|Date||25 June 2021|
Location: Virtual Zoom Meeting
Title: Focus on female carriers of dystrophinopathy: refining recommendations for prevention, diagnosis, surveillance and treatment
Date: 25 June 2021
Organisers: Alessandra Ferlini (Italy), Anna Sarkozy (UK), John Bourke (UK), Ros Quinlivan (UK)
Participants: Ines Barthelemy (France), Emily Crossley (UK), Nathalie Dooreweerd (The Netherlands), Fernanda Fortunato (Italy), Pia Galliano (Spain) , Nathalie Goemans (Belgium), Michela Guglieri (UK), Jana Haberlova (Czech Republic), Saskia Houwen (The Netherlands), Aleksandra Pietrusz (UK), Erik Niks (The Netherlands), Rahul Phadke (UK), Luisa Politano (Italy), John Vissing (Denmark), Nicol Voermans (The Netherlands), Elizabeth Vroom (The Netherlands)
Dystrophinopathy (DMD) female carriers are a complex clinical and still neglected patient group. Management and research for DMD female carriers still is considered a “low priority”. There is poor definition of “female carrier status” and “manifesting carrier”, of clinical outcome measures, assessment and management of non-muscle symptoms and use of various novel therapies.
The aims of the workshop are to:
1) raise priority and need for much greater clinical and research focus on DMD female carriers,
2) highlight unmet needs,
3) propose a clinically useful classification of carrier status, and
4) demonstrate how available preventative and therapeutic approaches can improve patient outcomes.
The key deliverables are to 1) Summarise the current state of knowledge about DMD female carriers; 2) Propose clinically useful definitions of female carriers phenotypes; 3) Explore cognitive involvement in female carriers, related outcome measures and therapies; 4) Make recommendations to improve genetic diagnosis, prevention, psychological and ethical aspects of carrier care and 5) Highlight the future value of developing registries of female carriers to better define the natural history of carriers and as a prerequisite for conducting clinical trials.
In this first virtual workshop, we aim to keep the momentum by defining and agree on key questions to be addressed in and on preparatory work for the 2nd virtual and the planned face to face workshop, and to identify hot research topics for EU or other Agencies' funding applications.
What it means to be a carrier, perspective on being a DMD carrier
Emily Crossley and Elizabeth Vroom provided useful insights on what being a carrier means and how this WS can address unmet needs of this group of individuals. In particular, it was highlighted that following the diagnosis of DMD in a male child, all the focus is on the child and not on the possibly carrier mothers, who often don’t have time to look after themselves and their health needs. This WS is indeed long overdue to fill the many gaps and areas that need to be pursued for DMD carriers. A particular gap in support occurs just after the time of their son’s diagnosis, when mothers are told that they themselves carry the abnormal gene. At that time, mothers often do not register their own diagnosis, as they are focused on their sons, the grief and the worry of that diagnosis. Another challenge for women relates to the possibility of having additional affected children. Often, at time of diagnosis of an older boy, families already have a second child developing early symptoms. This underlies the argument for newborn DMD screening – since genetic counseling based on neo-natal diagnosis could prevent families from having multiple affected children.
Gaps in psychosocial support for parents and carrier mothers at/around time of diagnosis was highlighted, to help understand what the next steps are. While genetic counselling is offered to most families, this does not provide emotional counselling or support for emotional aspects of the overall situation - in particular, how to manage the devastating DMD diagnosis. There are also ethical aspects to consider, decisions about testing of family members, family planning and testing during future pregnancies. Often, families have to make highly emotionally charged decisions at a time when parents feel that the “ground has been ripped under their feet” and they are “in the eye of the storm”. It would be helpful for parents to have greater support and guidance about their available options with regard to future pregnancies in particular, when mother is diagnosed as a carrier.
Another key aspect of a carrier’s journey is their own health risks. Carrier females are told about the cardiac risks and the need for monitoring. However, there might be more to know for carrier females, and due to the lack of natural history (NH) data for carrier women, the uncertainity of the results of some investigations might leave mothers in great uncertainty, in a 'watch and wait' situation. Additional information that can be shared/analysed and published to help health care practioners to plan management and care of female carriers is missing and needed.
A further point to keep in mind relates to female siblings of index carriers, including the need to understand how and when to tell sisters / daughters about their risks, and when to start genetic and clinical screening. That currently is mostly done from age 16 years. Often discussions about female siblings is low on the priority list of families.
Finally, many carrier mothers in the community might not have full understanding of their genetic risks, and they need help and guidance to make decisions in that immediate phase of their patient-journey.
The workshop participants talked about questions that often come up in the DMD community and reflected on already available (survey) data and still lacking data:
• Is the name “manifesting carrier” the name we want to use? Or would it be better to indicate “females with dystrophinopathy”? If females are only called “carriers”, they might not be taken seriously, as this might indicate they don’t have a condition. So it is key to review the definition of carrier.
• Care is often only focused on cardiac care, but female carriers often have questions regarding the need to be seen in a neuromuscular (NM) clinic, by a physiotherapist, pneumologist, or psychologist. And what type of NM or physiotherapy (PT) assessments should be offered to females routinely?
• An important relatively new clinical concern is the impression that female carriers can have learning difficulties – probably related to their genetic status. As genetic diagnosis is usually only achieved after age >16 years, that is often too late to assess/support learning/educational needs of paediatric carriers. This would suggest the need for female relatives at risk of being carriers to be screened routinely at a much younger age to identify learning/educational needs specifically. Female carriers should also be screened on behavioural and cognitive difficulties.
• Also attention should be paid to female carriers experiencing psychological problems, like symptoms related to anxiety depression and obsessive compulsive disorder.
• What about immunization and pharmacological therapy for female carriers? Should carriers be treated with glucocorticoids (GC) in case of moderate or severe disease? Case examples were presented by clinicians in the group.
• Should carrier mothers be offered support to manage fatigue, a commonly reported symptom, to be able to better take care of their affected children. Guidance and information to mothers about the when and how to seek support requires renewal and should be part of our discussions.
• Additional information is also needed about what additional burden is there on mothers to tell their family about their risk of being carriers? At/around time of diagnosis in their sons, carrier mothers are asked to contact their families to discuss complex issues and this, probably inevitably, causes additional worries and anxieties. Whose responsability is it, to raise these points with related family risks members?
• Carriers should be made aware of what therapies and services are available in their own countries and what possible clinical trials are open to them for participation in light of their genetic status.
• Females with dystrophinopathy often feel neglected as we often speak about the males and we should pay more attentions to them.
Summary, take away messages, follow-up tasks, planning
These initial discussions have highlighted several important ‘unknowns’ and have led the organisers to ask each participant to now examine their data sets to see what information can be ‘pulled together’ in advance of the next meeting in November 2021.
2nd Virtual meeting Friday 26th November ’21
Face-to-face meeting: Friday-Sunday May 13-15th 2022, Hoofddorp, Courtyard Amsterdam Airport Hotel