Tag Archives: whole exome sequencing

Two NUBPL Families Meet For First Time, 2,000 miles apart

A little over two years ago, we received Katherine’s results for Whole Exome Sequencing (WES), giving us a name, NUBPL, to the disease that was a mystery to her doctors and is responsible for the atrophy of her cerebellum. Although we finally knew the name of the mutated gene, and that it was considered a rare form of Mitochondrial Complex 1 Deficiency, we didn’t know much more than that. In fact, at the time we quickly learned that her disease was recently discovered.

Although we were elated to receive a diagnosis, we realized that we didn’t know how the disease would affect Katherine’s life. Her doctor had never seen another patient with NUBPL, so he didn’t have much to tell us in terms of disease progression.

We searched the Internet looking for any information we could find, which included a couple of scientific articles citing six patients from 5 unrelated families. From these articles, we learned more about the patients, including sex, age, country of origin, clinical signs, MRI details, when and if they walked independently, and cognitive function. We had no way of contacting any of these families without knowing their names or doctors. We didn’t even have a photograph.

I felt like a detective scouring the Internet hoping to find a clue. I started tagging everything we shared with “NUBPL” and searched the Internet several times a day for a signal from anyone out there who had this disease. I posted in Facebook groups and wrote blog posts, anything I could think of that might put us in contact with another family with this same disease.

Just a few weeks later, I was looking through posts on the Global Genes Facebook page when I noticed a post from a mom sharing a link to a documentary about their 14-year journey to a diagnosis for both her daughters who were diagnosed with NUBPL. As I watched the documentary, tears rolled down my face as I picked up the phone to call Dave to tell him I’d found another family. And that they looked happy and one was walking independently. After living with a misdiagnosis for nearly two years of a quickly fatal disease, I’ll never forget the moment that I saw the smiling face of a 16-year old girl with same disease as Katherine.

Everything is about perspective in this life. After being told that my child was going to die by the age of seven, that first glimpse at Cali Spooner’s face added  years to my child’s life. In her photograph I saw Katherine smiling back at the camera. For the first time, I saw Katherine as a teenager.

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And then I saw Ryaan Spooner’s face and recognized my Katherine in her as well. And she could walk independently. Their body types were even similar.

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The Spooner Family

I got off the phone with Dave and contacted their mom, Cristy, who responded immediately and we’ve been in contact ever since. She put us in touch with their doctor at UC-Irvine, Dr. Virginia Kimonis, who was growing fibroblasts to learn more about the disease. We contacted Dr. Kimonis and sent Katherine’s skin biopsy for research.

Last week, our family traveled to California to attend the first NUBPL Family Conference at UC-Irvine and to spend time with the Spooner Family.

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We heard from several researchers and toured the lab where they have been growing our daughter’s fibroblasts.

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And a few days later, we were able to introduce our girls to one another for the very first time.

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Both of our families instantly hit it off as we watched our girls play together. We were all sad that the night had to end and we had to go back to living on opposite coasts.

Katherine and Ryaan share a love of dolls and both are fiercely determined and independent. They are very similar in many ways. Katherine watched Ryaan walk independently, which she learned to do at Katherine’s age (they are two years apart). After seeing Ryaan walking, Katherine is now determined more than ever that she’s going to do the same. And I know she will.

Our girls are three of 11 NUBPL patients identified in the world. After spending time with The Spooner Family, I am reassured more than ever that we will find more NUBPL families in the future. These things take time and we are just getting started.

We are two families brought together through science, hope, love, and a fierce determination to give our girls the best chance possible at life. Where science hasn’t caught up, we will fund the research ourselves through our non-profits. Where there are barriers to diagnosing more patients in the future, we will spend our time to eliminate those barriers. And when we cannot find those patients as they are diagnosed, we will do everything we can to make sure they can find us.

As our families were spending time together in California, a mom with two daughters made contact with both of us. Yes, I am hopeful that we will grow our NUBPL community.

A Response To Our Naysayers: Rare Disease Statistics Are Absurd Because They Are Accurate

On the Home Page  of our blog, we state that “Rare diseases affect more people than all cancers plus HIV combined, yet half of the patients do not know what is wrong.” In a recent Reddit string (we were not part of this conversation, but merely stumbled on it), this statistic raised a particular person’s ire, but not for the right reasons, in our opinion.  He/she stated:

“‘Rare diseases affect more people than all cancers plus HIV combined, yet half of the patients do not know what is wrong’…I’m calling BS on this. Well yeah, because … No.”

