The "Female" Side of Duchenne

It was a long time ago that I sat in the exam room and received the diagnosis. My boys had Duchenne. The diagnosis was followed by a series of questions about my family history, the doctor assuming that somewhere along the line, there was another boy long ago. In my case, there was no history. None. I asked every living member of my mother’s family what they knew, if there was someone who had an unnamed ‘problem’, someone who was weak, or a child who died young from an unnamed illness. One of my cousins talked about my "crazy Uncle Harry” who fell off the roof, but it hardly fit the picture I was looking for. I had a brother Jack, who died young, at the age of 42. A heart attack after jogging. He was my closest friend and I wondered if he might have had a mild form of Duchenne – decent muscle strength, but severe cardiomyopathy. It was always a question.

I guess it would have been easier to simply test my mother, but she had her own issues with the diagnosis. Catholic guilt. She had the sense that a god would punish her for past deeds and I did not want to create additional burden for her. I left it alone, an open wound. For years, I wondered. In retrospect, I wonder if I just wanted to be able to point the finger at someone else. I didn’t want to be the first carrier, the de novo mutation in my family. It seemed so unfair and it felt like I did something wrong somehow. OK, intellectually, I realize, spontaneous mutations occur frequently. The dystrophin gene is particularly susceptible based on its large size. Eric Hoffman suggests 1:10,000 egg and sperm cells carry the mutation as a new event. Random. Right, but emotionally it still hurts. Motherhood and guilt.

Just before the FACES meeting in Colorado, we met with Ivy Scherbarth and Angela Knight. It is always a question. Are you a carrier?. We discussed and compared carrier vs non carrier. Ivy had tears in her eyes as she had looked back through her family, tracing what must have been Duchenne generations back. Angela, not a carrier, said that either way, having a child diagnosed with a genetic disease is accompanied by guilt. I think she’s right. There is no way and no need to compare the feelings. Mom’s feel responsible. But there are more questions and strings attached to the word “Carrier” and the word stings somehow, sometimes feels like an indictment, with questions about prior knowledge, muscle weakness and concerns about the risk heart disease.

Carriers are working on two dystrophin genes, one carrying the mutation and one without. And we are hopeful that our cells opt to use the “good” gene, the gene that does not carry the mutation, producing normal quantities of dystrophin in every muscle and tissue of our bodies. But sometimes it does not work that way. When moms talk about this openly, some share stories of muscle cramps, weakness, fatigue. One mom recently mentioned she had a weak handshake and her doctor thought it was characteristic of a carrier. That sounds a little over the top to me as handshakes are personal, dictated by much more than muscle strength. I think the answer may be somewhere in the middle. Some moms have weakness ranging from mild to severe. These moms are referred to as ‘manifesting carriers’, their cells opting to utilize the genetic recipe for dystrophin that is inaccurate, incomplete. This is referred to as X-linked inactivation, where the cells essentially turn off the ‘good’ gene with the accurate recipe for dystrophin. And, depending on the degree of the X-linked inactivation, there will be weakness, from cramping to weakness to loss of function, sometimes severe.

Carrier moms also need to take care of their heart. Statistics suggest that 10% of female carriers are at risk. I’m not sure where that statistic comes from. I have seen some papers suggesting the risk is greater. To be honest, I think the statistic is not important as the fact that we need to take care of ourselves. As moms, we often ignore our health to take care of our family. How we feel is last on our list as long as we are getting out of bed and managing to get through the day. I think all women need to pay attention to their heart. Heart disease is common in women and it is essential that we keep our hearts beating strong for ourselves and for everyone who depends on us. Carrier or not – take care of your heart.

And girls with Duchenne. If a young man with Duchenne married a carrier of Duchenne, it is possible that they could have a daughter with Duchenne. I would guess this is indeed very rare. But it could happen. For the most part, girls with Duchenne have X-linked inactivation, where the cells turn off the normal or ‘good’ dystrophin gene. Depending on the degree of this X-linked inactivation, their progression could be the same as a boy with Duchenne. Because Duchenne affects boys 99% of the time, we talk about Duchenne in male terms. Every photo you see will show a boy. In the US, we are guessing around 10-15 girls have Duchenne. While Duchenne is not a club you want to join, I cannot imagine how it feels to be in the club but feel that you are standing in the back of the crowd, unnoticed.

I think this is a discussion we need to have – Carriers, manifesting carriers, girls with Duchenne. If you have any ideas about this, please let me know. You can always email me at Pat@parentprojectmd.org.

