|Date||25 May 2022|
Location: First 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.
Second Virtual meeting Friday 26th November2021
For an overview of the minutes of this virtual meeting please click here
Third -hybrid- meeting 13-15 May 2022
Location: partly Marriott conference hotel, partly online
Title: Focus on female carriers of dystrophinopathy: refining recommendations for prevention, diagnosis, surveillance and treatment.
Organisers: Prof. A. Ferlini Italy, Dr Anna Sarkozy UK, Dr John Bourke UK, Prof Rosaline Quinlivan UK
Participants : Prof John Vissing Denmark, Dr Michela Guglieri UK, Dr Nicol Voermans Netherlands, Dr Erik Niks Netherlands, Dr Anca Floran Germany, Dr Ines Barthelemy France, Dr Saskia Houwen Netherlands, Dr Fernanda Fortunato Italy, Ms Aleksandra Pietrusz UK, Ms Lidia Gonzalez Quereda Spain, Ms Elizabeth Vroom Netherlands, Prof. Teresinha Evangelista France, Prof. Linda Cripe USA, Dr Rahul Padke UK, Prof. Luisa Politano Italy
Translations of the lay report:
Portugese by Prof. Teresinha Evangelista
Italian by Prof. Luisa Politano
Dutch by Ms. Saskia Houwen
French by Dr Inès Barthelemy
Danish by Prof. John Vissing
Spanish by Dr Lidia Gonzalez Quereda
Description and aims of the workshop
The 263rdENMC workshop was convened as a hybrid face-to-face and virtual format between 13th-15th May 2022 and brought together 19 experts covering a range of specialties from across Europe and the United States to discuss the diagnosis, clinical features and impact of skeletal and cardiac manifestations in women carrying pathogenic variants (mutations) in the DMD gene. The workshop also reviewed the implications for medical care including cardiac surveillance. Because of COVID-pandemic restrictions, two virtual sessions had taken place in June and November ’21 in preparation for this workshop.
Females who carry a DMD gene mutation can present with a spectrum of features from no symptoms or abnormalities on blood or cardiac testing (the majority), some will have no symptoms but will have a raised blood creatine kinase, some will develop cardiomyopathy and some may develop muscle pains and or muscle weakness. In some women muscle weakness and cardiac features can have a significant impact upon quality of life.
How best to manage those women presenting with symptoms is not clear due to the lack of both natural history data and dedicated research. This workshop was convened to understand what is already known from research and what the gaps might be. In addition, the care-needs of those women presenting with symptoms were discussed and consensus recommendations included the need for a more holistic and systematic approach to management.
Key points discussed at the meeting
The participants shared their clinical expertise and research undertaken in this area and lively discussion highlighted the following key points:
- The current terms used to describe asymptomatic women including DMD-/BMD-carrier and ‘manifesting-carrier’ are not appropriate to the women affected. The term ‘carrier of a DMD gene mutation’ should be reserved to indicate a female carrying a DMD gene mutation who is asymptomatic and with normal investigations.
- For females in whom there is evidence of clinical involvement (signs or symptoms), the term ‘manifesting carriers’ was not felt to be appropriate. Instead, such women would be better described as ‘female patients with dystrophinopathy’, including ‘female patients with muscular dystrophy and/or cardiomyopathy caused by dystrophinopathy’.
- Affected women develop symptoms possibly due to inactivation of an X chromosome. However, results presented on this are conflicting and so, knowing the degree of X chromosome inactivation cannot predict whether or how severely a female will be affected. For this reason, measuring the degree of X inactivation is currently not helpful clinically.
- To improve access to diagnosis, support services and therapy, there is a clear need increase awareness of the potential for developing symptoms in muscle and or heart amongst women who carry a DMD gene mutation. These are usually, but not always, the mothers and sisters of affected boys.
- There is also a need to increase awareness among health-care professionals (eg: Neurologists-adult and Paediatric-, Clinical Geneticists, Cardiologists, and general practitioners) of the range of possible phenotypes and their significance. This is so that these affected can benefit from the full range of preventive measures, from genetic diagnosis, timely therapies and prenatal or preimplantation testing options.
- There may be an important role for educational psychologists also in assessing cognitive problems due to dystrophin deficits in the brain of these females.
- There is a pressing need to step-up the pace of research and systematic data collection as there are many gaps in research and our current understanding of the condition.
The following recommendations were made:
- The participants agreed that the name “manifesting carrier” is unhelpful and should be changed to reflect the clinical picture.
- Minimum care standards should include full genetic testing of all females at risk of being a carrier of a DMD gene mutation.
- All females shown to be carriers of a DMD gene mutation should be referred to a neuromuscular and cardiology specialist for further assessment.
- Efforts to increase awareness around female carriers of DMD gene mutation should continue at various levels and it was acknowledged that advocacy groups could be particularly helpful in this achieving this.
- It was agreed that international research collaborations are critical to improving care and treatment standards for affected females. This may include the development of patient registries and natural history studies leading to robust outcome measures for clinical trials and research funding applications.
A full report of the conference is published in Neuromuscular Disorders (pdf)