Source: fpwr.org

Vision problems in those with PWS

Issues with vision can be very prevalent among people with PWS, however, there has not been a great deal of data published to date. Recent results of a study based on data from the Global PWS Registry on vision impairments in those with PWS has been published.  The study involved a survey of more than 900 participants.  Its main findings showed that rates of strabismus (deviated eye or cross eyed) were much higher than the typical population (40% compared to 2-3%).  PWS genetic sub-type or growth hormone therapy status had no impact on the rate of strabismus.

Rates of farsightedness (inability to see things clearly up close) in PWS were also higher (25% compared to <10%).  Rates of lazy eye (where one eye strongly dominates vision) was found to be 16% in those with PWS compared to approx. 2% in the typical population.

Oxytocin, stress behaviours and hyperphagia

Oxytocin is known as the love hormone but in those with PWS and other conditions where high anxiety is characteristic, oxytocin, or the lack of it, is thought to drive stress behaviours. There are currently several clinical trials involving oxytocin or analogues of oxytocin worldwide. A full overview of oxytocin trials can be found in the January 2020 edition of Laneway.

Levo Therapeutics has recently completed its trial of LV-101, an intranasal form of carbetocin which is an analogue of oxytocin.  Phase 2 and 3 trials showed meaningful improvements in hyperphagia (excessive eating from excess hunger or increased appetite) and associated behavioural symptoms in those with PWS.  LV-101 is positioned to become the first potential PWS treatment in more than two decades to complete a New Drug Application review. A decision about approval in the USA is expected before the end of the year. 

The Destiny (DCCR) trail

The DESTINY trial being run by Soleno Therapeutics is testing Diazoxide Choline Controlled-Release (DCCR) for hyperphagia suppression in PWS. Diazoxide works by blocking two proteins in the brain which are believed to drive hyperphagia seen in PWS (DCCR trial). DCCR is what is known as an orphan drug and is one that has been reprocessed and reformulated for this trial. In its original formulation diazoxide is used to treat chronic low blood sugar and, for this use has some reported side effects, including loss of appetite (beneficial in the case of PWS), stomach upset and changes in sense of taste, not to mention elevated blood sugars. In the extended trials so far conducted, there have been no reported adverse side effects. The most recent results show a significant improvement in hyperphagia and stress behaviours for those on the DCCR trial.

Genetics of PWS

The Foundation of Prader Willi Research (FPWR) has launched the PWS Genome Project which is mapping 50 PWS genomes. The study will identify genetic variants that influence the risk and severity of symptoms, and in the long term, will help the understanding of how DNA variants impact response to different treatments for PWS.  This work is an extension of the Global PWS Registry study.

Sleep Apnoea and growth hormone

In a recently published study, Australian researchers have found an increase in moderate/severe obstructive sleep apnoea in a subgroup of patients once they start growth hormone.  The results lend support to the current advice to perform follow up sleep studies in children with PWS after starting growth hormone treatment.

Upcoming conferences

11^th International Prader Willi Syndrome Organisation Conference – 6-10 July 2022, Limerick, Ireland

Held every 3 years, this event is for all those affected by PWS and those helping to improve the lives of those with the condition.  The conference has many themes, including a clinical and scientific programme; a parent’s programme; a symposium for adults with PWS; a children’s programme and a new interdisciplinary programme which will focus on the holistic treatment and support of those with PWS.  For more details see 11^th IPWSO Conference.

The post PWS Research Update appeared first on Prader-Willi Syndrome Association of Victoria, Australia.

Source: Foundation for Prader-Willi Research

Genetic research 

PWS is caused by the absence of paternally expressed gene products from a small section of chromosome 15 (hence 15 for 15).  A recently published article describes efforts to activate the normally silent maternal section of chromosome 15 without negatively affecting other functions.  The approach was successful suggesting that activation of the maternal section of chromosome 15 might have potential as a therapeutic strategy for those with PWS.  There is still a long way to go with this work but it is an encouraging step forward. 

Another recent work gives a good general overview of PWS, the role of genetics in clinical presentation and potential treatments for those with the condition. 

