning
avoided anterior approached, and paid special attention to the characteristic
osteopenia and cervicothoracic kyphosis of PWS. Post surgery, extubation was
delayed, followed by BiPAP or CPAP. Oral intake was delayed. He concludes that
scoliosis surgery can be performed safely in children with PWS, as long as
there is careful attention to their special physiological and emotional
characteristics.
General anaesthesia
The
topic of general anaesthetics has always been one of concern to parents and
Graziano Grugni, of S Andrea Hospital, Vercelli, Italy, described his team’s
survey of 49 patients with PWS who had, in total, 101 surgical episodes,
programmed in 95 cases, and as an emergency in 6. Of these, only four patients
reported problems after general anaesthesia, two with respiratory insufficiency
and two with psychomotor agitation. The researchers concluded that no
complication leading to lasting disability or death had been observed.
Nutrition in children with PWS
Chris
Smith, who is the dietitian attached to the PWS Multidisciplinary Clinic at
Brighton and Sussex University Hospitals Trust, reported on an analysis of food
diaries kept by 11 parents of children with PWS over 10 years. His team found
that PWS children on average have 30% less calorific intake, compared to other
children of the same age. The proportions of % energy from fat, carbohydrate
and protein (compared to UK recommendations) were 25% (35%), 59% (50%) and 16%
(15%) respectively. The lower fat intake meant that children were at increased
risk of inadequate intake of polyunsaturated fats, but there appeared to be
little detrimental effect on micronutrient intake overall.
Post-prandial metabolic profile in adults with PWS
This
study by Louise Purtell and her team at The Children’s Hospital, Sydney,
Australia, set out to investigate the basis behind the development of obesity
in PWS, and especially why even those who are on a closely controlled
calorie-restricted diet still become obese. They hypothesized that this may be
due to the way people with PWS metabolise energy after eating a meal, but their
study found there were no differences in measures of meal metabolism between
those with PWS and non-PWS obese people when the amount of lean body mass was
taken into account. The study did not detect an intrinsic metabolic problem in
people with PWS and suggested that the development of obesity in PWS, even on a
strict diet, may be due to other factors.
A poster
presentation by Elena Borgova from Russia showed significantly higher levels of
Brain Derived Neurotrophic Factor (BDBF) over two control groups of non-PWS
obese individuals and lean controls. Brain-derived neurotrophic factor (BDNF)
is a neurotrophin, known to affect neuron maintenance or function, and it also
contributes to the central control of food intake.
Dr
Bogova’s study suggests possible resistance to BDNF at its receptor in
individuals with PWS. BDNF signaling in PWS needs to be full defined and may
lead to new treatment strategies.
GLP-1 based therapies (Liraglutide and Exenatide) – effect on
weight loss and stomach emptying
Anthony
Goldstone’s team at Imperial College London looked at the potential for using
drugs such as Liraglutide and Exenatide, normally used for treating diabetes,
in stimulating insulin release and weight loss in people with PWS. However,
there had been theoretical concerns about the safety of using these drugs in
PWS because they are known to cause delayed stomach emptying, already known to
be a potentially fatal issue in PWS because of the risk of stomach rupture.
While Liraglutide improved sugar control, it did not have a major impact on
hyperphagia or weight gain other than helping to prevent weight gain related to
the use of insulin. The team therefore advises caution in the use of these
drugs.
Very
similar results were obtain in another study of GLP-1 treatment in PWS presented
by the Italian collaborative endocrine group.
Pain and PWS
The
Italian collaborative group presented a study investigating the cause of the
high pain threshold in PWS in 11 adults with PWS, 3 obese non-diabetic people
and 7 age-matched normal weight healthy adults, using nerve conduction and
somatosensory evoked potential studies, quantitative sensory testing,
quantitative insulin-sensitivity, and a skin biopsy. They found normal
electroneurographic studies, but significantly higher thermal and pain
thresholds and reduced proximal and distal intraepidermal nerve fibres in PWS.
They conclude that altered perceptions of pain in PWS are mainly based on loss
of sensory neurons in dorsal root ganglia.
