This advertorial was written and paid for by PTC Therapeutics, Inc. and is aimed to be of interest to parents, patients, healthcare professionals and academics interested in the burden of care for children with rare diseases.
Complex, severely disabling childhood disorders take a huge toll on caregivers, as shown by first of a kind quality of life (QoL) data for the rare neurotransmitter disorder, AADC deficiency.1.
It is difficult to really understand how emotionally and physically demanding it is to care for a child with a life-limiting disease that not only requires 24-hour care, but one that is so rare that only those caring day-in-day-out for a child living with the disorder can truly understand. How do you manage having every waking moment consumed with tending to your child’s most basic needs, often while bearing their pain and distress? To have to visit as many as 24 doctors just to get some answers or a diagnosis? Then to live with the threat that your child will be taken too early by a common complication?
At this year’s Virtual ISPOR North America 2021 Conference, PTC Therapeutics presented the first data detailing the impact of providing care for people living with the ultra-rare neurological disorder, Aromatic L-Amino acid Decarboxylase (AADC) deficiency, which can present with similar symptoms to cerebral palsy. 2.
AADC deficiency - a severely disabling and fatal paediatric neurotransmitter disorder 3,4,5,6
AADC deficiency is caused by mutations in the dopa decarboxylase (DDC) gene.3 The condition decreases AADC enzyme activity, which in turn leads to a lack of key neurotransmitters, such as dopamine, impacting development, motor skills, growth, function, cognitive and language skills, and behaviour.3.
The condition typically presents from three to six months with hypotonia (low muscle tone), oculogyric crises (seizure-like episodes that cause the eyes to roll up in the head and can last for hours) and autonomic dysfunction (e.g., excessive sweating)7. In the patient quality of life data reported at ISPOR, the level of motor function ranged from having no motor function at all to being able to take a few steps without support.1. Most children with AADC deficiency were completely dependent on their caregivers for all aspects of their lives.1. Caregivers also reported a range of symptoms like gastrointestinal symptoms, sleep disruption, and excessive crying.3. One mother of a 7-year-old said:
He can’t sleep, and his eyes are just wide awake, and the frustration is all over his face, you can definitely tell that he has a lot of discomfort.8.
What does it mean to spend every waking hour caring for a child’s every need?
As with so many rare diseases, there is an underestimation of the colossal impact endured by a family caring for a child with AADC deficiency. To help understand the burden, PTC sought insights from twelve caregivers from Italy, Portugal, Spain and the United States via online questionnaires.
These data, presented at ISPOR, found that the primary carers for children with AADC deficiency spend on average 13 hours per day, or 90 hours per week caring for their child’s basic needs, like washing, dressing and feeding, as well as providing much-needed comfort and emotional support.1. Time spent varied but ranged from 56 to as many as 140 hours per week.1. In addition, primary carers also spend an average of 15 hours a week planning activities or travelling to and attending appointments related to the child’s condition.1. This means an average total of 105 hours per week, or 15 hours a day, of care, leaving barely enough time for sleep, let alone anything else.1.
For most, the burden cannot be shouldered by one person alone, with more than half of the caregivers (55%) needing additional help, paid or unpaid, to supplement the care they were providing their child.1. The unpaid support usually came from a partner who provided, on average, 37 hours of help a week.1. If families hired additional support, it was provided by a registered nurse or training nursing assistant who provided, on average, 27 additional hours of help.1.
The knock-on effect for caregivers is huge, affecting every aspect of life. 75% had to either reduce their working hours or stop work completely in order to care for their child.1. Caregivers are challenged to find time for themselves, even just to take a shower, let alone exercise or socialise.
Several participants in the study described how being a caregiver had a substantial impact on their emotional and physical wellbeing, with reports of depression and anxiety, as well as back pain and lack of sleep.9. These caregivers expressed a feeling of fear for the future. 8.
Seeking a diagnosis for AADC deficiency – a long and winding road
The low awareness of this rare disease means that the journey to diagnosis can be extremely challenging for patients, with some having to travel extensively, sometimes outside of their home country, to receive the correct diagnosis. For parents, the financial and emotional implications of navigating a complex diagnostic journey while also caring for a very disabled child can be extremely distressing.
Results from the study presented at ISPOR, showed that caregivers saw between 1 and 24 clinicians or experts before finally getting a diagnosis – a process that took an average of 19 months from the first symptom being acknowledged.1.
We need to value the experience of carers
Previously, researchers have compared caregiving to being exposed to a severe, long-term chronic stressor.10 Whether physical, social, mental or financial, the burden of looking after someone with a rare disease, like AADC deficiency, is substantial and and it is therefore important that this is given due weight when considering the overall disease burden.
ISPOR – the Professional Society for Health Economics and Outcomes Research – is an international, multi-stakeholder, non-profit organisation
that aims to improve healthcare decision making through scientific research.
EE/AADC/UK/21/0026 | Date of preparation: May 2021
About PTC Therapeutics, Inc.
PTC is a science-driven, global biopharmaceutical company focused on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to patients with rare disorders. PTC's ability to globally commercialize products is the foundation that drives investment in a robust pipeline of transformative medicines and our mission to provide access to best-in-class treatments for patients who have an unmet medical need. To learn more about PTC, please visit us on www.ptcbio.co.uk and follow us on Facebook, on Twitter at @PTCBio, and on LinkedIn.