Biology of PWS 

Those with PWS are understood to have impaired hypothalamic endocrine (hormone) function but the reason for this is not clear.  A recent study by Victor Chen et al. has shown that deficits in secretory granules, which store chemicals known as neuropeptides for release into the blood.  The paper postulates that the lower numbers of secretory granules could be one of the reasons for the clinical characteristics of those with PWS.  The authors suggest that these findings suggest unanticipated approaches for therapeutic intervention (treatment), thus alleviating several pathogenic processes in those with PWS.  Again, there is still much work to be done but the results are promising. 

A study from the laboratories of Dr Golder and colleagues recently published an article in Translational Psychiatry on the relationship between 2 PWS-related genes and autism. Increased UBE3A mRNA levels were correlated with developmental functioning scores in the deletion group, and increased autism features in the non-deletion PWS group. 

Zhang-Molina, Schmit and Cai have modelled a biochemical mechanism that is consistent with feeding behaviours seen in those with PWS.  They found that activating a chemical called PKC-d and inhibiting another called Htr2a suppresses feeding whereas the opposite is true for increasing feeding.  If both chemicals are activated feeding is also suppressed.  This could be significant in treatment and therapy options for those with PWS. 

Pace et al. relate decreased expression of the SNORD116 gene (one that is made in the region where PWS defects are seen) to abnormal sleep patterns, food intake and temperature regulation. 

Clinical research  

A study of weight Body Mass Index (BMI) change over by Theresa Strong et al. of 165 adolescents and adults with PWS has shown a relatively small increase in weight and BMI over a 6-month period.  Significantly, those individuals on growth hormone started with lower BMIs and were more likely not to show weight increases according to the study. 

Drs. Pascal Barone and Maithe Tauber and their teams at the University of Toulouse in France have been working to understand how those with PWS process facial cues and sounds, including voices.  They found that  

“deficits in voice and non-voice recognition (sounds that aren’t voices), difficulty distinguishing voices from environmental sounds, slower processing times and poor emotional recognition means that individuals with PWS may be at a disadvantage compared to their typical peers in staying attuned to social cues. All individuals with PWS are impacted, but those with PWS by Uniparental Disomy (UPD) are more likely to have a harder time. The development of tailored PWS interventions, based on an understanding of the specific weaknesses exhibited by those with PWS, may lead to more fulfilling social interactions for individuals with PWS and their social group.”  

Source: https://www.fpwr.org/blog/facial-and-voice-processing-issues-affect-social-interactions-in-pws 

Although hip dysplasia is far more prevalent in those with PWS than the general population (8 to 30 times higher) Dr Harold van Bosse and collaborators have released new guidance on treatment of the condition in babies and infants with PWS.  Based on a decade-long study of outpatients from hospitals in the United States that reviewed 9.4 million patients who received hip or knee replacements, only 65 were diagnosed with PWS, indicating that the increased prevalence of hip dysplasia in those with PWS does not lead to increased likelihood of hip and knee replacements. The new guidance suggests observation rather than surgical intervention for those with stable or improving hips. 

Measuring hyperphagia in those with PWS is usually assessed through a survey response.  To try to find a more accurate and definitive measure of hyperphagia researchers have been evaluating eye tracking.  The study compared how children between the ages of 3 and 11 years looked pictures of food, animals and household items.  They found there wasn’t a significant difference between those with PWS and those without PWS but found those with more advanced food-seeking behaviours looked at pictures of food for longer periods.  The researchers concluded that, based on this finding research into eye tracking should continue. 

Please note that the Prader-Willi Syndrome Association of Victoria provides this information to report to its members – not to impose any particular treatment options.  Any decisions about treatment options should be made in consultation with your own medical team

The post Prader-Willi Syndrome Research Update (January 2021) appeared first on Prader-Willi Syndrome Association of Victoria, Australia.

