Tag Archives: Mitochondrial Disease

Kentucky Gives Day 2017: Support NUBPL Foundation

“Never doubt that a small group of thoughtful, committed citizens can change the world. Indeed, it is the only thing that ever has.”
Margaret Mead

In 2015, our (now) 5-year old daughter, Katherine Belle, was diagnosed with an extremely rare Mitochondrial Complex 1 disease caused by mutations in the NUBPL gene.

The harsh reality is we have a vibrant and amazing five-year old daughter who fights daily with everything she has, but because NUBPL is a recently discovered disease without any available treatments, we do not know what the future holds in terms of her health and disease progression.

As tireless advocates for our daughter, we decided to do more. We founded the NUBPL Foundation to fund research for NUBPL, which causes progressive atrophy in our daughter’s cerebellum, as well as speech and developmental delays.

Katherine is just one of 11 patients in the WORLD identified in scientific research, although we believe the number of confirmed NUBPL patients is likely closer to between 25 to 50. All patients have been diagnosed through Whole Exome Sequencing (WES), and we have no doubt that the NUBPL patient population will continue to increase as more families use WES to diagnosis their children. We have been very public about our story so that we can help clinicians and families better diagnose NUBPL in the future.

Because orphan diseases are rare, they lack support groups and national organizations. And, 95% of rare diseases do not have any FDA approved treatments, including NUBPL. Orphan diseases don’t attract as many research dollars because few people are affected, and for pharmaceutical companies, there’s less incentive to fund the research for a treatment that will not produce a good return on their investment.

Our daughter and other affected children deserve better.

NUBPL Foundation

We have carefully listened to proposals from top researchers from around the country and have decided to fund the promising research of Dr. Marni Falk at the University of Pennsylvania. The Mitochondrial-Genetic Disease Clinic at Children’s Hospital of Philadelphia (CHOP) is one of the top research centers in the nation for Mitochondrial related diseases. This research gives us hope that therapies will soon be developed to help treat the mitochondrial dysfunction of Katherine and other NUBPL patients.

100% of your tax-deductible donation will directly fund the research of Dr. Marni Falk and her team at CHOP to research the NUBPL gene and to develop life-enhancing treatments for the mitochondrial dysfunction of Katherine and other NUBPL patients. 

Our matching gift pool from our Double The Hope partners will match every donation – DOLLAR FOR DOLLAR – we receive from you on April 18, 2017, to ensure we reach our $25,000 goal.

Click on the picture to donate to the NUBPL Foundation:

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Rare Bourbon for Rare Disease Fundraiser

NUBPL is a form of Mitochondrial Complex 1 Disorder. Discovered just a few years ago that mutations of this gene are disease causing (our five year old daughter has two mutated copies of her NUBPL gene – one mutated copy from mom, one mutated copy from dad), our family wants to know more so our daughter can have treatments and/or a cure.

The bottom line is that we need to fund the research. Researchers need money to study diseases. We founded our very own non-profit, NUBPL Foundation, to do just that. NUBPL Foundation is an all-volunteer (we do all of the work ourselves and for FREE!) non-profit with the mission to elevate NUBPL research and awareness. Simply put, we are raising money to fund research and find other patients with this disease.

We are starting at ground zero with this research. The good news is there are scientists and physicians who want to perform this research, but they need money. For starters, we need to raise $50,000 to purchase a mouse. There has already been NUBPL research performed on plants, but now we need to see what happens when a mouse has NUBPL. There is much to learn from a NUBPL mouse. What is learned from the mouse will determine what comes next.

Rare Bourbon for Rare Disease is our first NUBPL Foundation fundraiser on Saturday, February 25, 2017, at Haymarket Whiskey Bar in Louisville, Kentucky.

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This is your opportunity to taste bourbon from a bygone era – a 1982 O.F.C. vintage-dated bourbon – and fund rare disease research at the same time. Only 50 bottles of this very rare bourbon were ever bottled, placing each bottle’s worth at $10,000. Buffalo Trace released all 50 in 2016 to charities for fundraising. One recipient was The NUBPL Foundation. (For more information, click here.)

The NUBPL Foundation, Inc., is a 501c (3) corporation, funding research for a very rare Mitochondrial disease caused by mutations in the NUBPL gene. This disease causes progressive atrophy of the cerebellum in affected children, among other dire complications, and mutations of the NUBPL gene have also been linked to Parkinson’s disease. The hope is that further research will lead to life-enhancing, life-saving treatments for both NUBPL and Parkinson’s patients.

Be a part of bourbon history while supporting an important cause. Join the NUBPL Foundation and 5 Bourbon Societies – Paducah Bourbon Society, Owensboro Bourbon Society, Lexington Bourbon Society, The Bourbon Society, and JB’s Whiskey House of Nashville – at the legendary Haymarket in Louisville. All ticket holders will enjoy light appetizers provided by our event food sponsor Masonic Homes of Kentucky, Inc.

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There will be three tiers of entry:

Tier 1 – $250 Donation: (Quantity available: 50)
-1 Flight of 4 Rare Bourbons, including OFC Vintage 1982, 20 Year Pappy Van Winkle distilled by Stitzel Weller, a 20 year Willett Family Reserve (barrel C43A), and a 1971 Old Grand Dad.
-1 Bottle of a Special Knob Creek Single Barrel Private Selection

Tier 2 – $100 Donation: (Quantity available: 50)
-1 Flight of 3 Rare Bourbons, including AH Hirsch 16 year, a 21 Year Old Willett Family Estate (barrel 3936, Liquor Barn Holiday Selection), and a 1970s Ancient Ancient Age.
-1 Bottle of a Special Knob Creek Single Barrel Private Selection

Tier 3 – $50 Entry Donation: (Quantity available: 100)
-1 Bottle of a Special Knob Creek Single Barrel Private Selection

Fred Noe, Master Distiller and 7th generation Jim Beam family member, will attend the event from 7-8:30 to sign bottles of the Knob Creek.