1. Buesch K, Williams K, et al. Caring for an Individual with Aromatic L-amino Acid Decarboxylase (AADC) Deficiency: Analysis of Reported Time for Practical and Emotional Care and Paid/Unpaid Help. Poster presented at Virtual ISPOR North America 2021 Conference.
2. Chien YH, et al. 3-O-methyldopa levels in newborns: Result of newborn screening for aromatic l-amino-acid decarboxylase deficiency. Mol Genet Metab. August 2016;118(4):259-263.
3.Wassenberg T, et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis. 2017;12(1):12.
4. Hwu WL et al. Natural History of Aromatic L-Amino Acid Decarboxylase Deficiency in Taiwan. JIMD Rep. 2018; 40:1-6.
5.Himmelreich N, et al. Aromatic amino acid decarboxylase deficiency: Molecular and metabolic basis and therapeutic outlook. Mol Genet Metab. 2019;127(1):12-22.
6. Chien YH, et al. Lancet Child Adolesc Health. 2017;1(4):265-273.
7. Pearson TS, Gilbert L, Opladen T, et al. AADC deficiency from infancy to adulthood: Symptoms and developmental outcome in an international cohort of 63 patients. J Inherit Metab Dis. 2020;43(5):1121-1130.
8. Williams K. et al. Symptoms and impacts of aromatic l-amino acid decarboxylase (AADC) deficiency: A qualitative study. Poster presented at Virtual ISPOR North America 2021 Conference.
9. Skrobanski H, et al. A qualitative study on the impact of caring for an individual with aromatic l-amino acid decarboxylase deficiency (AADCd) [Abstract] ISPOR US 2021.
10. ScienceDirect. Caregiver Burden. Accessible at: https://www.sciencedirect.com/topics/medicine-and-dentistry/caregiver-burden. Accessed May 2021.
Surjeet Kaur (Ritu) is a multiple sclerosis (MS) warrior and inspiring advocate. Since her diagnosis in 2012 Ritu has gone on to create a global community for MS patients and those that support them. With a following of over 20k on social media Ritu is creating a hub for education, awareness and acceptance of MS amongst the patient’s families, friends, colleagues and society.
It was an ordinary day in November 2012 and I woke up with a stiff neck. I tried to brush this off thinking I had slept funny. This sensation then progressed down to the right side of my whole body with extreme touch sensitivity. In addition, I started to experience the strangest electric shock sensation throughout my body. Slowly my right side became so numb that I had started limping and I couldn’t even eat food by myself.
It was difficult to understand what was actually happening to me and what my future would look like
Little did I know that something I thought to be so simple would change my life forever. After visiting a number of neurologists who undertook various tests, I was diagnosed with multiple sclerosis (MS). MS? I barely had an inkling about what MS is let alone be faced with such a diagnosis myself. Despite my shock and the endless questions spinning through my head, I was somewhat relieved that I was finally given a diagnosis so that I could start to look at the road to recovery.
I had lots of questions pondering in my mind like, what about my future? Will I be able to walk properly? Will I die early? Will I be able to work like before? Will anyone accept me and marry me?
It was difficult to understand what was actually happening to me and what my future would look like. However, I was thankful for my family who supported me in every way. My sister who is a near specialised physiotherapist had a great role to play in the diagnosis of MS. My parents supported me mentally and financially. Whereas my little brother has been my strength and reason to smile.
I also create various MS Awareness campaigns in which I invite MS patients to participate. Some of the successful MS campaigns we have done are “Workout MS” , “How MS Feels” and “Beat MS With”. These campaigns are available on our IGTV and YouTube channel. Currently we are running a campaign called “We Switch MS” campaign.
To create knowledge about MS, I regularly interview multiple sclerosis specialists, doctors, nutritionists etc via Instagram Live which has proved to be extremely popular amongst the MS Community. What is great is that fellow warriors can put questions to the experts during my live sessions for free of charge. So if someone needs an opinion of an MS specialist, they can ask their questions without any hesitation or fear.
What is great is that fellow warriors can put questions to the experts during my live sessions for free of charge
Recently, I also launched a podcast “10 Minutes for MS”, where I interview doctors to speak about various topics related to MS. All of my content is available free of charge, at no cost at all to my viewers and listeners. This podcast is streaming on all major platforms like Spotify, Apple Podcast, Google Podcast and YouTube.
Today, I feel confident and strong. It is said that “everything happens for a reason” and I think that MS has given me a reason to do something great for the society and help others. I have become a torchbearer and spread awareness with love and courage to face it.
I have been an MS warrior for the last 9 years and in these years I have learnt that MS is a unique disease and it is different for everyone. No two patients of MS are alike and not everyone, as is widely believed ends up in a wheel chair. Through my efforts I am trying to remove the fear about MS and the taboo associated with this disease, so that the patients can live without fear and there is acceptance for the same in the society.
MS just doesn’t affect a person physically; it also affects mentally and can cause depression. When we as MS warriors are fighting with MS, we are also fighting with mental health. MS caregivers and society need to be educated around MS. MS is definitely nothing to be ashamed of and MS doesn’t define any person, we are stronger than MS.
