Pat Furlong's Journal

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November 28, 2007

The Search for Genetic Modifiers

Genetic modifiers? Genetic modifiers are genes that influence progression, in this case in Duchenne muscular dystrophy. Actually genetic modifiers are the primary reason for variation in many things: disease course, response to drugs, and susceptibility or resistance to certain diseases, to name a few.

Genetic modifiers influence or change the predicted course. This may be a bad example, but it is the only one I can come up with at the moment…

The Cincinnati Bengals (a football team) are a mess – bad defense, slow offense, star players arrested, and bad management. No one is predicting a Super Bowl in their future. I assume the Bengals know the game of football so their ‘football’ genetics are in place. Hopefully they map out their strategy, their plays, and, with some luck, they have been in training and attend practice. But they are losing. If Cincinnati recruits different players, changes management, and instills some sort of understanding for the law, maybe things would change. These changes, these sorts of “genetic modifiers,” would positively impact what happens over time. In short, the Bengals could benefit from a few genetic modifiers of their own.

The diagnosis of Duchenne often arrives with a prediction about what to expect and what you should expect to see in the not too distant future. I actually have never understood why some physicians are so interested in “fortune telling”; how they think they are able to describe, in exact detail, what the future holds and in this case, what your son’s future will look like. I often hear the same horror story from parents/family members. You know the one because it will echo in your brain forever – A parent is told, “Your son has Duchenne muscular dystrophy. It follows a predicted course. He will stop walking…” and ends with the phrase “nothing to do.” It makes me cringe.

I realize at that very moment, as your heart is shredding cell by cell, you are not actually in a position to respond or even speak a sensible word. A fitting response is impossible at that moment and no one would want to repeat this day just to figure it out. And when I hear these stories, I feel an intense desire to grab that physician by the throat and ask if he/she has some sort of a crystal ball or some sort of need to make sure the family ‘accepts’ the diagnosis. No one can predict the future, even in Duchenne, and isn’t the diagnosis enough information for one day? (Okay, step down from your soapbox Furlong!)

On a certain level (in business speak, you might hear something about the 60,000 foot level), Duchenne might be predictable. From that very high platform (and it is pretty frightening to look down when you are up that high), one might suggest that boys with Duchenne are diagnosed between the ages of 2 and 7, that they stop walking somewhere in the range of 8-15 years of age, and that Duchenne is lethal at some point, but it is variable. Even at 60,000 foot, there is a great deal of variability. It is like saying all the trees in the forest are the same just because they have roots, a trunk, branches, and leaves. It’s just not true and identifying some of those differences, figuring out why differences exist, will enable us to improve care, and provide targets for new therapies.

Close up, Duchenne is highly variable. You are probably intensely aware of this fact. Just connect with another parent who has a son the same age and with the same genetic mutation. It will become quite apparent that there are significant differences:
o Why one individual appeared to have normal muscle function with perhaps only speech delay at diagnosis.
o Why one can jump with both feet off the ground or ride a bike and another could never manage this feat.
o Why one has certain behaviors and/or significant cognitive issues, others are straight-A students without any apparent learning issues, and why another has the diagnosis of autism and Duchenne.
o Why some are walking just fine but have significant arm weakness and why others’ arms are quite strong, but struggle with fine motor control.
o Why some have accompanying smooth muscle problems (swallowing, reflux, constipation, bladder weakness).
o Why some children have significant changes on their echocardiogram and others not.
o Why some parents suggest their son has ‘severe progression’ and others think their son has a ‘mild’ progression, and why physicians refer to a severe Becker or mild Duchenne.
o Why physicians talk about ‘outliers,’ individuals who are not following the normal progression, shake their head, and are unable to offer an explanation.
o Why some children have no response to steroids, and others have a dramatic response.
o Why brothers, with the same genetic mutation, often have different rates of progression, and why some identical twins are not ‘identical’ when it comes to Duchenne.

We might spend the day arguing about steroids and supplements and perhaps other approved drugs, but the reality is that there are different rates of progression and many of these differences are only explained with genes that modify progression. Individuals with the same mutation demonstrate significant variation. And simply saying a mutation is ‘in frame’ (the genetic sentence makes sense) or ‘out of frame’ (genetic sentence makes no sense) does not completely explain the rate of progression. Some individuals do well, in spite of having the ‘out of frame’ mutation and ‘zero dystrophin,’ while other boys who are expected to do well based on the presence of dystrophin have significant weakness.