And to end my own personal story. I did have my mother tested just last year, assuming in my heart that she would be a carrier as well. She was not.

My father’s company manufactured Doctor bags, the old time doctor bags you may have seen in films. To this day, they are called “Schell bags”. Every Sunday, I would ride with him into town, to the factory (Schell Leather Goods) where he would light the glue pots, so that by Monday, when the men working in the factory arrived, the glue would have reached the appropriate temperature for the leather to adhere to the wood frame. I remember a strange sweet smell wafting through the plant after a few minutes. In conversations with other carriers, some mentioned that their fathers worked with chemicals – fertilizers, pesticides, stuff.

I’ll always wonder. It’s human nature. 

Watching From Israel

Duchenne Israel held its first conference on Tuesday evening. Professor Yoram Nevo, the leading pediatric neurologist and CINRG director opened the meeting with a discussion about his efforts to combine Losartin and Copaxone as a potential substitute for steroids. He has data on each compound and will now test the combination in the mdx mouse. 60+ family members, doctors, researchers, and healthcare professionals attended the meeting. The room was filled – over 60 family members, doctors, researchers and healthcare professionals gathered together for this meeting. The room was filled with excitement, with community, with hope. This is my first trip to Israel and as I stood on that podium, I saw the diversity in the room –different cultures, different belief systems – united in the universal language called Duchenne muscular dystrophy. It was exactly right. We should be together, working side by side.

This afternoon my wonderful hosts took me to the Wailing Wall and to the tunnels, the excavation site to expose the entire Western Wall. Our tour guide provided the historical prospective. We looked back in order to look forward. As we climbed down into the tunnels, the guide explained we were in the central part of the Western Wall, the place thought to be nearest to the Holy of Holy places. We stopped there in prayer, wrote names of the young men we lost this year and placed the notes into the wall.

We walked down the Via Dolorosa, the path Jesus carried His cross. We touched the stone where his body was placed after He died. We again prayed for all of our sons and daughters. We prayed for all of us. Israel. Faith. Hope.

Today is the last day to vote for PPMD in the Chase Community Giving challenge on Facebook. I have voted for Duchenne, for my own sons and for yours. We may not win the $1 million grand prize, but we must vote so that the Facebook universe understands how important our fight is. And so that our children understand how precious we think they are. This contest was never about a big cash prize (sure that would be great, we'll never turn down $1 million!) - it's about awareness.

I'm on the other side of the world from most of you and the faces of Duchenne are just as beautiful here as they are back in the States. Your vote for PPMD and Darius Goes West (another Duchenne specific organization that shares our mission to end Duchenne) is not just for your son or your friend's son, but for the young people all around this world living with Duchenne.

The Marathons of Life

On January 9, I ran the Disney ½ marathon in Orlando. Well, ‘run’ may be a loose term, I walked, but I walked fast enough to complete the race in the required time, crossing the finish line, greeted by a wonderful volunteer holding the coveted Donald Duck medal. It was my third marathon.

I started walk/running in 1984, just after the word Duchenne entered my vocabulary. I was running for something, my own private marathon. I walked for my sons. I wanted to take steps for them, wanted to make up for the steps they would not take and wanted to take steps for others as well. I didn’t calculate how many steps that might take, but I knew that after taking one step, I would be able to continue the momentum.

And now, my private marathons are public, are part of something much larger than myself, something that belongs to all of us. I’m a believer.

55,000 people were running those races in Disney. 55,000 running for something or someone they care about, something or someone they are committed to. 55,000 people committed to succeed.

There is another marathon, but this time, it does not involve running. This uses no energy and with one single click on the computer, will help change the world for 250,000 boys with Duchenne and a few girls and millions of people who love them.

PPMD recently was announced as a finalist in the Chase Community Giving challenge on Facebook. Over 500,000 organizations competed for 100 finalist slots and a $25,000 prize. You voted, and we made it! Now these 100 organizations will compete for five $100,000 prizes and one grand prize of $1 million.

So we need you to vote. And we need you to tell everyone you know on Facebook to vote. And we need you to get everyone who is not on Facebook, to join Facebook, and then vote. The power your one vote could have is incredible. That vote could mean $1 million for Duchenne research. That vote could buy us time.

1 vote. 1 minute. $1 million for Duchenne research.

And if you have 5 minutes we have a list of super easy, super effective ways you can reach as many people on Facebook and have them cast their vote for PPMD. We need all the support on Facebook we can get. Every vote counts!