World multiple sclerosis day is celebrated on the 30th May each year, to find out how you can be involved and raise awareness for everyone affected by MS go to:
For more information about Surjeet Kaur (Ritu) and her advocacy please click the buttons below:
The International Gaucher Alliance: a foothold in national grassroots advocacy and a collaborative global perspective
Q. Can you tell us about the IGA and the areas it operates?
Back in 1994 in Trieste, Italy, at the first European Working Group on Gaucher Disease, several different European patient groups sat in the back row and listened to the presentations. This was the beginning of the European Gaucher Alliance (EGA). In 2018, the EGA changed its name to the International Gaucher Alliance (IGA) recognising its global constituency. Today we have 56 members representing 54 countries around the globe and represent approximately 85% of the global Gaucher community.
The IGA operates under three strategic imperatives that seek to achieve a strong voice for Gaucher patients through collaboration and partnership:
1.To improve Gaucher patients’ access to optimal diagnosis, treatment, and care
2.To influence the Gaucher research agenda so that it’s focused on addressing key unmet needs
3.To support member organisations to be more effective and sustainable
Q. How challenging is it to operate internationally and across languages and how does IGA overcome these challenges to represent patient organisations globally?
Whether it's disease awareness, access to care and treatment, or personal challenges (social and economic) connected to the countries the individuals with Gaucher disease live in, there are many challenges: our communities are so diverse. As an umbrella organisation we work with our members who support us by acting as volunteer translators and buddies across (geography’s) cultures and languages. We have also begun a review of our literature and in 2021 we will be working to translate some of our key information into several languages and use subtitles on our webinars.
Q. How important do you feel it is to the success of research and the development of new treatments to have this international approach?
As an international organisation we have an overarching view of everything that is going on through our collaboration with all stakeholders. We are therefore in an ideal position to bring people together with common goals and interests, drive research into areas of unmet need, and be able to contribute to research and the development of new treatments.
Q. Through your work and involvement across many countries what do you see as the biggest needs/challenges of the Gaucher community and is there much variation from country to country?
There is huge variation but also similar challenges. As a global community we can allocate resources by sharing best practices and using our knowledge and experience as an organisation to support national patient groups and individual patients and their families. The biggest challenges are access to diagnosis, treatment, and clinical care in many countries, particularly in low to middle-income countries, but also in many other parts of the world. Other challenges include: no licensed treatment for the neuronopathic manifestations of the disease; the delay in getting access to licensed treatment due to the high cost of the treatments even in countries with established healthcare systems; and the increasing understanding of the challenges comorbidities create for clinical care and treatment.
As a global community we can allocate resources by sharing best practices and using our knowledge and experience as an organisation to support national patient groups and individual patients and their families.
With COVID 19 impacting access to treatment, the IGA are now tackling this by working in collaboration with stakeholders to raise awareness of the benefits of home therapy, and to share best practices and exchange knowledge of where home therapy is available.
Q. Does working internationally highlight in-equity in healthcare and treatments for people with Gaucher disease and if so, is IGA involved in trying to address this?
Yes, for individuals with Gaucher and for those with rare diseases in general. All of our work, including work (or our collaborations) with other stakeholders, is guided by our three strategic imperatives, which are each aimed at achieving equity. Internationally, we focus on building sustainable infrastructures and are driven by the patient community to support them with the tools they need.
Our regional manager programme was developed to provide additional on-the-ground resources as the eyes and ears of the IGA in the many different countries where there are Gaucher patients but do not have any formal patient organisation or where there are many challenges. This programme seeks to collect information on the status of awareness, education, diagnostics, treatment, doctors, and patient numbers within a country and then develop a collaborative development plan with all stakeholders to build a sustainable infrastructure for patient care and support.
To read part two of this article, 'UK Gaucher Alliance: a foothold in national grassroots advocacy and a collaborative global perspective', click here:
To continue learning about Gaucher disease and patient support you can read the following articles in this Digital Spotlight here:
Journey to diagnosis: “They didn’t think to look for a rare disorder in such a small community.''
Looking back, Pierre’s short stature, his bruising easily and his unexplained stomach pain all pointed towards the diagnosis he would eventually receive. But it wasn’t until Pierre was rushed to the ER with severe and progressive abdominal pain that the pieces of the puzzle started to come together. He was 15 years old. It was 1995 when the doctor in the ER room raised concerns that Pierre had an enlarged liver and spleen. An ultrasound was ordered and showed gallstones. Pre-op blood tests were scheduled and Pierre was given an operation date to remove his gallbladder a month later.
Post-surgery, Pierre’s surgeon expressed concerns over not only the size of Pierre’s gallbladder, which was more than twice the normal size, but also the amount he bled during surgery. On inspection of Pierre’s medical chart, it was discovered that the surgeon had not been given the results from Pierre’s pre-op blood test. Pierre was sent home to recover from his surgery while they tracked down the results. Two weeks later, Pierre’s family received an urgent call.
Pierre was told his platelet count was very low and, fearing it was leukaemia, he was referred to a hematologist for a bone marrow test. Following the test results, Pierre was presented with the term that would soon become a significant part of his life: Gaucher disease. It was now March 1996, seven months after his admittance into the ER.
Pierre believes the length of his diagnostic journey was partly due to the population size of where he was living. Pierre explains,
In big cities with higher populations, doctors are exposed to more cases of rare disorders. Doctors don’t really think of looking for these rare disorders in such a small community.