We might also speak with experts in Duchenne and discuss how often progression is different in a certain area or a certain country. During discussions with Helen Posselt from Australia, she talks about her aboriginal boys and how they seem to have a very rapid progression, often stop walking by five or six years old, and typically have no response to steroids. Why I wonder? She and I have discussed muscle fiber types and how humans differ from the mdx mouse. You are probably well aware that we have two fiber types (fast and slow twitch) and the mdx mouse has 4 fiber types (and infinite regenerative capacity). The only mouse muscles that contain fast and slow twitch fibers are the soleus and diaphragm. So we cannot compare the mdx and human equally. And there is no way (at the moment) to quantify an individual’s fast versus slow twitch fibers. We do know that the fast twitch fibers wear out first and certainly fast versus slow is an interesting discussion.

We might also discuss environment and it is pretty clear, weather has a significant influence on our health. We know individuals with Duchenne/Becker have more difficulty in the cold and freezing temperatures make it very difficult for them to move. We know that they are able to move easier and feel better in warmer climates. Ok, ok, who doesn’t feel better with the sun shining on your back. Throw in a little ocean breeze and the beach and we are all happy. But I think we all recognize climate changes are significant for individuals with Duchenne.

Of course there are a range of possibilities that can influence progression: care, treatment regimens (steroids, ace inhibitors, supplements, stretching, etc.), positive home environment, climate, and most definitely genetic modifiers. We are collaborating with researchers at UCLA in an effort to identify these genetic modifiers, to understand what genes are up-regulated or down-regulated, and how progression is influenced or modified. This is a critical piece of the puzzle.

You are already aware we launched DuchenneConnect (www.duchenneconnect.org). DuchenneConnect will expand over time, with surveys on behavior, services, progression, and information related to clinical trials, as well as information about specific projects.

Genetic modifiers – peeling back the genetic layers to understand progression – will be one such project. The project will involve collecting DNA samples (sputum) for analysis and comparison. UCLA researchers are interested in collecting samples from individuals with Duchenne/Becker. Of course, the more individuals participating, the more robust the data set. What will also help a great deal is to learn about ‘outliers,’ individuals who are following a different course than expected or predicted, and brothers or twins who have different rates of progression.

I think we all know that things are changing, though I fully realize it will never be fast enough. We do know that our children will have the opportunity to participate in promising clinical trials. We also know that it will not be easy or simple; there will be some children who do not respond to a certain therapy and some children who will do really well. Understanding genetic modifiers and looking at differences will be key to maximizing therapies, identifying new therapies, and helping to tailor therapies to an individual in order to achieve maximum benefit.

Please register with DuchenneConnect. You will be hearing more about our participation in the Genetic Modifiers project in the next few months and how we intend to begin collecting samples. It is one more way we need to work together as a community to End Duchenne.

Posted by ppmd at 11:31 AM | Comments (0)

November 20, 2007

Chutes and Ladders

Did you ever play the game “Chutes and Ladders’ with your child(ren)? It is a very simple game of counting -100 steps in all, but offering shortcuts in the form of ladders and missteps (or chutes) that send you falling. My children absolutely loved this game. They were delighted when they slowly and carefully moved their pawn along the path, holding their breath as they landed just before or after a chute. They especially giggled when I landed on the wrong step and slid down the chute. Some chutes are short and recovery is easy. With others, you fall back and nearly have to start all over again. With one roll of the dice we all knew, we might be instant winners or sent spiraling down into oblivion. The goal was to avoid the chutes of course, but often one roll of the dice would change everything. It wasn’t exactly something you could plan for. It just happened. That’s it isn’t it. Life – hardly a game, but filled with chutes and ladders.

Is Duchenne a chute or ladder?

Your instant response – CHUTE! Of course it is a chute, a downward slide, a spiral into a cavern of loneliness and sadness. Your heart feels like it is breaking over and over. That makes sense doesn’t it? Duchenne was not part of the plan. You grew up with a certain set of expectations. You carried around a set of plans. You had them all organized in an imaginary box in your mind, adding dreams, wishes, and thoughts all along the way; things you want to do, things you are sure would happen, things you knew you would have – love (partner, husband/wife, love of your life), career, family, healthy children, grandchildren, health. You would pull them out at the right time and in the right place and watch your life evolve. There was no plan for the diagnosis of Duchenne. It couldn’t happen and wouldn’t happen on your watch.

And then out of the blue (or maybe not so out of the blue) some worry crosses your mind or someone says something, makes a comment. Your son is not keeping up. It’s that roll of the dice and you feel your step is no longer solid. You feel yourself falling. You might have suspected something, saw some something that you could not quite put your finger on. You might have mentioned it to friends, to relatives, to teachers, to the doctor. Early on, you were dismissed. It’s nothing. But something changed in you. You became more vigilant. You knew.

And then the word Duchenne. You can feel yourself sliding down that chute and it feels like you cannot get your footing, cannot find a ledge...Everything you planned for, that box of dreams you once carried, drops right on the ground, the contents spilling out everywhere. Everything has changed. Not only has the dream changed, but the box has shattered as well. How will you cope? Is it worth going on? Words like Joy, Laugh, and Smile are now foreign concepts, not to be found as you hit rock bottom.