The COVID-19 pandemic is causing disruption globally.  There is almost no one left unaffected.  Particularly challenging for those with PWS, where educational needs can be significantly different to those of a mainstream education, is how to continue to access schooling and other educational services now when the services that are being offered have drastically changed or in some cases, have ceased.  Schooling from home in 2020 is vastly different to how home schooling might have been a generation, or even a decade ago, with the ability to set up on-line classrooms and to submit work and other tasks remotely.  But even with these technological advancements, there are many challenges, not least juggling the demands of various family members as they conduct their daily lives from home.  Here I summarise thoughts on learning from home from a presentation titled ‘At home learning strategies for those with PWS’ delivered to the US Foundation for Prader Willi Research by Senior Research Specialist, Elizabeth Roof of the Vanderbilt Center in the USA.  

With education from home, one must remember that your home is not a school and most of us aren’t teachers.  So, having realistic expectations of ourselves and our children is important.  Most schools will also have realistic (reduced) expectations of what can be achieved in a home learning environment too.  

Having a routine is critical.  As most of us are aware, this is particularly important for those with PWS.  The majority of the advice that has been broadcast about remote learning in the last few weeks advises a schedule as close to that of a normal school day as possible, meaning starting and ending the school day at the same times, having breaks at the same times, and ensuring breaks are taken, and for those who have different subjects during the day or week to continue with this practice as per the regular school timetable.  Elizabeth Roof suggests that if it isn’t possible to have a timetable that matches a typical school day something that works for you and your child is better than something that satisfies one of you only.  If only one of you is satisfied, ultimately both will be unhappy when things break down.  

Designate a ‘school zone’ or ‘work zone’ at home if possible and be sure to prepare everything that is needed ahead of time so that disruptions can be minimised.  For engagement and socialisation, face-to-face time is important, but not always possible.  Elizabeth Roof emphasises that making the process of learning fun and encouraging some independence is crucial but can be difficult for parents without teaching qualifications.  Using everyday tasks to teach is a good way of getting the children hands-on, which is really important for those with PWS.  Examples of this are teaching counting and colours by doing laundry or practicing fractions by measuring quantities for a recipe or for feeding a pet.  The benefit of this approach is that you can teach and do the chores at the same time, so you kill two birds at the same time.

Due to the changed environment it will be more difficult for individuals to learn new skills, so reteaching and reinforcing learned skills is a good way to build confidence.  Taking learned skills and applying them to new situations is also good for this.  Be sure to praise your child and reinforce good behaviour.

During break time involve your child in non-school activities such as cleaning, working on special projects or physical activity.  As mentioned above, some of this can double as educational activities.  

Most often those with PWS are more alert and attentive in the morning, so academic work should be undertaken before lunch for best results.  The afternoon can be for physical education, other physical activity and other less academically strenuous work.  Be aware of when your child has had enough and offer a distraction or end things to prevent behaviour changing for the worse.

Review each day with your child at its conclusion.  Highlight what went well and why.  Focus on these highlights and if something didn’t go well, don’t do it again or do it differently next time. If you find yourself running out of ideas of things to do, come up with new ways to do old things.  Lastly, remember to look after yourselves! For more information on Elizabeth Roof’s presentation where you can find the webinar and the slides from the presentation.

The post At home learning strategies for people with PWS during COVID-19 appeared first on Prader-Willi Syndrome Association of Victoria, Australia.

This article briefly summarises research activities and clinical trials associated with PWS.  Its intent is to make members aware of what is happening in this space.  None of these studies is definitive and ongoing research is necessary.  More information can be accessed through the links.  Please seek appropriate professional medical advice before acting on any information provided here.

Waking ‘sleeping’ genes could help those with PWS

Research grants from the Prader-Willi Research Foundation of Australia and the US Foundation for Prader-Willi Research will enable Associate Professor Marnie Blewitt to investigate whether awakening ‘sleeping’ genes could overcome some of the genetic errors underlying Prader-Willi syndrome, and reduce the severity of some of its symptoms. The researchers hope that in the long-term new drugs could be developed that keep these key genes awake, improving the quality of life of people with Prader-Willi syndrome.

For more information please see here. 

Newborn Experience Research

PWRFA recently launched its first ever grant for research proposals to support the newborn experience of children and families living with PWS. This grant generated a number of proposals and the Scientific Advisory Council will be announcing the successful candidates in the coming months.  