Gaucher and bone pain: understanding pain levels
Pierre explains there are two types of bone pain: day-to-day bone pain, which Pierre learned to live with over the years and managed with medication, and bone crisis. Pierre explains, to those fortunate enough to have never experienced it, how a bone crisis can feel:
If breaking a bone is a 10/10 pain, then bone crisis is an 11.
For Pierre, a bone crisis could last anywhere from a few days to a week and sometimes even longer with pain levels so high it was impossible to sleep.
The difficulty in raising awareness for invisible symptoms like bone pain and fatigue: “I don’t look sick.”
Invisible symptoms such as chronic and severe pain and associated fatigue is often misunderstood and the burden underestimated. Pierre suffers from fatigue frequently as a symptom of Gaucher disease. Often, very active days can leave Pierre feeling exhausted, and his evenings are spent recovering.
Fatigue is something that’s really hard to explain to people. My immune system is constantly trying to fight my disease, but because it can’t get rid of it, the result is chronic fatigue. This is my normal.
To demonstrate just how misunderstood invisible illnesses are, Pierre shared with us the experience of a National Gaucher Foundation of Canada advocate, who was trying to have a newly approved treatment for Gaucher approved in Canada. The advocacy leader had met several times, unsuccessfully, with health ministers to fight for the approval of the new treatment. However, prior to one such meeting, the advocate had a bone crisis and rearranged the meeting to take place at the hospital where he had been admitted. The Deputy Minister of Health now saw him at his worst. “That’s what it took for treatment to be to be approved in Ontario. At every meeting before that, he had been viewed by others as healthy and his condition not treated seriously because he didn’t look sick.”
Early disease intervention: issues with meeting health requirements
With Gaucher, and in the case of many other rare diseases, access to treatments depends on the individual being eligible. This can mean that some people may be deemed “not sick enough” to benefit from new therapeutics, and this difficult balancing act must weigh up the benefits of early disease intervention and need for treatment.
In Canada, where Pierre lives, there are certain requirements and criteria that must be met in order for patients to start treatments. In Pierre’s case, he did not meet the criteria for some time; however, his bone crisis in 1998, meant his doctor was then able to champion his cause and successfully apply for treatment approval.
My Gaucher Expedition
To continue learning about Gaucher disease and patient support you can read the following articles in this Digital Spotlight here:
National Gaucher Foundation of Canada | The power of individual stories to spark widespread advocacy
Christine White, President of the National Gaucher Foundation of Canada, discusses how publishing personal Gaucher stories acted as a catalyst for widespread media campaigns that gained political attention resulting in access to a new life-changing therapy for the Gaucher community.
Q. Can you tell us about your work with the National Gaucher Foundation for Canada and how your organisation supports your community?
The National Gaucher Foundation of Canada was founded by—and continues to comprise—individuals living with Gaucher and family members of those individuals. We support our community through education, advocacy, peer support and much more. We provide support to those affected by Gaucher disease every step of the way, up to and including helping to facilitate a diagnosis.
Q. What do you feel are your community’s biggest needs/challenges and how does your organisation work towards trying to resolve and raise the agenda for these?
Currently, our biggest challenge is access to new medications; for example, we do not have a first-line oral therapy listed on our provincial formulary—drugs for Gaucher in Canada are paid for by the government, and only those Canadians who have private insurance have access to therapies that are not listed with provincial plans.
We will have the opportunity very shortly to submit evidence to the government that this is an impactful and necessary therapy for patients; we have been successful in the past in gaining access and are hopeful that we can demonstrate a strong need for oral therapy.
This very unfair policy often results in patients being “prisoners in their own province”.
Q. I read on your website how instrumental you were in making the treatment Ceredase available in Canada, how challenging is the topic of treatment equity, and what advice would you give to patient organisations who face a similar challenge?
Treatment equity is still a big challenge here in Canada, quite often where you reside will determine which therapy you receive. This very unfair policy often results in patients being “prisoners in their own province”. This means that even if a patient has access in their province, moving elsewhere in the country could result in a change in drug therapy.
As we work very closely with the Canadian Organisation for Rare Disease (CORD), we recently had the opportunity to make a submission to Health Canada regarding a federal rare disease strategy. I would advise patient organisations that have similar challenges to reach out to CORD and other patient organisations for support and advice.
I find the rare disease community is very collegial and greatly supportive of one another here in Canada.
Q. With some treatments already in existence for Gaucher disease, why is there a need to keep researching new treatments?
Currently, the available therapies do not address the needs of all individuals living with Gaucher. At present, there is no cure for type 2 Gaucher disease, and sadly, many infants and very young children die. Also, there is not an effective treatment available for type 3 Gaucher disease as current therapies do not cross the blood-brain barrier. This leaves little hope for individuals afflicted with the more severe forms of Gaucher.
Q. What can people with Gaucher disease do to get involved with advocacy and why is it important that they do so?
One of the key strategies in advocacy is awareness—it is important for individuals living with Gaucher to tell their stories. For example, we gained access to a life-changing therapy once we began an awareness campaign through the media. Before our media exposure, every request we made to the government was denied, but once people heard the stories we promoted, they began to pressure the government to change their position which resulted in a successful outcome.