Could Duchenne be (or become) a ladder?

I think I cried nonstop for the first three months after Chris and Patrick were diagnosed. I was sitting at the bottom of the chute staring up. I spent a good bit of time concentrating on all the things I thought I would not have, could not have, and would miss. I was sad for my boys, for my girls and for my family. But at a certain moment, I stopped crying. Maybe I ran out of tears. I found I could no longer justify my crying. After all, this was not about me. It was about my boys and my girls. They were happy and life was going on. As much as I wanted to shut it down, life kept moving. It changed for me to be sure. My dreams changed. My box of plans had to be opened, re-jigged, and remodeled, but I could not sit at the bottom of the chute motionless. I had to stand up and roll the dice, try to take another step forward, and I found that when I rolled the dice, I could take a one step and then another. It was not easy, but I found the more steps I took, the more I could take. And I found others to help – all of you – cheering me on, saying I could take the next step, and the next, and the next. It made me smile. But smiling isn’t right in Duchenne? At least I thought so… but maybe not. Maybe there are reasons to smile again.

I see it in the marathon, at the conferences, on the message board, everywhere. All of us, together believing we can take the next step and knowing that with each step, we will find ladders or build ladders where we need them and when we need them. We are moving and climbing those ladders together. We just need to stand still for a moment and realize what we can do together.

It’s Thanksgiving in the U.S. this week. It’s a day when we spend a few moments thinking about what we are thankful for and since this is my blog, I wanted to take advantage of the opportunity to tell you how grateful I am to have all of you in my life.

You are my ladders.
You inspire me and make me grow.
You are strong when I need to lean.
You are firm when I need to hold on.
You are creative.
You build ladders where they did not exist.

You are all on my “what I am thankful for” list.

o To Chris, Patrick, Jenny and Michelle…you are and always will be my teachers, my inspiration, and the loves of my life.
o To every family and every boy, girl, young man, and adult with Duchenne or Becker muscular dystrophy…you are my heroes.
o To every person who has donated to PPMD, run in marathons, volunteered, wished us success…you are my angels.
o To every researcher who has dedicated him/herself to make a difference in this space…you are my Superman and Wonder Woman.
o To every physician and healthcare professional who places his/her tender hands on our children, looks carefully and comprehensively with hope…you are our protectors and the guardians of our children.
o To the pharmaceuticals and biotech companies committed to Duchenne…you are working to make our dreams come true and we wish you Godspeed.
o To the Congress of the United States for hearing our voice…you are our champions.
o To the Board of PPMD…you are our visionaries
o To Kimberly, Will, Ryan, Sandra, Cecilia, Janet, Stephanie, Sue, Sandy…you build our ladders and our hope.

Posted by ppmd at 11:37 AM | Comments (0)

November 12, 2007

If I knew then what I know now….

On Thursday last week I met with some dear friends. They were in Cincinnati with their son for a follow-up visit with the Cincinnati Children’s Hospital Neuromuscular Team. Their son is now 14 and we recalled the ‘early days,’ 10 years ago when he was diagnosed. At that time, both parents went on the internet searching for information about DMD and, just like you, they were overwhelmed. They spent their waking hours and their sleepless nights searching. They immersed themselves with information and descriptions. They looked through textbooks with illustrations of muscle weakness and scoliosis. And somewhere in their mind and heart, they envisioned what the next few years would hold. It terrified them. With each passing moment and most certainly with each birthday, they had a sense of impending doom and anticipatory grief. They watched. They waited.

Soon after his diagnosis, their son was started on the weekend dose of steroids. That regimen seemed to ‘hold’ him and seemed to stabilize his motor function for a period of time. While attending PPMD conferences long ago in Pittsburgh, they became aware of a number of different regimens for steroids – weekend, intermittent (10 days on, 10 off, every other day, etc.) and daily regimens. They spoke with other parents and made the decision to change from the weekend regimen to a daily regimen of Deflazacort. For this young man, changing the regimen was a good decision. His strength improved and he, once again, seemed to stabilize.

Today he is 14. The diagnosis was 10 years ago. At 14 years, he continues to walk and walk well. He is able to run. (OK, so I am well aware of how our sons ‘run’, but for them, it is a ‘run’ and I’ll take that!) At 14, he is in high school taking four honors classes. At 14, he has friends, loads of them. At 14, he is doing well. He does have some complaints related to his height and his red, puffy cheeks, but all in all, he is doing really well.