This event will also include a Silent Auction, featuring E.H. Taylor Sour Mash, E.H. Taylor Tornado, 2012 Angels Envy Cask Strength, and multiple years of Pappy Van Winkle.

Other items, available via an on-site raffle or live auction, will include gift baskets from Jim Beam, Sazerac, and Four Roses, special bottles of Private Selections from participating bourbon groups, and other donations from bourbon groups.

Tickets are limited.

To purchase your tickets, click here.

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You may also mail donations:

NUBPL Foundation
230 Lancaster Avenue
Richmond, KY 40475

Mitochondrial Disease Awareness Week (September 18-24)

In honor of Mitochondrial Disease Awareness week, we would like to help you better understand Mitochondrial Disease, especially as it relates to our daughter. There are families that do not like to discuss their child’s disorder, and although we can respect that decision and honor their wishes, we have a very different perspective when it comes to our own daughter.

For starters, we cannot hide the fact that Katherine cannot walk, has a mild tremor, and an irregular speech pattern.  Knowing our child is a wonderful opportunity to learn about rare diseases as you get to know her personally, and since she is unable to fully articulate the ins and outs of her disorder, we are her voice. No, we do not think her disorder defines her, but it is as much a part of her as anything else. Second, we are not embarrassed by her disorder and do not want her to feel that it should only be discussed behind closed doors. Third, knowledge is powerful. We don’t want people to guess why our child cannot walk – we want to educate you with the facts so you can help spread awareness just by being informed.

This is the way we understand or think about our daughter’s condition: Katherine has a very rare genetic disorder known as Mitochondrial Complex I (or 1) Deficiency caused by mutations in her NUBPL gene. There are dozens of types of “Mitochondrial Complex I Deficiencies” but her particular type is very rare. To date, only 6 people have been diagnosed with it in the United States and approximately 25 in the world. That said, it has only been known about since 2010, and can only be diagnosed through Whole Exome Sequencing – a complex and often expensive genetic test. We expect many more to be diagnosed with it in the future.

One of the patients (residing in the U.S.) has identical mutations to Katherine. We know a little about her through research papers.

Because there are so many types of Mitochondrial Complex I disorders and each is different, we sometimes refer to Katherine’s type as “NUBPL,” the name of the gene affected.

So what is NUBPL/Mitochondrial Complex I Deficiency?

When people think of “mitochondria,” many think of DNA from just the mother. This is true only with respect to some of the DNA making up the mitochondria. In fact, they are put together mostly from gene pairs with one gene from each parent (nuclear DNA), plus just a handful involving just one gene coming from the mom (mitochondrial DNA).

All of our cells (except red blood cells) contain mitochondria. The mitochondria produce the energy our cells need to function, to replicate, and to repair themselves. They are the “powerhouses” of the cell.

This “power” is produced through a series of chemical reactions taking place in 5 different physical structures. These are called complexes I through V (or 1 through 5). They work together like an assembly line. If a problem exists in one “complex,” it can harm production down the line in another, ultimately resulting in too little “energy” being produced.

Like an actual power plant, the process of producing usable energy also produces chemical byproducts that can be toxic. Our bodies clean these byproducts through, among other things, “anti-oxidants.” However, sometimes a person with a mitochondrial disease produces too many toxic byproducts for the anti-oxidants to work, leading to a build-up of toxins. This process is called “oxidative stress.”

Thus, a good analogy is a power plant with five buildings, each producing products that are sent down the line, ultimately producing energy from the final building, Complex V, while also producing polluted water that is filtered and cleaned by another facility before being released into a stream. A person with a mitochondrial disease has a problem in at least one building of the five. As a result, she may not produce enough product to be passed along and ultimately turned into energy to meet the needs of the cell (not enough energy is coming out of Complex V) or may be spitting out too much pollutant to be filtered and the water in the stream is getting polluted.

Either of these can result in premature cell death or impaired function.

The nature of these diseases is that they often cause damage over time — again, like pollution from a factory. Similarly, illness can increase energy needs of the body, and cells can become damaged because of their inability to meet the needs in times of higher demand. Both of these things occurs in all of us as we age (mitochondrial dysfunction is a significant contributor to the symptoms of old age, including wrinkles, loss of muscle, loss of brain function, clumsiness, and heart disease). Patients with a primary mitochondrial disease just suffer this fate differently, earlier, and in different parts of their bodies. Note, however, that this is not the “premature aging” disease. Regardless, by their very nature, these diseases often progress.

The extent to which Katherine’s particular condition, NUBPL, is progressive is not yet known. In most cases, it progresses to a degree – it has with Katherine. Fortunately, many of the patients have long periods without any advancement of the disease and many are thought to have become stable. The reasons are not clear, nor has the disease been known about long enough to determine if this is typical.

The patient with Katherine’s identical mutations is now 13. Our information is now 5 years out of date (it was in a 2010 research paper). As of 2010, she could walk with a walker and had normal intelligence. She had not had much regression after an initial period of regression experienced when she was a toddler.

Different cell types have different energy needs. Skin cells, for example, need little energy, so contain few mitochondria. Heart, kidney, liver, and brain cells, on the other hand, have high energy needs, so contain the most mitochondria. Liver cells, for example, may contain as many as 2,000 mitochondria per cell. As a result, these parts of the body are susceptible to “mitochondrial diseases,” either because the energy needs are not being met, or in meeting them too much “pollution” is being produced. Some of these diseases affect only one of these parts of the body, while others may affect multiple systems.