This person went on in another post to call us “pretty absurd,” following up with the following statement: “It’s pretty basic statistics that researchers do. From this document, we can infer that cancer prevalence is about 4.5% (14.5 million / 318.9 million). It’s pretty absurd to claim that these rare diseases, each of which 50 people have in the whole world, add up to more than 4.5%.”

When someone else stated that it might be feasible, he/she then stated: “No, it’s not really plausible. Given that the source is some layperson’s blog post on the internet, I don’t understand why you’re trying to find a way to give it credence… To give a bit of perspective, how many people have you known who have had cancer? How many have you known with one of these ultra-rare diseases? To broaden this a little bit, in my two clinical years of med school, I saw exactly one case of a rare disease while nearly all of my peers saw none. We all saw hundreds of patients with cancer.”

When someone finally pointed out that this response relied on anecdotal experience, he/she ended with:

“No kidding. And yet it’s stronger evidence than what she [Glenda] gave.”

We will bite our tongues on the lack of civility and arrogance in the tone of these posts, particularly when one considers that it is in response to efforts to raise awareness about rare diseases in general, and to share with the world our story. Others were also skeptical – though none were quite so arrogant. Therefore, we feel it merits a response and to provide the support for our statement. And, for the record, we are trying to make our blog readable, not a series of medical journal articles. Therefore, we are not loading it up with footnotes and citations. That does not mean we do not try to make sure our factual comments are accurate.

Let us clarify this prior statement. … It is correct exactly as worded, “Rare diseases affect more people than all cancers plus HIV combined, yet half of the patients do not know what is wrong.”

To use the words of the commenter, who goes by the user name uicucengineer, “well, yeah, because… yes.”

We “lay” “bloggers” did not originate this statement. You need not give us “credence” to believe it. We first heard it from a neurologist speaking as part of a panel of neurologists and geneticists at the United Mitochondrial Disease Symposium in DC.

Before we repeated it, we actually did some research. This statement is repeated on the Global Genes website  – go to the bottom, under “care about rare” you will see it come up as part of the rolling information. It and the statistics we set forth below, are repeated in many reports and studies. They are simple to find for anyone caring to look before they speak or post – Dear uicucengineer, Google is your friend.

One problem with uicucengineer is that he/she did not bother to educate himself/herself on the definition of “rare disease” before sounding forth. “Rare disease” has an actual definition. It is not just a disease “50 people have in the whole world” as uicucengineer (who claims to have two clinical years of med school) believes. While it is true that such a disease would qualify, in the United States, a condition is considered “rare” if it affects fewer than 200,000 persons (in the US) combined in a particular rare disease group.

Don’t want to take the word of a “lay blogger?” How about Federal law? Forty-two United States Code section 287a-1(c), provides as follows: “For purposes of this section, the term ‘rare disease’ means any disease or condition that affects less than 200,000 persons in the United States.”

There are over 7,000 diseases that qualify. See Globalgenes.org.

The numbers add up.  According to the Global Genes’ website:

  1. 30 million people in the United States are living with rare diseases (this number is supported by the NIH);
  2. This equates to 1 in 10 Americans or 10% of the U.S. population;
  3. Similar to the United States, Europe has approximately 30 million people living with rare diseases;
  4. It is estimated that 350 million people worldwide suffer from rare diseases; and
  5. If all of the people with rare diseases lived in one country, it would be the world’s 3rd most populous country.

By contrast, according to SEER.cancer.gov, there are currently a little under 13.8 million cancer patients and survivors in the United States as of 2015. That’s right, 30 million versus 13.8 (rounding up).

HIV totals do not make up the 16.2 million difference. The global total of HIV infections is estimated at 34 million, with 1.4 million in all of North America (according to AVERT).

While cancer and HIV rates vary somewhat from country to country, these prevalence rates generally carry through. Cancer and HIV patients and survivors add up to far fewer than rare disease patients. Alone we are rare, together we are common.