I am not a seasoned athlete, but I am always able to finish because of the energy of those around me. That energy, YOUR energy, will help us win $1 million to be used in the fight to end Duchenne.

I hope you'll vote today. No training required.

Staying the Course

2010, January

As I spend time on the community site and Facebook, I feel a little jittery. Expectations are high. Everyone is counting days and everyone seems to have a different calendar, a different opinion, and a different bit of information. Some have contacted a clinical center, asking how to get their son in a certain trial, wishing to be first in line. Others have gotten less than expert opinions on genetic testing and the potential ability to participate in an upcoming trial.

This week we have had a number of calls from parents, worried about what is happening with regard to antisense trials and always the ‘when’ question.

The words are familiar – clinical trials, exon skipping (51, 44), first quarter 2010, name dropping of potential sites, conversations with doctors or clinical coordinators followed by a cryptic report on the community site or Facebook. Fear, frustration, disappointment, anger, panic – all wrapped up into one. TIME seems to be slipping away while you are waiting… waiting. The Google alerts are rampant, but it seems there is silence on the exon skipping front, specifically the news you are waiting to hear. And when there is silence, we tend to fill in the blanks… ‘What if something is wrong’, ‘did the company make different decisions’, ‘problems with ???’. Worries increase, tears flow, and the world looks pretty dark. We never simply stop and think – they are working nonstop, need no distractions, and are on track. Once Duchenne enters our lives, we live waiting for the next shoe to drop.

As a community we really need to hold it together and try our best not to over think things.

Prosensa is moving forward. You are already aware of the GSK deal. This is amazing news, exactly what is needed and required for progress. Having GSK as a partner expands opportunities, may change the landscape a bit, but does not change the direction. They are still moving forward. Trials are in development. Discussions with FDA (EMEA) are ongoing. The commitment is solid.

Do not jump with every comment or every post. It is easy to say and very hard to do. Because you are not hearing from someone frequently does not mean the Prosensa/GSK folks are distracted. Be thankful. They are working nonstop to move these compounds forward. They are aware of this great need, very aware that our sons (and some daughters) have no time to wait. They ‘get’ this. This makes every step critical to ensure that the trials are successful and the therapies become approved and everyone who stands to benefit from the compound will have access.

I hear all of you saying – we are willing to take the risk. And I understand that statement, but down deep in your heart there is a follow-up comment – “as long as nothing happens to my son.”

I’m not saying to have patience. That word went out the window with the diagnosis of Duchenne. I’m saying, do not panic. Prosensa, AVI, BioMarin, PTC Therapeutics and many others are all committed to moving as fast as possible and silence should suggest Focus and Commitment.

Last evening Dr Giles Campion, Chief Medical Officer for Prosensa wrote:

Dear Pat

Just tell them that on the authority of the Chief Medical Officer for Prosensa and a member of the GSK Joint Project Team you have it that there is no question of delaying the trial until 2011, on the contrary, everyone on the team is working very hard to run the necessary clinical study as soon as possible.

Regards,
Giles

Stay the Course. 2010 will be a good year for Duchenne.

Aligning the Stars

PPMD is growing. We have an amazing Board, an equally amazing staff (commonly referred to as the Cult), and a wonderful community. So what should be the logical next step? This has been our conversation for the last year. It is easy right? Add staff. But as you begin to think of who that person might be, you start to develop a wish list, naming all of the qualities/skills you are hoping to find in a person. And then there is Duchenne. How do you explain Duchenne to someone who has no experience? It is not an easy subject and certainly not simple. This means, the wish list expands to find someone with a passion for Duchenne, someone who understands the need to buy TIME, someone with significant experience and knowledge about research, someone who ‘gets it’, understands the full impact of the diagnosis. Someone like Sharon Hesterlee. Boy, if only we had a Sharon Hesterlee.

Sundays are not my favorite days. People rest. I fidget. On Sunday some months ago, I received a message from Sharon Hesterlee. She wanted to talk. The thing is, I like to talk with Sharon Hesterlee. I met her long ago, when she joined the MDA to lead their research investments. She is smart, well-versed, knows the field and the players. She understands the investments and is a well-respected leader in the field. She knows the obstacles, the bottlenecks, and the politics. And, she has been around this community for over 10 years. She understands the value of developing collaborations, recognizes the need to leverage money, and understands all of the moving parts. This Sunday was looking up!