Katherine’s disorder is a problem in “Complex I,” thus the name “Mitochondrial Complex I Deficiency.” This is the largest of the five complexes, the one involving the most genes for its assembly and function. It is the most common place for these diseases to arise.

Knowing that Katherine has a disorder in Complex I tells you very little. Returning to the power plant analogy, it is like telling you there is some sort of problem in “building one” of a five building complex, but not knowing what that problem is; it could be something small, like a clogged toilet, or it could be something large, like the complete collapse of the building. The devil is in the details.

Some Complex I deficiencies are quickly fatal. Others are far more benign. Indeed, it is likely that many are so benign that a person can live a long healthy life without knowing they have a disorder. Still others may suffer problems only late in life, such as developing Parkinson’s or heart disease.

Thus, Mitochondrial Complex I Disorders can range from quickly fatal to unnoticed and insignificant. No known patient has died from the disease and only one has died at all (from what is not clear, nor is it entirely clear that NUBPL was the only condition he had, as he was the first NUBPL patient and died before current testing methods were developed).

In Katherine’s case, the gene affected, NUBPL, is “nuclear,” meaning she inherited one gene from each of us. In order to manifest as a disease, Katherine had to receive one mutated gene from both of us – one mutated gene and one normal one will not result in disease, but only “carrier” status (Glenda and I are both carriers, each having one mutated gene, but not two). Having a single mutation of this gene is rare. Having parents who each have one mutation of the gene, rarer still. Having both pass one mutated gene to the child is extremely rare (there is only a 25% chance that two carriers will have a child with two mutations) – lottery-level odds (more people win the Powerball each year than are known to have NUBPL, worldwide).

Because it is so rare and so newly-discovered (discovered in 2010), not a lot is known about Katherine’s form of Mitochondrial Complex I Disorder. What is known or suspected is as follows:

The NUBPL gene is known as an “assembly gene.” This means that it is not part of the physical design or structure of Complex I, but is a gene that contributes to its assembly. In particular, it is involved in the assembly of “iron-sulfur clusters” that transfer electrons during the chemical reactions in Complex I.

Think of it as Katherine having an accurate blueprint for “building one” of her power plant, but someone used defective wiring or put the wiring in it the wrong way. What this means is not fully understood. One possible result of this is that the electrons that are supposed to be carried by this “wiring” may leak out and be transferred to chemicals other than those intended, producing the toxins referred to above (known as “Reactive Oxygen Species” or “ROS”).

While it would seem like this defect would affect the mitochondria throughout the body (and NUBPL patients must monitor all systems to make sure problems do not crop up), to date, NUBPL mutations seem concentrated in the brain of patients. While some NUBPL patients have issues throughout the brain, most are concentrated in the cerebellum.

Katherine is fortunate in that her brain appears to be spared except for the cerebellum and one very small inflammation in her corpus callosum that has not changed and may well resolve or never affect her in any way.

As far as energy production, Katherine’s Complex I residual function appears to be low normal in fibroblasts grown from her skin cells. No brain cells have been tested due to dangers from brain surgery. This is where it is likely to be most affected, so low normal residual function does not tell us much about her brain issues. She does not appear to lack energy, in general (a common issue in “mito kids”) – and exercise is likely good for her.

The cerebellum is not the part of the brain primarily involved in “higher” brain functions, nor is it involved in the autonomic functions (like breathing and heartbeat). That said, there are connections between the cerebellum and cognition in many cases (the role of the cerebellum in cognition is not fully understood). Some NUBPL patients have lower than normal cognitive abilities, while others (including the person with the same mutations as Katherine) have little to no cognitive impairment at all. This may depend on whether other areas of the brain are affected and to what extent, or it may be happenstance of what part of the cerebellum is or may come to be affected. We just don’t know.

We do know that the cerebellum helps regulate and direct the signals coming into and out of your brain. For example, the cerebellum does not initiate the signal from your brain telling your legs to move. However, that signal passes through the cerebellum before it is sent to the legs, and the cerebellum helps direct it and tell it how much pressure, strength and speed to use. The leg then sends the signal back the brain to tell it what has happened. That signal also passes through the cerebellum before being sent to the part of the brain in control of the leg. With a damaged/abnormal cerebellum, those signals can get mixed up, amplified, muted, or misdirected. This results in clumsiness, difficulty controlling the force or pressure of one’s muscles, difficulty writing, poor articulation of speech, poor motor planning, and a lack of coordination when walking, clapping, playing patty-cake, etc.

Because these signals travel through the cerebellum thousands of times per second from all parts of our bodies, significant problems can occur. As an example, the simple (to most of us) act of standing, alone, requires thousands of these signals to pass through the cerebellum each second; nerves of the ankles, feet, knees, thighs, torso, arms, neck, and head signal the brain about what they are doing, the inner ear tells it up from down, the eyes tell it what is going on around us, etc. These signals pass through the cerebellum, are regulated, and passed on to the higher brain for interpretation. That higher brain then decides what to do, and signals back how the body needs to adjust given all the signals coming in from all of these body parts. Maintaining balance while standing is a coordinated and complex function—one that modern computers could not hope to replicate – that we take for granted and do not even think about. That is not the case for Katherine. Katherine’s entire “balance center” of her cerebellum is the most affected, making balance a daunting task, requiring a great deal of concentration. It is like a normal person trying to walk a tight-rope in windy conditions. Add to that trying to coordinate all of these body parts to walk, and the task is beyond her current abilities.

The brain is remarkably adaptable, however. People suffering from significant brain injuries can re-learn to walk, talk, and function. Repetition and rehabilitation allow the brain to make new pathways and connections to do what it once did elsewhere.

Sensory input is hard for Katherine to process. She can be overwhelmed by chaotic environments, as her brain is not telling her what is going on in the same way as the rest of us. She processes things more slowly. This probably is not so much of a function of her higher intelligence, as her body’s way of communicating between her senses and her higher brain.