Sorry you did not see more of us in your two clinical years at med school, uicucengineer, but we are out there. We are all around you. Please open your eyes and learn about us, what we suffer through, and what we need. Please do not go into medicine if you are not willing to learn and to research before you speak – unknowledgeable medical professionals are already a significant problem to the rare disease world.

Another commenter on this string (was far more civil) and stated:

“I do have a bit of an issue with this statement: ‘Rare diseases affect more people than all cancers plus HIV combined, yet half of the patients do not know what is wrong.’ Well yeah, because cancers and HIV are specific diseases whereas ‘rare’ diseases can be any number of undiagnosable things. I’m not sure what their point is.”

When someone chimed in with some points about funding (thank you 88Wolves, whoever you are), the original poster responded:

“But funding for cancer can be applied across a finite number of diseases, whereas for rare diseases it’s literally anything. It does seem the funding would support increased genetic research which I suppose can only be a good thing, but a ‘rare’ disease is never going to be able to receive the funding that cancer or HIV do because they’re rare.”

This comment makes some valid points, and deserves a response. Here are a few additional facts:

  1. (From Global Genes) 80% of rare diseases are genetic in origin;
  2. (not from Global Genes, but carrying through on the math contained therein) That means of the approximately 30 million people in the U.S. with a rare disease, approximately 24 million have a genetic origin;
  3. (Global Genes) Approximately 50% of the people affected by rare diseases are children;
  4. (Id.) 30% of children with rare disease will not live to see their 5th birthday;
  5. (Id.) Rare diseases are responsible for 35% of deaths in the first year of life;
  6. (Id.) The prevalence distribution of rare diseases is skewed – 80% of all rare disease patients are affected by approximately 350 rare diseases;
  7. (According to the Kakkis EveryLife Foundation) 95% of rare diseases have not one single FDA approved drug treatment;
  8. (Global Genes) During the first 25 years of the Orphan Drug Act (passed in 1983), only 326 new drugs were approved by the FDA and brought to market for all rare disease patients combined;
  9. (According to the National Institutes of Health Office of Rare Disease Research) Approximately 6% of the inquiries made to the Genetic and Rare Disease Information Center (GARD) are in reference to an undiagnosed disease;
  10. (Id.) Approximately 50% of rare diseases do not have a disease specific foundation supporting or researching their rare disease;
  11. (According to the Rare Disease Impact Report) The average time to diagnosis for a rare disease is about 7.6 years in the U.S., and 5.6 in the U.K.;
  12. (Id.) The typical patient goes through 8 physicians before getting a diagnosis;
  13. (Id.) The average patient is misdiagnosed between 2 and 3 times before getting an accurate diagnosis;
  14. Few insurance policies will cover the genetic tests necessary to diagnose these diseases; and
  15. (Id.) While over 90% of rare disease patients/families surveyed had insurance, 55% had uncovered expenses related to the disease, 53% had to spend their savings to reach a diagnosis, 34% had to obtain charitable or public assistance, and 23% had to use their retirement accounts.

While it is true that research into one disease might not benefit another, this is not invariably true and there are many common issues across diseases.

For example, since most of these diseases have a genetic cause, it is important to all of the disease population to have easier, cheaper, and faster access to genetic testing. Insurance companies need to stop refusing to cover these tests and should drop requirements that all non-genetic tests be exhausted before genetic tests are considered. In our case, our daughter went through numerous tests before Whole Exome Sequencing, all because we had no prayer for insurance approval until we did so. These included two MRIs, two skin biopsies, a spinal tap, an EMG, an EEG, an EKG, a genetic ophthalmologist appointment, dozens of blood tests and numerous urine tests. These required our daughter to be anesthetized several times, and some were invasive (EMG, spinal tap, and biopsies). None led to answers, only a misdiagnosis of Infantile Neuroaxonal Dystrophy. The Whole Exome Test required a mere blood draw and gave us a correct diagnosis – a year and a half later and after two insurance denials and appeals and having to live with a misdiagnosis that gave our child a life-expectancy of 7 to 10 years of age. No patient should go through this. With progressive diseases, as many of these are, delays can cause irreversible damage as possible treatments (like EPI-743 and Mitochondrial Cocktails) are not given.  Patients need to be allowed access to the best diagnostic tools available, to have access to the less invasive and better test first, and to the insurance coverage they thought they were paying for, not to have insurance companies delay diagnosis, dictate care, and refuse coverage. With expanded knowledge, with coordination and a gathering of our voices, pressure can be put on insurance companies (or legislation when necessary) to stop these practices.