To continue learning about Gaucher disease and patient support you can read the following articles in this Digital Spotlight here:
Cyndi Frank, co-founder of the Gaucher Community Alliance (GCA) spoke with us about driving their fledgling organisation through listening to the community.
What is the Gaucher Community Alliance and what services does it offer to individuals with Gaucher disease?
Founded in 2019, the GCA has established itself with a clear mission to provide peer support and community-building for individuals living with all types of Gaucher disease. The alliance is a diverse community of individuals living with Gaucher, family members and representatives of Gaucher disease. The team works closely with other representatives, including the executive director of the Canadian NGF, a professional advisory council made up of patients, doctors, industry representatives and other partnerships, who all meet twice a year and discuss how they can work in harmony to best support one another and patient needs.
Cyndi and fellow co-founder, Aviva Rosenberg, are enthusiastic about collaboration and “conquering that patient advocacy triangle” (those with the disease, the industry, and healthcare professionals). The GCA is passionate about keeping lines of communication open, with a strong emphasis on the importance of regular and, most importantly, transparent communication from all parties to tackle unmet needs and issues.
The GCA aims to ensure everyone who wants to be involved in the community is both enabled and encouraged through a “buddy system”. The buddy system offers volunteers partnership opportunities with other individuals who are interested in similar areas of volunteer work and who may have more experience of it. This often helps individuals to feel more involved in the community and feel supported.
What are the biggest needs for the Gaucher community and how well are these currently being addressed?
High prices of drugs and insurance issues are some of Cyndi’s biggest concerns when it comes to community needs. Cyndi explains that the GCA team is working hard to address this area and will not allow this topic to fall silent. The GCA has built a programme around this issue through the use of volunteers who have now formed their own committee.
Issues around treatment access for types 2 and 3 Gaucher are also a problem due to there being no treatment that can cross the blood–brain barrier. With more treatments now available for type 1 Gaucher disease, there is a clear demand for more transparent information to allow people to make informed choices. The GCA is working hard to ensure this content is more widely available to the community via reliable and trusted medical organisations.
Opportunities for research in Gaucher disease: issues around condition management
Gaucher disease affects individuals differently, even within the same type and family. Some individuals have mild symptoms while others will have more severe symptoms, and for some, bone pain, inflammation and fatigue are parts of their symptoms. Cyndi believes that more research is needed into controlled diets for managing symptoms associated with inflammation, such as bone pain. As some emerging studies are beginning to link diet to inflammation levels, Cyndi feels the timing could be right for research in this area for Gaucher and that conversations and research on the topic could lead to a substantial discovery in aiding condition management.
Leveraging technology for global education: GCA’s webinar events
Safe, warm environment where individuals can share information
For anyone considering joining one of GCA’s webinar events, you can expect to hear important discussions on topical news in the Gaucher community. The GCA’s live webinar events offer a secure space to interact with guest speakers by allowing viewers to ask questions in a chat room which can then be answered live. Cyndi describes the webinars as a “safe, warm environment where individuals can share information”.
GCA’s most attended webinar, Gene Therapy: A Personal Gaucher Story, can be accessed freely on the GCA website. The webinar hosts several guest speakers, including Dr Aneal Khan of Alberta Children’s Hospital in Calgary, who discuss both a new gene therapy trial to treat Gaucher disease type 1 and the science behind it. The webinar also features Shondra, the first individual to be dosed in the clinical trial for a new investigational gene therapy. Shondra shares a raw account of her journey from diagnosis to therapy and the reality of how it affected her.
Engaging their community: future plans for the GCA and how to deliver big ideas with a volunteer team
With great excitement and anticipation, Cyndi discusses her plans to run in-person events after Covid-19 restrictions lift, including a large-scale conference to feature speaker sessions and workshops.
Future plans also include a Youth Advisory Committee, a more interactive social media platform to connect with a younger community and welcome boxes for those who are newly diagnosed.
The GCA is committed to services that support long-lasting connections with their community, whether they are adults or young people.
By reaching out to universities and opening the door for internship opportunities, students can help support permanent volunteers and bring particular skill sets to help develop a larger social media presence and form crucial connections between individuals with Gaucher disease.
Get involved: why should individuals get involved in advocacy?
The GCA are always delighted to hear from new individuals who either want to share their personal stories about living with Gaucher or to get involved in volunteer work for the community. The GCA continuously responds to unmet need through listening to their community. The more people who reach out, start conversations and feedback, the better GCA can respond to the unmet need-providing benefit to the wider community and driving more developments in research, collaborations and individual connections.
Gaucher consultant Dr Neal Weinreb: the function and complications of bones in individuals with Gaucher and advice to physicians and patients in managing and tracking symptoms
Despite being a busy practicing hematologist-oncologist, I was able to retain my interest and involvement in GD developments. When enzyme replacement therapy for GD was approved in 1991, I became a founding member of the International Collaborative Gaucher Group (ICGG) Scientific Advisory Board and a regional coordinator for the newly organized ICGG Registry. In this capacity, I functioned as an educator and advisor for physicians who were interested in caring for GD patients and had the opportunity to collaborate in clinical research with remarkable GD expert scientists and physicians from all over the world. During my career, I have cared for about 250 GD patients and I have been privileged to participate as an investigator in many of the key clinical trials and studies that have greatly advanced our knowledge of the natural history and management of patients with this rare disorder.