You can expect Katherine to be off balance. She will have trouble with writing. She may become overwhelmed or confused by sensory input. She will have trouble articulating her words. She will have difficulty controlling the volume and pitch of her speech. She will be clumsy and uncoordinated. She does not yet have a good grasp of the body’s “potty” warning signals — she is better at telling you she has gone, than telling you she is about to go. All of these things can frustrate her, cause her to withdraw from others at times, or become anxious. That said, she has a very good vocabulary and understanding of things.

Children with Mitochondrial disease have some difficulty controlling their body temperature, can become fatigued, need to stay hydrated, and can suffer more when ill than other children. So far, these do not appear to be problems with NUBPL patients, other than some worries when they become ill. However, there are things to be aware of in case they occur.

Katherine is currently on an experimental medication called EPI-743 (or is on a placebo. She will receive 6 months of both over a 14 month double-blind clinical trial). It is part of a clinical trial run by the National Institutes of Health. This is essentially a very potent anti-oxidant, thousands of times more powerful at the cellular level than any anti-oxidant you can get in food or supplements.  While administration and action of the medication in the body is a far more complicated thing, in a laboratory setting fibroblasts grown from her cells demonstrated susceptibility to oxidative stress (discussed above) and an 80% or higher return to viability from administration of the medication. We hope that predicts that the EPI-743 will clean up the toxins she may be producing and will help her cells produce energy, and arrest any progression of the disease. It could do more.  While it cannot revive dead cells, it may save those that were damaged and dying, and allow them to function better, improving her condition (along with physical and occupational therapy), not just arresting its decline.

She also is on a compounded medication commonly called a “mitochondrial cocktail” that does many of the same things in different ways, as well as supplement one of the chemical products of Complex I, being a substance called Ubiquinol, a form of CoQ10.

We lived with a misdiagnosis that guaranteed us that Katherine was going to die in the next few years. The NUBPL diagnosis is serious and full of unknowns, but “serious and unknown” is better than “known and hopeless.”

We want to stress that we think it is important for other children and their families to understand Katherine. This provides insight into the rare disease community in general, mitochondrial disease patients, in particular, and Katherine, individually. It will help them get to know Katherine (and others like her) and explain why she cannot walk or do other things they take for granted.

Tips for Successful Legislative Advocacy

In April 2016, Kentucky became the first state in the country to pass legislation that mandates private insurance cover prescribed vitamins and supplements for mitochondrial disease patients.

Twice a day our five-year-old daughter takes a compounded mixture of vitamins and supplements known as a “Mito cocktail.” Prescribed by her neurologist, this cocktail has shown many positive results, including increased muscle tone, stamina, stability, and a lessened intention tremor.

To date, the Mito Cocktail is the only treatment currently available for mitochondrial diseases.

However, less than 10% of insurance carriers cover this needed medication. Although Kentucky law already mandated coverage, our private insurance carrier continued to deny coverage every month, even going so far as to insinuate that our daughter takes it for “cosmetic purposes and performance enhancement.”

Frustrated and angry over the blatant wrongdoing by insurance companies, we decided it was time to clarify what was already mandated in existing Kentucky law.

Over the past few months, many have asked for advice so they can duplicate our success in other states. Before offering a few general tips to help get you started, I would be remiss not to mention that, combined, my husband and I  have a legal and policy background. We have good friends who are Kentucky state legislators and we are familiar with the political players of our state. Further, since 2013, we have become vocal, well-known advocates for our daughter through our various social media accounts, our blog, Hope For Katherine Belle,  as a contributing writer for the The Mighty, and by appearing in The New York Times Motherlode Blog. Yes, our careers and platform were instrumental in the speed with which we passed this bill, but don’t be discouraged if you don’t have a similar background.

Finally, I believe timing played an important role in rapid passage. During the same session, Senate Bill 146, known as “Noah’s Law,” called on insurance companies to cover amino acid based formulas, just as we were calling on insurance companies to cover prescribed vitamins and supplements for mitochondrial disease patients. Early passage of Senate Bill 146 and subsequent publicity was fortuitous: Legislators became familiar with the ways insurance companies manipulate language to deny coverage for medically fragile patients. Senate Bill 146 sponsor and physician Senator Ralph Alvardo had another bill filed relating to insurance – Senate Bill 18 – to which the following floor amendment was later added:

HFA2/HM( R. Smart ) – Amend KRS 304.17A-258 to specify that mitochondrial disease is an inborn error of metabolism or genetics to be treated by products defined as “therapeutic food, formulas, and supplements” and that health benefit plans that provide prescription drug coverage shall include in that coverage therapeutic food, formulas, supplements, and low-protein modified food products for the treatment of mitochondrial disease; specify that this act shall take effect January 1, 2017.

Tips for Successful Legislative Advocacy: 

1. The best advocate is an individual personally affected by the proposed legislation. Although a legal and policy background is helpful, it is not required to be an effective advocate for your child or yourself. Advocacy work is not for the faint at heart – it’s a slow, frustrating, deeply personal process, and, arguably, the most crucial part of the  legislative process. With hundreds of bills filed per session, legislators depend on advocates to educate them about a subject matter and, as the expert, you are the most qualified person for the job.

2. Request a face-to-face meeting with your representatives or their staff during the slower months between legislative sessions.
They represent your interests and should be willing to listen to your concerns. Tell your representatives your story. You are the expert; teach them everything they need to know. Schedules are packed during session, so it’s best to establish a relationship well before the start of session – this will give you ample time to tell your story and draft any proposed bill language. Likewise, meeting with legislators is an excellent way to learn more about the internal dynamics of your state legislature. Your legislator may not be able to help you directly, but they can help you navigate your way to the person who can be most helpful. And trust me, if you worked around legislators, you would quickly realize there’s no reason to be intimated by them. Yes, they are public figures, but they’re human just like the rest of us.

