All posts by Puneet Rai

Fruit fly model reveals possible therapeutic for PLAN

A recent scientific paper (linked below) reports that PLAN is associated with ceramide accumulation in a fruit fly model of this disorder. Ceramide is a type of fat (lipid) used widely in the body, especially in the membranes of cells. The authors report that accumulation of ceramide in the nervous system puts stress on an organelle in the cell called the lysosome, which has the job of breaking down waste products. An FDA-approved drug called desipramine, a tricyclic antidepressant, can block ceramide accumulation and its downstream consequences in the fly model.

Individuals with PLAN or their family members/care providers may wish to provide this paper to their neurologists or primary care physicians. Since this is an FDA-approved drug available for other medical indications, feasibility of using it on an “off label” basis in PLAN could be considered. We have no experience yet with this drug in PLAN, so monitoring for safety, including of cardiac rhythm functions as well as other safety parameters, would be important for anyone prescribing it. While our NBIAcure team has a significant interest in learning whether there is a therapeutic role for desipramine, we currently do not have the resources to start a new trial at OHSU. We therefore hope to help make the PLAN community aware of this new data in an informed and thoughtful way so that it can be discussed further with individual providers. For those with PLAN who are currently enrolled in our online natural history study, PLANready, it will be key to continue with participation so that we can collect information over time about any impact from the addition of desipramine treatment. We would encourage those not enrolled in PLANready to do so before starting desipramine and then continue in the study for the same reason. Any questions related to this information can be directed to our general box at

Scientific paper: Desipramine in Fruit Flies with PLAN
Letter to share with health care provider: Desipramine Doctor Letter
Enroll in PLANready here: PLANready (Natural History Study)

Susan J. Hayflick, MD
Penelope Hogarth, MD
Allison Gregory, MS, CGC

MEPAN Page Added to Website

Approximately two years ago, our team worked with researchers in Israel and several other countries to discover a new disease-causing gene called MECR. Mutations in this gene cause a condition that we named MEPAN, which stands for “mitochondrial enoyl CoA reductase protein-associated neurodegeneration.” Although MEPAN does not cause brain iron accumulation, both the symptoms and the brain regions involved overlap with NBIA disorders. Therefore, we consider MEPAN a NBIA “mimic” and the individuals who have MEPAN as part of the NBIA community. Last year we wrote an article describing the 20 year journey it took for one NBIA community member, who many of you know well, to receive a diagnosis of MEPAN. You can read that article here:

We’ve now added a page all about MEPAN to our website. We started with just one person, but now there are 13 individuals with confirmed MEPAN diagnoses around the world. We imagine this number will continue to grow as more individuals with unknown diagnoses have whole exome sequencing completed or have their previous whole exome sequencing reanalyzed. There is so little information currently available about this ultra-rare condition that we hope this page will help individuals who are newly diagnosed learn more about MEPAN.

Searching for a Diagnosis using Whole Exome Sequencing

This article and other news can be found in the latest issue of our newsletter which can be downloaded/viewed here: August 2018.

In 2014 the Hayflick lab started a project with the University of Washington to sequence DNA for our patients who did not yet have a genetic diagnosis. These 54 subjects had symptoms similar to those of NBIA but they did not have variants in any of the known NBIA genes. These samples were tested at the University of Washington using Whole Exome Sequencing (WES). The team at UW sent us back all the genetic variants they had found. These included genetic changes that were benign (not disease causing), changes that were pathogenic (disease causing), and changes with unknown effects.

Dr. Caleb Rogers started his search narrow, and looked for any variants in known NBIA genes. He then progressively broadened his scope, including genes that are associated with ataxia, dystonia and other neurological diseases. For patients who still did not have a diagnosis, he looked at genes that were known to have a strong, negative impact on the body if they are not functioning correctly. Once a potential variant is found in a gene, lab scientists like Dr. Suh Young Jeong look at the function of that gene to see if it is related to iron accumulation, CoA, autophagy, or anything else we have seen in NBIA. Dr. Hayflick and Dr. Hogarth also weigh in, and determine whether losing function in this gene would match the symptoms of the patient. If all this lines up, then a tentative diagnosis is given to the patient, and the search to find more patients with this diagnosis begins. A great example of this project in action is Mike Cohn’s road to a diagnosis of MEPAN, which you can read about here:

Even with our team searching through WES data with a fine-toothed comb, 63% of the families still have not received a diagnosis. This is the case for many reasons, such as sequencing mistakes, variants that are not in the part of the DNA that WES sequences, and the fact that we do not yet know what all of the genes in our DNA do. However, the search continues. Each time we learn about a new gene, we go through our data again, searching for another diagnosis.

WES Stats

- Written by Katrina Wakeman

Is BPAN the Most Common NBIA Disorder?

This article and other news can be found in the latest issue of our newsletter which can be downloaded/viewed here: June 2018.