His parents have become very good friends over those 10 years. I lean on them often for advice, for help…for just about anything. We discussed those early days, the first year(s) after the diagnosis. The dad looked at me and said “I would have saved a lot of sleepless nights if I could have had some clue about how my son would look at age 14, about the quality of his life, about the quality of life for our entire family; if I could have had some assurance that we would be NORMAL.” And they are!
NORMAL. How many times have we all wished for this? NORMAL is a strange word and I am sure each one of us will have a different definition. In the context of Duchenne and our frame of reference, I would guess NORMAL is actually referring to muscle function as in walking, running, and keeping up with peers. I actually think we need to reframe the word NORMAL because I’m pretty sure we are all NORMAL.
Actor Colin Farrell has done a great job of reframing ‘normal.’ His son is diagnosed with Angelman Syndrome. Angelman Syndrome is diagnosed between 3 and 7 years of age. Early signs are developmental delay which is functionally severe, speech impairment with minimal use of words, movement disorders, and unique behaviors such as short attention span, hand flapping movements and excitable personality. Many of these children have delayed or disproportionate growth in head circumference. When Colin Farrell talks about his son’s condition, he says, "With my son, the only time I'm reminded that there is something different about him – that he has some deviation of what is perceived to be normal – is when I see him with other four-year-olds. Then I go, 'Oh yeah', and it comes back to me. But from day one I felt that he's the way he's meant to be.” He also says that he feels incredibly blessed to have his son in his life. "There is no heartbreak about it…it's not a sad story. I'm incredibly blessed to have him in my life," he told Britain's Daily Mail. “He has enriched my life incredibly and I wouldn't have it any other way."
It is the same for us. Our children inspire us. They teach us. They are our gifts. And our lives are NORMAL – NORMAL for us. That is not to say we are content – not at all. We are working like hell to make sure we have our sons longer, that they can fully participate, that they can lead active, fulfilling lives, and that they have opportunities, lots of them. But in the meantime, it seems very important to recognize every moment of every day is important and definitely worth celebrating.

Posted by ppmd at 12:00 PM | Comments (0)

November 05, 2007

Genetic Testing.

When we think about genetic testing, we think Dystrophin gene – deletions, duplications, point mutations, splicing errors. We think Duchenne. And while genotyping the Duchenne/Becker population is foremost in our mind and we are discussing the need for insurers to cover this type of testing, it is actually only one type of testing. There are other types of testing that will be important in our future as well.

One type of testing is predictive: identify your genetic predisposition to a certain disease (e.g., BRAC 1 gene for breast cancer) or how you might respond to a certain drug (e.g., wafarin (vitamin K antagonist) for blood thinning after embolism, valve replacement, etc.). This type of testing will hopefully be our future as well because we know some individuals will respond positively to certain treatments and some will not. Understanding and predicting what interventions will be most effective for a certain individual is part and parcel of the personalized medicine we will see in the future.

Another type of genetic testing is referred to as ”direct to consumer.” Certain companies advertise directly about genetically testing a hair sample (an example of this approach). They will then perform testing and notify you about what type of foods are best for you or what type of supplements will improve your health. This testing is often expensive (both the testing and recommendations) and there is little evidence to support its validity. Insurers are not, at this time, willing or interested in covering this type of testing.

At the moment, for all of us, genetic testing is specific – it is specifically related to our sons. We want and need to know about our son’s specific mutation. We want to know exactly what happened in his Dystrophin gene that prevented his cell machinery from producing Dystrophin or produced a truncated (shortened) form of the protein that is unusable. For many of our families, especially those with younger boys, we are guessing genotyping has been done. But the real answer is that we do not know how many children have been genotyped, how many have ‘old’ or outdated testing, and how many have not been tested at all. In some clinics, physicians recommend biopsy, because biopsy is reliable for diagnosis and it is typically covered by insurance. Genotyping – sequencing the dystrophin gene – may or may not be covered by insurance. In addition, many healthcare providers may not be aware of this fast changing technology, may not understand why this is critical information for families, and may not have the knowledge base or resources to interpret results of testing.

The environment has changed dramatically. Genetic testing is a critical piece and essential for participation in upcoming clinical trials. Some of the early testing was unable to provide detailed test results and the technology has changed dramatically. Most recently, Madhuri Hedge, from Emory University, published her chip technology with 99% accuracy and a 7 day turn around time. You are probably aware that we have been working with Emory, the CETT program and others, to develop Duchenne Connect. We are working with MDA to develop a genotyping program and will do our best to reach across the US and around the world to ensure every child diagnosed (and those yet to be diagnosed) have accurate genetic testing, that their data is collected, and that they are potentially able to be considered for participation in upcoming clinical trials. Older boys, with outdated testing, may need to be retested. It the testing is greater than 5 or 6 years old, please ask your physician about the need to be retested.

Posted by ppmd at 11:33 PM | Comments (0)