3. Do your homework and be specific.
While your personal story is the most powerful component, be prepared to share any relevant medical and scientific research as it relates to your cause. Likewise, you have a much better chance of success if you can present legislators with a complete package of drafted legislation, including where it falls in your state’s statutory scheme, as well as any statistical and economic information related the bill.

4. Create a “buzz” for your cause.
Establishing a “presence” through social media is a powerful tool to communicate your cause. Don’t limit your audience to just your own district or legislator – increase your reach across the entire state. For example, create a Facebook page dedicated to your legislative efforts, contact local media, or involve support organizations to broaden your reach. Ultimately, the bigger the “buzz,” the harder you are to ignore. For example, our daughter’s Facebook page and blog has a strong following. When we made the call for action, people listened and acted. Providing simple to follow links with letters to copy and paste and telephone numbers to dial, our grassroots strategy quickly gained momentum across the state. Voters were voicing their support for SB18 and legislators were listening to what their constituents were telling them. Just as you presented a complete package to your legislator, it’s as important to present a complete package to your supporters.

5. Know your audience and be prepared for the unexpected.
Do your research on the political climate and the key players in your state legislature. Even though your cause should be a non-partisan issue, I cannot emphasize enough the role politics play in the legislative process. Although this may not always be the case, brace yourself for the ugliness that is involved in the making of laws. Understand beforehand that it is within the realm of possibility that your cause will be used as a political football. Powerful opponents may come out against you. Establishing a public presence and creating a “buzz” for your legislation is key leverage should you need it. There is only so much a legislator can do from inside the legislature to get a bill passed. Your outside advocacy strategy may play an even more important role.

6. Never give up.
You are unlikely to succeed the first time you try to pass any legislation. Keep trying. Involve more advocates, make more alliances with key legislators, and never stop advocating for your child. Nothing on this planet is more powerful than a parent’s love for their child.
 

EPI-743 Trial Update

It’s the dawn of a new year and new possibilities. So much has happened since our last update, so let’s start there.

Katherine entered the EPI-743 clinical trial at the beginning of August. As a part of the trial, Katherine is monitored very closely – monthly blood work at home and/or at the National Institutes of Health (NIH) –  to look for changes in her body while she’s on EPI-743/placebo.

What is EPI-743?
EPI-743 is a small molecule drug that is currently in clinical trials in the United States and Europe. EPI-743 was recently granted orphan drug designation by the FDA to treat patients who are seriously ill and have inherited mitochondrial respiratory chain disorders. EPI-743 works by improving the regulation of cellular energy metabolism by targeting an enzyme NADPH quinone oxidoreductase 1 (NQO1).

How is it given?
EPI-743 is administered orally or through a gastrostomy tube.

How was EPI-743 discovered?
EPI-743 was discovered and developed by Edison Pharmaceuticals by using a technique called high throughput screening. Edison evaluated thousands of chemicals that target cellular electron handling, and finally selected EPI-743 based on its ability to work, be orally absorbed, and its safety.

Why can’t my doctor just prescribe EPI-743?
EPI-743 is an experimental drug. It cannot be prescribed yet because the FDA does not approve it. Access can only be obtained through clinical trial enrollment. Results will be closely monitored at specified enrollment sites, under the direction of clinical research investigators.

Are there additional clinical sites being established? Additional trial sites are being established in Europe, Japan, and in North America.

In a nutshell, EPI-743 is the closest thing to hope available (through clinical trial) in treatment form. Mitochondrial dysfunction is linked to many neurological diseases such as Parkinson’s, Alzheimer’s, ALS, and other diseases like diabetes and some cancers, so this research is important for so many.

In March 2016, Katherine will begin the “washout” phase of the trial – a two month period when she will not take anything, placebo or EPI. (It takes around two months to completely leave your system, thus the “washout” before entering phase II.)

Each person we’ve encountered at the National Institutes of Health is above and beyond wonderful. We feel so fortunate to be a part of their program and could not ask for a better experience. We are grateful for the opportunity to meet so many dedicated and caring individuals.

Many people ask us if we think Katherine is currently on the placebo or EPI? We have no idea, honestly. For example, she hasn’t DRASTICALLY improved, i.e. started walking independently; however, she has maintained her skills and improved in some areas, so it is hard to say.

She started Pre-K in August and loves it.

She is getting more therapy than EVER with three physical therapy sessions, two occupational therapy, and speech therapy per week. One physical therapy session is done on a machine called Geo, which uses treadmill therapy to make her walk. Not only is it creating muscle memory  and tone, it is creating new pathways to her brain. Very amazing technology.

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All of these changes have happened since she started the EPI trial, so it would be hard to say if she’s improving because of school and therapy or because she’s on the actual EPI drug and benefitting from it. Time will tell.

Of course we fantasize that she’s currently on the placebo and something miraculous will happen in the coming months. Realistically, though, miracles have already happened – at the moment she’s thriving, happy, loving school, and hard working at her therapies. Katherine is the most determined person I know, truly.

This time last year she was still undiagnosed (and we believed she had INAD), we were thinking about her Wish trip, and I had just prepared what I feared would be her last Christmas meal.

Placebo or EPI, we are fortunate in so many ways.

The constant for us is that we simply do not know what the future holds. That will never change. All I can do is keep you posted as it unfolds. Your perspective changes so much on this journey. In the end, EPI may or may not be the answer. Sometimes the benefit isn’t improvement, rather it prevents further regression. The good news is that if it proves beneficial, then she can continue to have access to the drug even if it is not on the market. I am hopeful because clinical trials exist and science is making great strides daily. None of this would have been possible just a few years ago, so I am thankful that our daughter can possibly benefit and contribute to research, treatment, and hopefully a cure.