Q. What are some of the unmet needs and challenges when treating Gaucher disease?
We still do not fully understand why the manifestations of Gaucher disease are so variable and the course is so unpredictable. The most common type of GD in the Western world (type 1) rarely affects the brain except in a small number of patients who develop GD-associated Parkinson disease later in life. However, other GD variants (types 2 and 3) are associated with brain damage that begins early in life and with death at a young age. Current treatments are largely ineffective for the neurological manifestations. However, there are some promising new treatment approaches under investigation. Because early diagnosis of these variants may be crucial for treatments to be effective, it is important to develop programmes for newborn screening or even prenatal screening in both developed and developing countries.
One of the triumphs of ERT is that splenectomy is now very uncommon and we rarely see young wheelchair-bound GD patients.
Regarding type 1 GD, it is challenging to treat older individuals who suffered irreversible bone or liver damage before effective treatment became available. Such patients require intensive palliative care and multifaceted interventions to minimise pain and disability. We also know that medical practices such as removal of the spleen that were unavoidable before the advent of modern treatments likely contributed to disabling skeletal disease. One of the triumphs of ERT is that splenectomy is now very uncommon and we rarely see young wheelchair-bound GD patients. Nevertheless, it is frustrating that some patients continue to suffer bone pain and disability either because they are not diagnosed sufficiently early or because initiation of treatment is delayed. Finally, ERT may not prevent all bone complications. Hence, new treatments with different mechanisms of action continue to be investigated and introduced.
Q. Can you tell us a little bit about how our bones work in general and what causes the bone complications in the case of Gaucher?
Bones are made up of two compartments, the external calcified bony framework and the internal bone marrow. All the body’s blood cells and immune regulatory cells are made in the bone marrow. One type of bone marrow cell that can also travel throughout the body is called a macrophage. This type of cell grabs on to, internalises, and disposes of foreign substances like bacteria that get into the body. It also signals immune cells to make antibodies to fight the invader. Macrophages “eat” old blood cells that are ready for “retirement.” In GD, because of the deficient glucocerebrosidase enzyme that causes the disease, macrophages cannot digest everything that they eat and become engorged with glucocerebroside substrate. We call them Gaucher cells. Gaucher cells respond to “indigestion” by creating inflammation. We believe this at least partly explains some of the pathology of GD.
The skeleton is a living tissue that constantly must be nourished and replenished. Without this process, bones would develop microfractures and become brittle and snap.
The strength and integrity of the bony skeleton also depend on bone marrow cells. Osteoblasts deposit the calcified bone matrix and become the mature bone cells that keep the bone alive. Specialised macrophages called osteoclasts absorb and remodel the bones. The skeleton is a living tissue that constantly must be nourished and replenished. Without this process, bones would develop microfractures and become brittle and snap. Osteoblasts and osteoclasts normally operate in balance. The osteoclasts absorb the old bone matrix and the osteoblasts lay down new, fresh bone. In patients with GD, the osteoclasts are on overdrive and the osteoblasts are “poisoned” by a chemical product of GD called glucosylsphingosine and fail to do their job of creating new bone. Consequently, there is a net loss of bone substance, calcium crystals are not deposited normally, the bone becomes thinned out, weak, and brittle and prone to fracture even with minimal stress.
Q. What is a bone crisis?
Inflammatory cells rush to the area to clean up the dead tissue and release chemicals that cause redness, swelling and intense pain. Hence, a bone “crisis.
As Gaucher cells fill up the bone marrow, they may increase fluid pressure around the blood vessels and cut off supply of oxygen causing bone death (necrosis). Inflammatory cells rush to the area to clean up the dead tissue and release chemicals that cause redness, swelling and intense pain. Hence, a bone “crisis.” Inflammation associated with the bone crisis can lead to fever and mimic an infection of the bone (osteomyelitis). There is no need for antibiotics and biopsies are inadvisable as they may increase the risk for actual infection. Bed rest and pain medications are usually indicated until the acute symptoms subside. Subsequently, physical therapy can help restore the function of the bone. Sometimes, however, the bone and its joints may never get back to normal and eventual joint replacement may be necessary. Fortunately, we are seeing fewer bone crises now that earlier diagnosis and treatment are more common.
Q. Is bone pain a red flag for Gaucher disease diagnosis?
Absolutely, although GD is certainly not the most common cause of bone or joint pain. If an individual has a significant bone problem and other findings commonly associated with GD such as an enlarged spleen or a decreased platelet count for which there is no logical explanation, then Gaucher disease should be considered. In children, failure of bone growth (short stature) can also be associated with Gaucher disease.
Q. What advice would you give to physicians in managing the bone care of their patients with Gaucher disease?
Take a detailed history at every visit. Ask about episodes of pain including location, frequency, severity, and the nature of the pain. Review all medications. Check for range of motion and observe how the patient walks.
Ask about falls and functional disabilities. In patients older than age 50, screen for immunoglobulin abnormalities (monoclonal gammopathy) annually as GD patients, even those with clinically mild disease, have an increased risk for developing plasma cell malignancies. Bone mineral density testing (DEXA)should be done at initial evaluation (whole body DEXA in children) and serially every 2-3 years. X-rays are of limited utility for follow up but MRI examinations of the lower extremities and low back are useful for monitoring bone marrow infiltration with Gaucher cells and calculating the bone marrow burden score.