Study links structure of the cerebellum in brains of those with PWS to behavioural problems 

Researchers in Japan have shown that in those with PWS who participated in the study, certain parts of the brain differ from those without PWS.  Specifically, people with PWS had a smaller cerebellum than individuals with typical development. There were also other differences identified.

These structural changes were shown to be significantly associated with different behavioural problems including hyperphagia; and autistic, obsessive and intellectual characteristics. 

The findings also suggest that structural changes in the cerebellum contribute to impaired brain connectivity in PWS patients. 

The researchers noted that larger studies were required to confirm these associations and better understand the underlying mechanisms of behavioural problems in people with PWS.

For more information please see here. 

Differences in growth (mass and height) trajectories in genetic subtypes of PWS

A study from the Murdoch Children’s Research Institute in Melbourne has shown that the subtype of PWS (deletion or non-deletion) has an impact weight (mass) and Body Mass Index (BMI – a measure that considers height and weight).  Using historically available height and weight data from the Victorian Prader Willi Syndrome Register (VPWSR), the researchers showed that weight and BMI were estimated to be higher in the deletion subtype compared to the non-deletion subtype, with the weight difference increasing with age.  They also said that no data existed regarding diet, use of hormone therapy, and physical activity in these groups, which was a limitation in the study.  

For more information see here.

Loss of gene associated with PWS linked to sleep and food irregularities in mouse model

A study on a PWS mouse model by researchers from Italy and Norway has shown a link between the loss of genetic information (Snord116) associated with PWS disrupts the control and transmission of nerve signals in part of the brain called the lateral hypothalamus (LH).  Mice lacking the copy of Snord116 had excessive activity in nerve cells associated with sleep compared with animals without the Snord116 deletion, as well as suppressed activity in nerve cells associated with wakefulness under certain conditions of sleep deprivation.  There was also a drop in the wakefulness hormone (orexin) in mice with the Snord116 deletion during eating, which could be linked to hyperphagia and obesity.  

The researchers propose that an imbalance between the wakefulness and sleepiness hormones in the LH of mice with the Snord116 deletion reflects a series of deficits seen in those with PWS, such as food intake and temperature control.

The full research article can be seen here.

Dietary Planning Helps Maintain Normal Fat Tissue Levels in PWS Children

Perhaps unsurprisingly, this study by Japanese researchers showed evidence that for individuals with PWS who have regular dietary planning Subcutaneous Adipose Tissue (SAT – fat below the skin) is lower than those who did not adhere to a careful dietary plan.  Visceral Adipose Tissue (VAT – fat found deep in the abdomen and around organs) was unaffected by the use of dietary planning.  

The full research article can be found here.

Growth Hormone Use Beyond Childhood Aids Young Adults With PWS, Study Finds

A recent Dutch study investigating continuing or recommenced use of Growth Hormone (GH) in young adults with PWS over a 3-year period has shown its use to be beneficial in terms of body composition (lean mass to fat mass).  As well as this, the study showed that these benefits of body composition could be restored after discontinuing GH for one year.

The full research article can be found here.

Clinical trials update

There are several research studies that are currently running in Australia which are looking to recruit patients.  Clinical trials are an important and essential step in the development of new treatments for PWS. While PWFRA and PWSA Vic do not endorse or recommend any specific study, we do seek to provide information about trials for information and to give the opportunity of participation to those members who are interested.  We encourage our families to follow the links to see if any of these projects are of interest.  Contact details are included in the link if you are interested. http://praderwilli.org.au/clinical-trials

Hyperphagia trials 

Enrolment in the Harmony Biosciences phase 2 trial of a drug called Pitolisant has again been delayed due to social distancing measures due to Coronavirus.  Pitolisant is being trialled to evaluate its efficacy for treating daytime sleepiness in those with PWS.  Recruitment of trial participants was due to commence at the beginning of March this year.  Participants ranging in age from 6 to 65 will be sought once recruitment recommences.  The study is looking for around 60 participants for an initial 11-week treatment phase. 

For more information please see here.  

Mindfulness-based intervention for temper outbursts (ages 13-30) 

As reported in the previous edition of Laneway, this study is still recruiting participants.  This study aims to evaluate mindfulness strategies for managing temper outbursts and anxiety in PWS.  The study will be conducted remotely via phone, email and video conference. 