I called. We discussed a range of issues, most specifically her interest in focusing on a single disease – Duchenne. You might imagine, I was smiling. And thrilled when she said she would like to work for PPMD. I called John Killian (our Chairman) and he connected with the Board. Sharon flew into NJ and met the staff. Sometimes you just know things and this felt exactly right.

After trying my best not to shout this news from the rooftops for the last few months, I’m thrilled to be able to say – Sharon Hesterlee works for PPMD. She is Senior Director of Research and Advocacy.

Some days, the stars line up just right. Happy 2010.

Holly PA

What’s new at PPMD? Holly Peay (pronounced P-A). Well, not exactly new, but new in that Holly has joined the staff of PPMD! We first met Holly when working on DuchenneConnect, the patient self-report registry. She came highly recommended as a genetic counselor, an educator, and an all-around, really smart woman. Her task was to create educational materials for families and for providers – educational information about Duchenne, about genetic testing, about care, about research, about clinical trials; and present it in such as way, that it would be comprehensive and understandable, even if the information was really fresh and even if tears might get in the way of your reading from time to time. She did it! She made very difficult information understandable.

Through DuchenneConnect and the PPMD Community site, we heard stories. Stories about delays in diagnosis…months…years at times. We thought about what we might do to help. We had some experience.

We submitted a grant to the Center for Disease Control (CDC) and were granted a cooperative agreement. The goal of the grant is to educate, to raise awareness about muscle weakness, and to impact the diagnostic odyssey. Our initial experience was in Mississippi. We developed partnerships with healthcare professionals likely to see children in the early years of life (ages birth to 5 years). We wanted to understand what happens when mom, dad, gram, or anyone really, expressed concern about a child’s muscle strength. What words did they use? What happened when they raised concern with the doctor (nurse, physician’s assistant, healthcare professional, teacher).

And we learned that some of the time, concerns are dismissed. We learned that some doctors/healthcare professionals are not exactly sure what they are to look for. We learned that some of the time, referrals to specialists are difficult with long waiting times. We learned that sometimes the response is to send the child to a PT or put them into an exercise program to improve strength. And the diagnostic odyssey continues. Typically mom, dad, gram’s worry is relieved for only a short time because they see something is still not quite right.

With this current cooperative agreement, we are expanding our horizons. Our goal is to educate healthcare professionals and this time, not in just a specific state but rather now through the professional societies. There are too many acronyms to list – but professional societies of every healthcare professional group you can think about – pediatrics, family doctors, physician’s assistants, nurse practitioners, nurses, physical therapy…you get the gist.

We have expanded this effort to include ‘primary muscle disorders of childhood’ – because the message will have greater impact. And Duchenne is the most common

We have developed common messages:

• Watch them walk, run, climb (in the confines of an exam room, sometimes it is difficult to really see what mom, dad, gram is talking about)
• Developmental Delay, include a CK (you already know this one)
• YOU CAN ALWAYS DO SOMETHING! (this is for everyone –do not dismiss worries/concerns. Typically when someone loves someone, they are pretty observant and usually right.)

There is a Task Force leading this effort. Kathy Matthews, MD is Chair. Brian Denger is Project Manager. Task Force Members include representatives from Professional Societies and Advocacy organizations - MDA, PPMD, CMD, SMA.

Holly Peay is the PI on this grant. She is now part of us, part of PPMD. If you see her in the hall, please say hello.

Welcome news!

Ataluren (PTC124®) in Nonambulatory Patients With Nonsense-Mutation-Mediated Duchenne/Becker Muscular Dystrophy (nmDMD/BMD)

I realize it is so difficult to see trials targeting specific mutations and feel like you are on the outside looking in, wondering when it will be your son’s turn. Prosensa and AVI’s trials are moving forward as well. More trials are in the planning stages – Sildenafil, Losartin, IGF-1 and others. Still some of our boys do not fit the criteria, either based on mutation or because they are not walking.

So this trial fills a hole. It is a safety trial but will validate outcome measures for the non-ambulatory boys. Outcome measures in the non-ambulatory population have been a significant barrier for inclusion in clinical trials and for this reason, trials have focused on ambulatory boys. How to measure? What to measure?
There has been considerable discussion about cardiac and pulmonary outcome measures, clinicians concerned about the length of time required to demonstrate decrease, stabilization or benefit.

While the Ataluren trial will include cardiac and pulmonary endpoints, it will include a variety of functional measures, assuming one or more will be validated as THE outcome measure(s) for the non-ambulatory population.

And then, at the end of the day, non-ambulatory boys will not feel like they are at the end of the line.

For more on this trial, click here.