Q. What pro-active steps can people with Gaucher and bone issues take in managing and tracking their symptoms?
Regular physical exercise, preferably supervised by a qualified instructor, is very important. However, high impact sports may not be advisable for patients with osteoporosis, an enlarged spleen or a bleeding tendency. Unhealthy substances like excess alcohol and cigarettes should be avoided as these are deleterious for bone health as well as health in general. A nutritious diet is commendable. Many patients with GD, even those on treatment, suffer from fatigue. Evaluation for a sleep disorder may sometimes be warranted.
A supportive network of GD-affected friends and families who understand what you are going through is also especially important.
Attention to mental wellbeing and freedom from anxiety is also important and should be openly discussed with your physician. Documentation of health-related quality of life scores can be useful in patient-physician communication. A survey instrument designed specifically for GD is currently in development.
Continuing education about the disease is an exercise in personal responsibility. There are many reliable resources available online for keeping up to date with new developments in Gaucher disease. A supportive network of GD-affected friends and families who understand what you are going through is also especially important. This is where Gaucher advocate organisations can provide great support.
UK Gauchers Association: a foothold in national grassroots advocacy and a collaborative global perspective
We provide an advocacy service to all individuals living with Gaucher and their families, including access to education, support to social care, and other personal non-medical issues. We pride ourselves in circulating up-to-date information on medical research and possible new treatments through newsletters, meetings, and online webinars.
We work hard to collaborate with clinicians, other patient groups, NHS England, and the pharmaceutical companies, ensuring voices from the Gaucher community are always heard. The Gauchers Association is committed to provide access to the highest standard of clinical care, share trusted information on new and appropriate treatments, and to drive research into unmet needs and securing new services that our community needs.
Q. Does the subject of bone pain/crisis come up a lot amongst your community and how much of an unmet need is this?
The Gaucher community is very heterogeneous and despite treatment being around for the visceral aspects of the disease for 30 years, we are aware that bone crisis is still very much an issue for our community.
Pain is extremely hard to measure and explain; however, with an earlier diagnosis and access to treatment and excellent clinical management, many individuals may not experience the type of bone disease we saw before treatment.
This is sadly not the case for older patients diagnosed before the advent of treatment and for other patients that for unknown reasons have major bone involvement or develop multiple myeloma.
There are also the bone aspects of neuronopathic Gaucher disease, such as kyphosis, that are not yet understood but continue to have an impact on the community.
Kyphosis is curvature of the spine that causes the top of the back to appear more rounded than normal.
Although everyone will have some degree of curvature in their spine, a curve of more than 45 degrees is considered excessive.
Kyphosis can cause back pain and stiffness, tenderness of the spine, and tiredness.1
Q. Do you feel there is enough understanding of this topic for both the patient community and HCP’s?
Gaucher disease comes under highly specialised services within the NHS; therefore, our community is seen at specialist UK centres across the devolved nations. There is a high level of expertise in Gaucher disease and bone disease, and its management is included in the current clinical guidelines. In addition, in 2016, the Medical Research Council awarded a grant to The National Gaucherite Project for an on-going, wide-scale observational cohort study of Gaucher disease in the UK. To find out more about The National Gaucherite Project visit: https://www.gaucher.org.uk/gaucherite
The results from this study provide an insight into the UK Gaucher community bone issues and the data to drive further research to improve diagnostics and the quality of life of individuals with Gaucher through possible new treatments and supportive care. By promoting the research findings of the study, we intend to generate more awareness, continue highlighting the importance of early diagnosis, and explore more avenues for care and management in Gaucher to share with our community.
To read part 1 of this article 'The International Gaucher Alliance: a foothold in national grassroots advocacy and a collaborative global perspective', click the button below:
1.NHS, Overview Kyphosis, (online), Available: https://www.nhs.uk/conditions/kyphosis/, 15th April 2021.
Getting involved in clinical research and the medication approval process
Research and patient accounts of their experiences suggest that bone complications—including bone pain and bone crisis—remain a significant challenge for people with Gaucher disease, even with available treatments like enzyme replacement therapy (ERT) and substrate reduction therapy (SRT).1,2,3
ERT has been life saving for people all over the world but it still requires infusions every other week for the rest of a patient’s life, which can mean port complications as well as interruptions at work or when engaging in activities with family, regardless of whether the infusions are done in an infusion center or at home.4,5,6,7 While ERT does improve some symptoms of Gaucher disease, bone issues remain an often-overlooked complication.8 SRT, taken as a pill every day4, generally helps with bone complications more than ERT, but is not suitable for all patients with Gaucher disease and still does not fully address all bone issues.
Therefore, a clear need exists for new treatment options that not only better address bone complications, but also address pain, fatigue, and neurologic symptoms, slow or halt disease progression, reduce the burden of bi-weekly treatments, and minimise adverse impact on quality of life.
Clinical trials are the lifeblood of new treatments and new discoveries for all diseases, and the success of clinical trials relies on the participation of patients and caregivers. Volunteering in a clinical trial means becoming a partner in scientific research and can help accelerate medical breakthroughs in treatments for Gaucher disease and other diseases across the world.