We wish all of you a very Happy 2016!

Mitochondrial Disease Explained for Non-Scientists

There are families that do not like to discuss their child’s disorder, and although we can respect that decision and honor their wishes, we have a very different perspective when it comes to our own daughter.

For starters, we cannot hide the fact that Katherine cannot walk, has a mild tremor, and an irregular speech pattern.  Knowing our child is a wonderful opportunity to learn about rare diseases as you get to know her personally, and since she is unable to fully articulate the ins and outs of her disorder, we are her voice. No, we do not think her disorder defines her, but it is as much a part of her as anything else. Second, we are not embarrassed by her disorder and do not want her to feel that it should only be discussed behind closed doors. Third, knowledge is powerful. We don’t want people to guess why our child cannot walk – we want to educate you with the facts so you can help spread awareness just by being informed.

This is the way we understand or think about our daughter’s condition: Katherine has a very rare genetic disorder known as Mitochondrial Complex I (or 1) Deficiency caused by mutations in her NUBPL gene. There are dozens of types of “Mitochondrial Complex I Deficiencies” but her particular type is very rare. To date, only 6 people have been diagnosed with it in the United States and approximately 25 in the world. That said, it has only been known about since 2010, and can only be diagnosed through Whole Exome Sequencing – a complex and often expensive genetic test. We expect many more to be diagnosed with it in the future.

One of the patients (residing in the U.S.) has identical mutations to Katherine. We know a little about her through research papers.

Because there are so many types of Mitochondrial Complex I disorders and each is different, we sometimes refer to Katherine’s type as “NUBPL,” the name of the gene affected.

So what is NUBPL/Mitochondrial Complex I Deficiency?

When people think of “mitochondria,” many think of DNA from just the mother. This is true only with respect to some of the DNA making up the mitochondria. In fact, they are put together mostly from gene pairs with one gene from each parent (nuclear DNA), plus just a handful involving just one gene coming from the mom (mitochondrial DNA).

All of our cells (except red blood cells) contain mitochondria. The mitochondria produce the energy our cells need to function, to replicate, and to repair themselves. They are the “powerhouses” of the cell.

This “power” is produced through a series of chemical reactions taking place in 5 different physical structures. These are called complexes I through V (or 1 through 5). They work together like an assembly line. If a problem exists in one “complex,” it can harm production down the line in another, ultimately resulting in too little “energy” being produced.

Like an actual power plant, the process of producing usable energy also produces chemical byproducts that can be toxic. Our bodies clean these byproducts through, among other things, “anti-oxidants.” However, sometimes a person with a mitochondrial disease produces too many toxic byproducts for the anti-oxidants to work, leading to a build-up of toxins. This process is called “oxidative stress.”

Thus, a good analogy is a power plant with five buildings, each producing products that are sent down the line, ultimately producing energy from the final building, Complex V, while also producing polluted water that is filtered and cleaned by another facility before being released into a stream. A person with a mitochondrial disease has a problem in at least one building of the five. As a result, she may not produce enough product to be passed along and ultimately turned into energy to meet the needs of the cell (not enough energy is coming out of Complex V) or may be spitting out too much pollutant to be filtered and the water in the stream is getting polluted.

Either of these can result in premature cell death or impaired function.

The nature of these diseases is that they often cause damage over time — again, like pollution from a factory. Similarly, illness can increase energy needs of the body, and cells can become damaged because of their inability to meet the needs in times of higher demand. Both of these things occurs in all of us as we age (mitochondrial dysfunction is a significant contributor to the symptoms of old age, including wrinkles, loss of muscle, loss of brain function, clumsiness, and heart disease). Patients with a primary mitochondrial disease just suffer this fate differently, earlier, and in different parts of their bodies. Note, however, that this is not the “premature aging” disease. Regardless, by their very nature, these diseases often progress.

The extent to which Katherine’s particular condition, NUBPL, is progressive is not yet known. In most cases, it progresses to a degree – it has with Katherine. Fortunately, many of the patients have long periods without any advancement of the disease and many are thought to have become stable. The reasons are not clear, nor has the disease been known about long enough to determine if this is typical.

The patient with Katherine’s identical mutations is now 13. Our information is now 5 years out of date (it was in a 2010 research paper). As of 2010, she could walk with a walker and had normal intelligence. She had not had much regression after an initial period of regression experienced when she was a toddler.

Different cell types have different energy needs. Skin cells, for example, need little energy, so contain few mitochondria. Heart, kidney, liver, and brain cells, on the other hand, have high energy needs, so contain the most mitochondria. Liver cells, for example, may contain as many as 2,000 mitochondria per cell. As a result, these parts of the body are susceptible to “mitochondrial diseases,” either because the energy needs are not being met, or in meeting them too much “pollution” is being produced. Some of these diseases affect only one of these parts of the body, while others may affect multiple systems.

Katherine’s disorder is a problem in “Complex I,” thus the name “Mitochondrial Complex I Deficiency.” This is the largest of the five complexes, the one involving the most genes for its assembly and function. It is the most common place for these diseases to arise.

Knowing that Katherine has a disorder in Complex I tells you very little. Returning to the power plant analogy, it is like telling you there is some sort of problem in “building one” of a five building complex, but not knowing what that problem is; it could be something small, like a clogged toilet, or it could be something large, like the complete collapse of the building. The devil is in the details.

Some Complex I deficiencies are quickly fatal. Others are far more benign. Indeed, it is likely that many are so benign that a person can live a long healthy life without knowing they have a disorder. Still others may suffer problems only late in life, such as developing Parkinson’s or heart disease.