With expanded genetic testing comes expanded understanding of our genetic code. This may lead to the next generation of medicine, including the genetic bases or susceptibilities toward all diseases.

Government initiatives like the Undiagnosed Disease Program at the NIH and the Precision Medicine Initiative can help spur research and diagnosis.

Some research and treatments can carry across diseases, including stem cell research, genetic therapies, and technologies like CRISPR (or the like).

With expanded genetic testing, screening can become cheaper, leading to treatments at an earlier age and the prevention of unnecessary disease progression.

The government can continue to provide incentives like the Orphan Drug Act to encourage companies to invest in rare disease treatments and research.

Databases with wider access can be created to allow professionals and advocates to make connections themselves.

According to the professionals (as discussed in the Rare Disease Impact Report), physicians are not sufficiently aware of rare diseases. Many have no idea how to spot them or where a referral needs to be made. See also uicucengineer.

Finally, many of these diseases have traditionally been the things that people “just don’t talk about.” The stigma of genetic disease needs to go away. Our rare children are beautiful and the world needs to know about them. See Katherine Belle.

NUBPL Gene – Mito Complex 1 (Diagnosed)

February 2015 – Katherine Belle was DIAGNOSED through Whole Exome Sequencing: Mitochondrial Complex 1 – NUBPL Gene.

We want to introduce you to the Spooner Family and their daughters Cali and Ryann, both of whom have mutated NUBPL genes like Katherine. We were undiagnosed for only two years…their oldest daughter was undiagnosed for thirteen years.

Although not identical, I can tell you that after seeing this video I immediately saw similarities between our daughters. After being misdiagnosed for so long with something that didn’t feel right in our hearts, it is so comforting to know and accept the correct diagnosis.

Please watch this video when you get some time. It’s lengthy, but very important and inspiring: The Life We Live

We are all interested in finding others with the same diagnosis.  They may contact me at gcmccoy1@aol.com.

Connected To The Past

Timing is everything in life.  Just as those who came before us, we all have a ticking clock over our head.

Lately, I’ve frequented antique shops scouting out props to use for food photography projects and collaborations.  More than ever I feel a greater connection to the past.  I find it impossible not to think about the lives, conversations, relationships, tragedies, etc. of the previous owners as I touch, repurpose, and use their personal household items.

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My most recent excursion brought tears to my eyes when I stumbled across a beautiful wooden cradle sitting silently in the corner. That cradle belonged to somebody else’s Katherine, and the bond between a parent and child is timeless.  What was that baby’s story?  Did she have a long, healthy life, or did she die young from Scarlett fever, influenza, an appendicitis, or a rare disease?

Although many medical advancements have occurred since that cradle was made, it’s hard not to feel stuck in the past when doctors say they believe your child is slowly dying of a disease they cannot diagnosis or treat.  Intellectually, I grasp and appreciate the fast-paced nature of genomic medicine; emotionally, however, I fear my own daughter’s timing may not be on the right side of science.  Then again, children still die from influenza.

None of us can escape death or its timing.

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Silhouette of Katherine Belle by Clay Rice.

As I closed my eyes and filled my mind with the sound of giggles and the tender moments shared between a mother and her child, I was reminded that hope is the only thing stronger than fear.  Yes, I am afraid, but my hope and faith are much stronger than my fears.

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Thanks For Your Support!

A very special thank you to the many generous family members, friends and strangers who have donated to our daughter’s gofundme account so we can find a diagnosis.

On October 6, 2014, we traveled to UNC – Chapel Hill to participate in our first research study.  We will go back in nine months for results.  In the meantime, we are in the process of finalizing another Whole Exome Sequencing (WES) through our insurance company and could receive those results as soon as six months.

We are forever grateful to each of you for your assistance and support through this medical journey.

Donations may be made at: http://www.gofundme/hopeforkatherinebelle.com

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Just a photo and not a link. Please use link above.

Now What?

Now what?  That’s the million dollar question.

We find ourselves in that place where nobody wants to live.  A place somewhere between a 90% diagnosis of something horrible and untreatable and an unlikely diagnosis that your child has that disease.  No doctor calls to check on your child; no medicine is given; no advice is offered.  All you know is that your child’s condition is worsening, yet the medical world is silent.  You’re sent back home with nothing actionable except for the things you can research on your own.