Clinical trials: Uncovering the facts
Clinical trials are research studies that evaluate therapies or medical devices. They are the primary way researchers and regulators find out if a new treatment is:
Clinical trials can also test ways to find a disease early, prevent or delay a health problem, or look at how to make life better for people. Sometimes, clinical trials will study the role of caregivers and support groups, too.10
In the United States, these trials are usually conducted by academic institutions or pharmaceutical or biotech companies that develop the therapies and are overseen by the U.S. Food and Drug Administration (FDA). In Europe, clinical trials are overseen by regulatory authorities in individual countries. Regulatory agencies such as the FDA and European Medicines Agency (EMA) rely on data from clinical trials to understand the benefits and risks of an investigational therapy, and whether a therapy should be approved for use. In addition to data from clinical trials, regulatory agencies also want and value patient input to inform their decisions. Below, you’ll find a few ways to engage with regulatory agencies in the medication approvals process.
Hope for the community
Clinical trials and the promise of new treatments provide hope to the rare disease community. Taking part in a clinical trial is an incredibly personal decision. For some people, the treatments they’ve tried so far may not have worked as effectively as they desired and being a part of a clinical trial may allow them to find out about new treatments before they are available.
For others, joining a clinical trial may be a way to take a more active role in their own care, to help researchers learn more about a condition, or to help family members or future generations.10
If you are interested in taking part in a clinical trial, learn as much as you can. Your doctor is an excellent resource that can help determine if a trial is a good option for you. Before you take part in a trial, make sure you understand the potential risks and benefits and share all your questions and concerns with your doctor and the researchers involved in the study. Patient advocacy organisations are also a great resource to learn about clinical trials.
Happening now! Clinical trials in Gaucher
There are many different types of clinical trials underway for Gaucher disease, including those that:11
For the most up-to-date information on clinical trials available in Gaucher disease, visit clinicaltrials.gov and search the term “Gaucher disease”.
How can you pave a new path?
Taking part in clinical trials means contributing to scientific research that makes future treatments possible for the community.
In addition to participating in clinical trials, engaging with regulatory agencies such as the FDA or EMA in the regulatory approval process (the process by which new medications and therapies are reviewed and authorized for use) or advocacy organisations can also help to make meaningful changes for individuals affected by rare conditions such as Gaucher disease:
Clinical trial volunteers are essential to advancing scientific research but engaging with regulatory agencies and patient advocacy groups to share your perspective is equally important in guiding clinical research activities.
1. Pastores GM, Hughes, D. Gaucher Disease. GeneReviews (online). https://www.ncbi.nlm.nih.gov/books/NBK1269/. Accessed April 15, 2021.
2. Deegan P, Khan A, Camelo JS Jr, et al. The International Collaborative Gaucher Group GRAF (Gaucher Risk Assessment for Fracture) score: a composite risk score for assessing adult fracture risk in imiglucerase-treated Gaucher disease type 1 patients. Orphanet J Rare Dis. 2021;16(1):92.
3. Limgala RP, Goker-Alpan O. Effect of substrate reduction therapy in comparison to enzyme replacement therapy on immune aspects and bone involvement in Gaucher disease. Biomolecules. 2020;10:1-12.
4. Van Rossum A, Holsopple M. Enzyme replacement or substrate reduction? A review of Gaucher disease treatment options. Hosp Pharm. 2016;51:553-563.
5. Wraith JE. J Inherit Metab Dis. 2006;29:442-447.
6. Smid BE, et al. Biochemical response to substrate reduction therapy versus enzyme replacement therapy in Gaucher disease type 1 patients. Orphanet J Rare Dis. 2016;11:28.
7. Copeland FD, Correia LA, White ML. Uncovering the burden of gaucher disease type 1: patient perspectives on unaddressed symptoms, impact of disease, and the future of treatment. Poster presented at: 17th Annual WORLDSymosium 2021; February 8-12, 2021.
8. National Gaucher Foundation. Bone disease: an often-overlooked complication of Gaucher disease. https://www.gaucherdisease.org/blog/bone-disease-an-often-overlooked-complication-of-gaucher-disease/. Accessed: March 31, 2021.
9. Clinicaltrials.gov. Study of Gene-Activated® Human Glucocerebrosidase (GA-GCB) ERT Compared With Imiglucerase in Type I Gaucher Disease. https://clinicaltrials.gov/ct2/show/NCT00553631?term=gaucher+and+non-inferiority&draw=2&rank=1. Accessed April 15, 2021.
10. US Department of Health and Human Services National Institutes of Health. What are Clinical Trials and Studies? https://www.nia.nih.gov/health/what-are-clinical-trials-and-studies. Accessed March 31, 2021.
11. US National Library of Medicine National Institutes of Health. https://clinicaltrials.gov/. Accessed March 31, 2021.
Rare diseases are complicated with signs and symptoms varying in severity and the time they take to present themselves. Gaucher disease has many symptoms, among the most common of these are bone pain and easily broken or fractured bones. For Gaucher patients bone symptoms can be a debilitating and life-limiting symptom of the disease. The infographic below highlights and explains the relationship between Gaucher disease and bones.
To download and share this infographic resource with your community click 'Download File' below:
Rare Revolution Editor