Thus, Mitochondrial Complex I Disorders can range from quickly fatal to unnoticed and insignificant. No known patient has died from the disease and only one has died at all (from what is not clear, nor is it entirely clear that NUBPL was the only condition he had, as he was the first NUBPL patient and died before current testing methods were developed).

In Katherine’s case, the gene affected, NUBPL, is “nuclear,” meaning she inherited one gene from each of us. In order to manifest as a disease, Katherine had to receive one mutated gene from both of us – one mutated gene and one normal one will not result in disease, but only “carrier” status (Glenda and I are both carriers, each having one mutated gene, but not two). Having a single mutation of this gene is rare. Having parents who each have one mutation of the gene, rarer still. Having both pass one mutated gene to the child is extremely rare (there is only a 25% chance that two carriers will have a child with two mutations) – lottery-level odds (more people win the Powerball each year than are known to have NUBPL, worldwide).

Because it is so rare and so newly-discovered (discovered in 2010), not a lot is known about Katherine’s form of Mitochondrial Complex I Disorder. What is known or suspected is as follows:

The NUBPL gene is known as an “assembly gene.” This means that it is not part of the physical design or structure of Complex I, but is a gene that contributes to its assembly. In particular, it is involved in the assembly of “iron-sulfur clusters” that transfer electrons during the chemical reactions in Complex I.

Think of it as Katherine having an accurate blueprint for “building one” of her power plant, but someone used defective wiring or put the wiring in it the wrong way. What this means is not fully understood. One possible result of this is that the electrons that are supposed to be carried by this “wiring” may leak out and be transferred to chemicals other than those intended, producing the toxins referred to above (known as “Reactive Oxygen Species” or “ROS”).

While it would seem like this defect would affect the mitochondria throughout the body (and NUBPL patients must monitor all systems to make sure problems do not crop up), to date, NUBPL mutations seem concentrated in the brain of patients. While some NUBPL patients have issues throughout the brain, most are concentrated in the cerebellum.

Katherine is fortunate in that her brain appears to be spared except for the cerebellum and one very small inflammation in her corpus callosum that has not changed and may well resolve or never affect her in any way.

As far as energy production, Katherine’s Complex I residual function appears to be low normal in fibroblasts grown from her skin cells. No brain cells have been tested due to dangers from brain surgery. This is where it is likely to be most affected, so low normal residual function does not tell us much about her brain issues. She does not appear to lack energy, in general (a common issue in “mito kids”) – and exercise is likely good for her.

The cerebellum is not the part of the brain primarily involved in “higher” brain functions, nor is it involved in the autonomic functions (like breathing and heartbeat). That said, there are connections between the cerebellum and cognition in many cases (the role of the cerebellum in cognition is not fully understood). Some NUBPL patients have lower than normal cognitive abilities, while others (including the person with the same mutations as Katherine) have little to no cognitive impairment at all. This may depend on whether other areas of the brain are affected and to what extent, or it may be happenstance of what part of the cerebellum is or may come to be affected. We just don’t know.

We do know that the cerebellum helps regulate and direct the signals coming into and out of your brain. For example, the cerebellum does not initiate the signal from your brain telling your legs to move. However, that signal passes through the cerebellum before it is sent to the legs, and the cerebellum helps direct it and tell it how much pressure, strength and speed to use. The leg then sends the signal back the brain to tell it what has happened. That signal also passes through the cerebellum before being sent to the part of the brain in control of the leg. With a damaged/abnormal cerebellum, those signals can get mixed up, amplified, muted, or misdirected. This results in clumsiness, difficulty controlling the force or pressure of one’s muscles, difficulty writing, poor articulation of speech, poor motor planning, and a lack of coordination when walking, clapping, playing patty-cake, etc.

Because these signals travel through the cerebellum thousands of times per second from all parts of our bodies, significant problems can occur. As an example, the simple (to most of us) act of standing, alone, requires thousands of these signals to pass through the cerebellum each second; nerves of the ankles, feet, knees, thighs, torso, arms, neck, and head signal the brain about what they are doing, the inner ear tells it up from down, the eyes tell it what is going on around us, etc. These signals pass through the cerebellum, are regulated, and passed on to the higher brain for interpretation. That higher brain then decides what to do, and signals back how the body needs to adjust given all the signals coming in from all of these body parts. Maintaining balance while standing is a coordinated and complex function—one that modern computers could not hope to replicate – that we take for granted and do not even think about. That is not the case for Katherine. Katherine’s entire “balance center” of her cerebellum is the most affected, making balance a daunting task, requiring a great deal of concentration. It is like a normal person trying to walk a tight-rope in windy conditions. Add to that trying to coordinate all of these body parts to walk, and the task is beyond her current abilities.

The brain is remarkably adaptable, however. People suffering from significant brain injuries can re-learn to walk, talk, and function. Repetition and rehabilitation allow the brain to make new pathways and connections to do what it once did elsewhere.

Sensory input is hard for Katherine to process. She can be overwhelmed by chaotic environments, as her brain is not telling her what is going on in the same way as the rest of us. She processes things more slowly. This probably is not so much of a function of her higher intelligence, as her body’s way of communicating between her senses and her higher brain.

You can expect Katherine to be off balance. She will have trouble with writing. She may become overwhelmed or confused by sensory input. She will have trouble articulating her words. She will have difficulty controlling the volume and pitch of her speech. She will be clumsy and uncoordinated. She does not yet have a good grasp of the body’s “potty” warning signals — she is better at telling you she has gone, than telling you she is about to go. All of these things can frustrate her, cause her to withdraw from others at times, or become anxious. That said, she has a very good vocabulary and understanding of things.

Children with Mitochondrial disease have some difficulty controlling their body temperature, can become fatigued, need to stay hydrated, and can suffer more when ill than other children. So far, these do not appear to be problems with NUBPL patients, other than some worries when they become ill. However, there are things to be aware of in case they occur.