There isn’t a single word I know that can adequately describe this place.

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At least everybody can agree on a few things: 1) Katherine’s MRI shows that whatever she has is spreading throughout her cerebellum; and 2) whole-exome sequencing is the next step and might lead us to answers.

Just one minute after reading Seth Mnookin’s New Yorker article, “One of a Kind” about the intersection of social media, genomics and rare diseases, I contacted Matt and Cristina Might.  It was not until that very moment that I realized (and truly digested) the crucial role we, as parents, play in diagnosing our daughter’s rare disease.  The Mights have been very helpful and introduced me to other families on a similar journey.  We hope to meet up with them sometime in the future, perhaps at the upcoming Global Genes Rare Patient Advocacy Summit in Huntington Beach, California (we are still in the process of deciding whether or not we can attend)?

In short, I have updated my current job status to “rare disease hunter,” which involves taking on Congress and encouraging each member to join the Rare Disease Caucus.  Just today I received a message that Representative Andy Barr (KY-06) is joining the caucus after reading our blog and letter I sent him.  Hooray!  Congressman John Yarmuth (KY-03) is also a member of the caucus.  Anyone want to help get the rest of the delegation on the Rare Disease Caucus? It only takes three minutes of your time to submit a request. If they are already on the caucus then your message will be sent as a “thank you!”  Simple.

Click here to ask your Representative to join the Rare Disease Caucus. (Mention Hope for Katherine Belle.  Send them to our blog at http://www.hopeforkatherinebelle.com.  Put a face to rare disease.  Tell them rare disease is a non-partisan issue.  Tell them it matters to you.)

In the meantime, in addition to contacting all family members and collecting every piece of genetic information available while reading “Genetics for Dummies,” I have decided to take a new approach to treating Katherine’s “unknown/untreatable” disease:

1.  Next Tuesday we have an appointment with a local Integrative Medical Expert who can evaluate her body as a “whole” and address nutritional and supplemental concerns, including the brain inflammation we are seeing on her MRI;

2.  Beginning last week Katherine had her first cranial-sacral therapy session, which she throughly enjoyed and said, “no shot” when it was over.  (I also noticed she was less shaky following this session!) For those of you who are not familiar with cranial-sacral therapy, it is “a form of bodywork focused on the concept of ‘primary respiration’ and regulating the flow of cerebrospinal fluid by using therapeutic touch to manipulate the synarthrodial joints of the cranium;

3.  We are very seriously researching the possibility of hyperbaric oxygen therapy; and

4.  We plan to take her to an immunologist at Duke.

Moving into fall, on October 6, 2014, we are taking part in our first whole-exome sequencing (WES) study at UNC – Chapel Hill. We also hope to do another WES test through Baylor once our insurance company tells us how much they will cover (crickets have been chirping since the end of June).

Results for these tests can take up to seven or eight months.

We continue to do physical and occupational therapy once a week.  I would also like to find the time to add some music therapy into our routine.  And, yesterday we signed the papers to put our house on the market…finally!

How Social Media Impacts Scientific Research

This article in the New Yorker is by far the most important article we’ve read to date that defines our purpose and hope for Katherine Belle.  Thanks to the Mights and Wilseys for confirming what we hope to achieve and proving there are other options than just waiting and hoping science “catches up.”  When parents are given no other option but to create websites and post articles with their genetic data to accelerate research and treatments for our dying children, there is a serious problem with the system.   We are an important part of the diagnostic team and can play a critical role in helping decipher the human genome.  My question is why aren’t more journalists talking about this problem?

Matt Might gave a talk titled “Accelerating Rare Disease.” After describing the effects of his blog post, he told the crowd that it was inevitable that parents of children with other newly discovered diseases would form proactive communities, much as he, Cristina, and the Wilseys had done. Vandana Shashi believes that such communities represent a new paradigm for conducting medical research. “It’s kind of a shift in the scientific world that we have to recognize—that, in this day of social media, dedicated, educated, and well-informed families have the ability to make a huge impact,” she told me. “Gone are the days when we could just say, ‘We’re a cloistered community of researchers, and we alone know how to do this.’

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