Infection and PWS
In a
poster, the Italian collaborative group presented a study that looked at the
risk of infection in 116 people with PWS compared with 113 normal subjects
matched for age, gender and environment. No difference between the two groups
was found despite the fact that there were more surgical procedures in the PWS
group. However, the PWS group showed more lower respiratory severe infections,
though fewer mild infections, possibly related to high threshold of pain and
vomiting.
Cognition – Executive functioning
Johann
Chevalere‘s team from Université
Bordeaux, Segalen, France suggested from two studies that executive functioning
in PWS is impaired and that the impairment is highly connected with the
intellectual disability. Differences were found between the deletion and the
m-UPD groups for the two task assessing, planning and mental switching, the
m-UPD performing worse than the deletion group. However the deficit on
switching and cognitive estimation is not totally attributable to intellectual
level, suggesting syndrome-specific association. Executive function seems to
vary with the genotype.
Behaviour
The team
from the Cerebra Centre in Birmingham, UK, demonstrated that changing routines
triggered more temper behaviours. They found that signalling any potential
changes in advance by showing a card to the person with PWS triggered less
temper outbursts, and they also recommended more research into increasing the
flexibility of routines from an early age as a potential helpful management
technique.
A Dutch
group studied 66 children with PWS using several different tests of social
cognitive functioning and showed a markedly reduced level of social cognitive
ability, suggesting that the approach to them should be adjusted accordingly.
Brain abnormalities between different genetic subtypes
Akvile
Lukoshe and the team from the Dutch Growth Research Foundation investigated
global brain morphology in children with PWS, using MRI imaging and comparing
the different genetic subtypes of deletion (DEL) and maternal uniparental
disomy (mUPD). They found that both subtypes show signs of impaired brain
growth indicated by smaller cortical surface area and smaller global white
matter volume. However, children with mUPD also show signs of early brain
atrophy and increased cortical thickness, similar to that found in autism. In
contrast, children with DEL have a proportionately developed, albeit smaller
brain compared to healthy age matched sibling controls. They suggest that the
results show divergent neurodevelopmental patterns in children with DEL and
mUPD.
Autism spectrum disorders
Symptoms of autism spectrum disorders in children with PWS
In a
poster presentation the team from the Dutch Growth Research Foundation and
Erasmus University, Rotterdam, tested 66 children aged 7 to 17 years using the
Theory of Mind Test-R (ToM) and the Diagnostic Interview for Social
Communication Disorders. ToM includes the ability to share feelings of others
(empathy). ToM development was related to IQ levels, but not to genetic
sub-type, and one third of the children scored positive for Autism Spectrum
Disorder. The team highlighted the importance of an adjusted approach to
children with PWS. Their impaired empathetic abilities require clear
communication such as avoidance of figurative language and naming things
precisely.
A study
contacted by researchers from Dokkyo Medical University, Japan, looked at 45
Japanese individuals with PWS. Their findings were consistent with previous
studies on Caucasian patients, and indicated that those with mUPD were more
prone to autism spectrum disorders, regardless of ethnicity. These were less
apparent in childhood.
Psychotic illness
Researchers
at the Maastricht University Medical Centre reviewed literature relating to
psychosis in PWS. Overall, in a total of 602 reported individuals, they found
that psychotic illness is more prevalent among those with disomy (mUPD) (15.6%)
than those with a deletion (8.8%).
In a
poster, Denise Thuilleaux presented results from a French-Spanish collaborative
psychopathological profile study of 154 adults with PWS. They found basal
(49%), impulsive (24%), compulsive (16%) and psychotic profiles. Overall, 11%
had psychosis, but those with UPD had a 25% prevalence of psychosis.
Tony
Holland, PWSA UK President, from the University of Cambridge proposed a clinical
trial to investigate whether psychosis can be prevented in PWS. This was based
on the case of an older adult with mUPD who had not become psychotic, but who
had been given antipsychotic medication to control behaviour problems earlier
in his life. It has also been noted that antipsychotic medication was very
effective where cases did occur, and relapse rates appeared to have been less
in those who continued the medication after recovery. They proposed to recruit
people with mUPD aged 16 to 20 years who had never had a psychotic illness,
allocating them to an experimental or a control group. Those in the
experimental group would be given low doses of antipsychotic medication. Tony
asked if this could be an international study, but also if such a study was
appropriate or ethically justified.