Katherine is currently on an experimental medication called EPI-743 (or is on a placebo. She will receive 6 months of both over a 14 month double-blind clinical trial). It is part of a clinical trial run by the National Institutes of Health. This is essentially a very potent anti-oxidant, thousands of times more powerful at the cellular level than any anti-oxidant you can get in food or supplements.  While administration and action of the medication in the body is a far more complicated thing, in a laboratory setting fibroblasts grown from her cells demonstrated susceptibility to oxidative stress (discussed above) and an 80% or higher return to viability from administration of the medication. We hope that predicts that the EPI-743 will clean up the toxins she may be producing and will help her cells produce energy, and arrest any progression of the disease. It could do more.  While it cannot revive dead cells, it may save those that were damaged and dying, and allow them to function better, improving her condition (along with physical and occupational therapy), not just arresting its decline.

She also is on a compounded medication commonly called a “mitochondrial cocktail” that does many of the same things in different ways, as well as supplement one of the chemical products of Complex I, being a substance called Ubiquinol, a form of CoQ10.

We lived with a misdiagnosis that guaranteed us that Katherine was going to die in the next few years. The NUBPL diagnosis is serious and full of unknowns, but “serious and unknown” is better than “known and hopeless.”

We want to stress that we think it is important for other children and their families to understand Katherine. This provides insight into the rare disease community in general, mitochondrial disease patients, in particular, and Katherine, individually. It will help them get to know Katherine (and others like her) and explain why she cannot walk or do other things they take for granted.

What is EPI-743?

If you follow us on Facebook (YOU REALLY SHOULD!), then you’ve seen our recent updates and photographs from the National Institutes of Health where Katherine started the clinical trial for EPI-743. I know how confusing this information may seem if you are not living it, so I’m sharing basic Q & A below from the United Mitochondrial Disease Foundation. (It took us a while to figure out that the “EPI” part of this trial drug name is the acronym for the manufacturer, Edison Pharmaceuticals Inc.)

What is EPI-743?
EPI-743 is a small molecule drug that is currently in clinical trials in the United States and Europe. EPI-743 was recently granted orphan drug designation by the FDA to treat patients who are seriously ill and have inherited mitochondrial respiratory chain disorders. EPI-743 works by improving the regulation of cellular energy metabolism by targeting an enzyme NADPH quinone oxidoreductase 1 (NQO1).

How is it given?
EPI-743 is administered orally or through a gastrostomy tube.

How was EPI-743 discovered?
EPI-743 was discovered and developed by Edison Pharmaceuticals by using a technique called high throughput screening. Edison evaluated thousands of chemicals that target cellular electron handling, and finally selected EPI-743 based on its ability to work, be orally absorbed, and its safety.

Why can’t my doctor just prescribe EPI-743?
EPI-743 is an experimental drug. It cannot be prescribed yet because the FDA does not approve it. Access can only be obtained through clinical trial enrollment. Results will be closely monitored at specified enrollment sites, under the direction of clinical research investigators.

Are there additional clinical sites being established?
Additional trial sites are being established in Europe, Japan, and in North America. (http://www.umdf.org/atf/cf/%7B858ACD34-ECC3-472A-8794-39B92E103561%7D/EPI.PDF)

In a nutshell, EPI-743 is the closest thing to hope available (through clinical trial) in treatment form. Mitochondrial dysfunction is linked to many neurological diseases such as Parkinson’s, Alzheimer’s, ALS, and other diseases like diabetes and some cancers, so this research is important for so many.

I first heard about this trial in September 2013 – just two days after we received Katherine’s first misdiagnosis for Infantile Neuroaxonal Dystrophy (INAD) – when Dave told me he found a trial that might be our only hope. He called the NIH directly and asked how we could get in the study. At the time we didn’t even know much about INAD or if it was even categorized as a “mitochondrial” disease, but Dave left no stone unturned. Fast forward to 2015 and a few months after Whole-Exome Sequencing (WES) results confirmed Katherine’s true diagnosis – NUBPL, Mitochondrial Complex 1 Deficiency. Dave’s early contact with the study (we were told EPI-743 wasn’t even in the building when he called that day) put us next in line when an opening became available in August 2015.

Once again we are reminded of the crucial role we play in advocating for our daughter. Nobody was going to make that call for us and ask how we could get our child on the list for the trial. YOU HAVE TO PICK UP THE PHONE AND DO IT YOURSELF. Thankfully, in our case, Dave did just that.IMG_8597As always, Katherine was a trooper. Before starting the drug (placebo or EPI-743 – it’s a double-blind study so she will get six months of EPI-743 and six months of a placebo with a two month washout in between), a variety of tests had to be performed to establish a baseline.
IMG_8609IMG_8642Between needle pokes, a neuropsychological evaluation, and an EKG and Echocardiogram, Katherine enjoyed playing at The Children’s Inn at NIH. She loved the many playgrounds, art camp, therapy dog, family dinners, and being around other children.IMG_8601IMG_8647We have a fridge full of EPI-743 or placebo vials and hope it will reverse or stop the progression of her disease. Only time will tell. In the meantime, we are moving forward.

Katherine starts pre-K this Thursday where she will receive speech therapy, occupational therapy, physical therapy, and water (aqua) therapy. Like everything, school will be a transitional time, so we are focused on making her life as “normal” and routine as possible. We go back to the NIH in early September, with follow-up lab work done here at home in between visits.
IMG_8653As for me? Besides looking for other NUBPL patients around the globe and running our NUBPL Foundation, I am looking forward to some much needed time for myself. As a constant caregiver, it is time that I take better care of myself, starting with a fancy new hairstyle that I might have time to recreate like my hair dresser (not likely). I am looking forward to the future once again and see great things to come on the horizon.

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