The trial is 18 weeks in length and will involve an individual with PWS between the ages of 13 and 30 with a mild intellectual disability or normal IQ.  Also required will be a parent or carer and a teacher or support worker.  The carers and support workers will be trained to use and teach the mindfulness intervention, and will be asked to monitor the PWS participant’s behaviour over the course of the trial.  For more information or to sign up to the trial please contact Lauren Rice on +61 2 9114 4106 or fhs.devpsych@sydney.edu.au 

Acceptance and commitment training (ages 13-18) – still recruiting

Acceptance and Commitment Training (ACT) is an empirically-based psychological intervention that uses acceptance and mindfulness strategies mixed in different ways with commitment and behaviour change strategies to increase psychological flexibility (source Wikipedia).  This training strives to accept rather than eliminate difficult feelings and move towards valued behaviour, or workability. 

This study which is led by Dr Janice Forster and Dr Stuart Libman in the United States seeks fathers of children with PWS from age 13 to 18 to participate in a 4-session, on-line, small-group ACT training exercise to reduce father’s perception of stress, improve parenting satisfaction and increase family involvement.  Participants must reside at home with their adolescent and the adolescent’s mother, have a computer with a camera, microphone and internet access, and agree to privacy and confidentiality of shared information. 

For more details see here. 

Phase 3 Levo Carbetocin Trial

The Phase 3 Carbetocin Trial – Queensland Children’s Hospital, Westmead Children’s Hospital and Randwick Hospital sites are ready to go, and other locations in Australia will be announced shortly. This trial studies the effect of intranasal (through the nose) delivery of carbetocin, on excessive eating and obsessive compulsive behaviours.    Interestingly the US FDA (Food and Drug Administration) has recently fast tracked the designation of Carbetocin for phase 3 trials. 

Read more about this here

The effect of Livoetide on food related behaviours in patients with PWS

These trails are held at Heildelberg Repatriation Hospital for patients 18+.

Tamara Debreceni 03 9496 4026 or Tamara.debreceni@unimelb.edu.au 
 Trials looking at the effect of Oxytocin has on the autonomic nevous system. Dr. Einfields Oxytocin study out of the University of Sydney that is recruiting patients aged 13-30 from Melbourne and Sydney : fhs.devpsych@sydney.edu.au

The post Research and Clinical trials news appeared first on Prader-Willi Syndrome Association of Victoria, Australia.

Hyperphagia trails

Of the hyperphagia drug trials that were mentioned in the last edition of Laneway there is one update: the Zephyr trail that, until recently was being run in Europe and the US by pharmaceutical company Millendo, has been discontinued. The trial was testing the effectiveness of a drug called livoletide, an analogue of unacylated ghrelin (UAG) for treatment of hyperphagia. Unfortunately, the trail results have not shown significant improvements in hunger suppression.

Enrolment in the Harmony Biosciences phase 2 trial of a drug called pitolisant has been delayed due to social distancing measures due to Coronavirus. Pitolisant is being trialled to evaluate its efficacy for treating daytime sleepiness in those with PWS. Recruitment of trial participants was due to commence at the beginning of March this year. Participants ranging in age from 6 to 65 will be sought once recruitment recommences. The study is looking for around 60 participants for an initial 11-week treatment phase. For more information please see here.

Mindfulness-based intervention for temper outbursts (ages 13-30)

This study aims to evaluate mindfulness strategies for managing temper outbursts and anxiety in PWS. The study will be conducted remotely via phone, email and video conference.

The trial is 18 weeks in length and will involve an individual with PWS between the ages of 13 and 30 with a mild intellectual disability or normal IQ. Also required will be a parent or carer and a teacher or support worker. The carers and support workers will be trained to use and teach the mindfulness intervention, and will be asked to monitor the PWS participant’s behaviour over the course of the trial. For more information or to sign up to the trial please contact Lauren Rice on +61 2 9114 4106 or fhs.devpsych@sydney.edu.au

Acceptance and commitment training (ages 13-18)

Acceptance and Commitment Training (ACT) is an empirically-based psychological intervention that uses acceptance and mindfulness strategies mixed in different ways with commitment and behaviour change strategies to increase psychological flexibility (source Wikipedia). This training strives to accept rather than eliminate difficult feelings and move towards valued behaviour, or workability.

This study which is led by Dr Janice Forster and Dr Stuart Libman in the United States seeks fathers of children with PWS from age 13 to 18 to participate in a 4-session, on-line, small-group ACT training exercise to reduce father’s perception of stress, improve parenting satisfaction and increase family involvement. Participants must reside at home with their adolescent and the adolescent’s mother, have a computer with a camera, microphone and internet access, and agree to privacy and confidentiality of shared information. For more details see here.

The post Clinical Trials Update appeared first on Prader-Willi Syndrome Association of Victoria, Australia.

The COVID-19 pandemic is causing disruption globally.  There is almost no one left unaffected.  Particularly challenging for those with PWS, where educational needs can be significantly different to those of a mainstream education, is how to continue to access schooling and other educational services now when the services that are being offered have drastically changed or in some cases, have ceased. 

Schooling from home in 2020 is vastly different to how home schooling might have been a generation, or even a decade ago, with the ability to set up on-line classrooms and to submit work and other tasks remotely.  But even with these technological advancements, there are many challenges, not least juggling the demands of various family members as they conduct their daily lives from home.  Here I summarise thoughts on learning from home from a presentation titled ‘At home learning strategies for those with PWS’ delivered to the US Foundation for Prader Willi Research by Senior Research Specialist, Elizabeth Roof of the Vanderbilt Center in the USA.  

With education from home, one must remember that your home is not a school and most of us aren’t teachers.  So, having realistic expectations of ourselves and our children is important.  Most schools will also have realistic (reduced) expectations of what can be achieved in a home learning environment too.  

Having a routine is critical.  As most of us are aware, this is particularly important for those with PWS.  The majority of the advice that has been broadcast about remote learning in the last few weeks advises a schedule as close to that of a normal school day as possible, meaning starting and ending the school day at the same times, having breaks at the same times, and ensuring breaks are taken, and for those who have different subjects during the day or week to continue with this practice as per the regular school timetable.  Elizabeth Roof suggests that if it isn’t possible to have a timetable that matches a typical school day something that works for you and your child is better than something that satisfies one of you only.  If only one of you is satisfied, ultimately both will be unhappy when things break down.  

Designate a ‘school zone’ or ‘work zone’ at home if possible and be sure to prepare everything that is needed ahead of time so that disruptions can be minimised.  For engagement and socialisation, face-to-face time is important, but not always possible.  Elizabeth Roof emphasises that making the process of learning fun and encouraging some independence is crucial but can be difficult for parents without teaching qualifications.  Using everyday tasks to teach is a good way of getting the children hands-on, which is really important for those with PWS.  Examples of this are teaching counting and colours by doing laundry or practicing fractions by measuring quantities for a recipe or for feeding a pet.  The benefit of this approach is that you can teach and do the chores at the same time, so you kill two birds at the same time.

Due to the changed environment it will be more difficult for individuals to learn new skills, so reteaching and reinforcing learned skills is a good way to build confidence.  Taking learned skills and applying them to new situations is also good for this.  Be sure to praise your child and reinforce good behaviour.

During break time involve your child in non-school activities such as cleaning, working on special projects or physical activity.  As mentioned above, some of this can double as educational activities.  

Most often those with PWS are more alert and attentive in the morning, so academic work should be undertaken before lunch for best results.  The afternoon can be for physical education, other physical activity and other less academically strenuous work.  Be aware of when your child has had enough and offer a distraction or end things to prevent behaviour changing for the worse.

Review each day with your child at its conclusion.  Highlight what went well and why.  Focus on these highlights and if something didn’t go well, don’t do it again or do it differently next time. If you find yourself running out of ideas of things to do, come up with new ways to do old things.  Lastly, remember to look after yourselves!

For more information on Elizabeth Roof’s presentation please click the button below where you can find the webinar and the slides from the presentation.

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