No one can say exactly how many people in the world have a NBIA disorder, but we can guess based on how many people have been diagnosed so far. Today, PKAN is the most common type of NBIA disorder, closely followed by PLAN and BPAN. However, overall numbers are not the entire story and there are three main factors that are contributing to a recent rise in BPAN diagnoses.

Discovery of the WDR45 Mutation

PANK2 gene mutations were discovered to be the cause of PKAN in 2003. Three years later the PLAN gene, PLA2G6, was discovered and ten years later mutations in the WDR45 gene were determined to be the cause of BPAN. Sequencing an individual’s DNA and finding a mutation in a specific gene is the most accurate way to give someone a diagnosis of NBIA. Doctors have only been able to make genetic diagnoses of BPAN for five years, instead of twelve to fifteen for PLAN and PKAN. However, most diseases are never diagnosed with genetic testing and only rely on clinical features. In other words, doctors can examine a patient and give them a diagnosis. However, this can be especially difficult in BPAN.

Clinical Features of BPAN

Individuals with BPAN are usually brought to see a doctor when they are young due to characteristics such as broad developmental delay, repetitive or even autistic behavior, and seizures. Unlike the symptoms of PKAN, these clinical features are common among a number of diseases, making it very difficult for doctors to diagnose. Additionally, the presence of brain iron accumulation on MRI may not show up until early adulthood for many individuals with BPAN. In comparison, people with PKAN have very distinct, “eye of the tiger” MRI patterns from a young age, making PKAN an easier disease to diagnose clinically. Once clinical features of a suspected genetic disease, such as PKAN or BPAN, are identified, a gene panel can be ordered. This is a genetic test of a few genes that are likely to have mutations based on the patients symptoms. The recent addition of the WDR45 gene to seizure panels has lead to an increase in early BPAN diagnoses. Also, as more research is done on BPAN, MRI characteristics for BPAN patients are emerging, creating a more defined clinical picture of the disease.

Whole Exome Sequencing

The last piece of this story is Whole Exome Sequencing(WES). WES is a type of genetic testing that is increasingly being used to diagnose patients with non-specific clinical features (like in BPAN). Unlike gene panels, WES does not focus on a few genes, but looks at all the coding genes in an individual’s DNA and catches most mutations that are present. In the past 18 months, our team has seen almost as many BPAN diagnoses as all the other NBIA disorders combined. This recent increase may be a result of targeted genetic testing with seizure panels, broad genetic testing using WES, and simply “catching up” with all the people who went undiagnosed before the discovery of the WDR45 gene. If the amount of people with BPAN continues to grow at the same rate, then BPAN may very well overtake PKAN and PLAN as the most common NBIA disorder. Time will tell whether this is true.

BPAN Today



These numbers were gathered through our database at OHSU, and represent people who have reached out to us, come for clinic visits, or participated in research.

- Written by Katrina Wakeman

BPANready has been launched!

We are excited to have BPAN families participate in this important natural history study of BPAN that will help lay the foundation for future clinical trials. The link below will take you to a landing page that explains more about how the study works and what is involved. After you look it over, click on the icon at the bottom to get started! If you have any questions or concerns, please email us at

Reflecting on three years of NBIA natural history studies

This article and other news can be found in the latest issue of our newsletter which can be downloaded/viewed here: April 2018.

Back in April 2015, the very first beta-testers started participating in our online natural history study, PKANready. These early testers helped us work out the bugs and finalize the design before the full launch of the study later that year. We just started beta-testing our newest study, BPANready, and it’s been three years since the first participant enrolled in PKANready, so we thought this was the perfect time to reflect on what we’ve learned, highlight the value of natural history studies and share some interesting statistics from PKANready.

What is a natural history study?

Natural history studies gather data about the natural progression of a disease. By tracking this data and doing statistical analysis, researchers can learn more about how a disease progresses over time. A natural history study can also identify disease markers (symptoms or measurements) which can be used during a clinical trial to determine if a possible therapeutic is actually changing how that disease would typically progress. Without having a baseline to compare to, it’s incredibly hard to prove that a possible therapeutic is working.

What type of data is gathered?

  • Demographics (age, gender, contact information, etc)
  • Milestones (smiling, babbling, crawling, talking, walking, etc)
  • Surgeries (g-tube, baclofen pump, DBS)
  • Medications (current meds and/or changes in meds)
  • Imaging (MRIs, ultrasounds, etc)
  • Biomarkers

In order to get the best statistical analysis, this data needs to be gathered consistently over time which is why you may be asked the same questions over and over again.

Why are natural history studies important?

In most cases, the FDA requires that a natural history study be completed prior to approval of a clinical trial for a rare disease. That’s why we named these studies PKANready, PLANready and BPANready. We want to be READY to go to clinical trial as soon as a potential therapeutic compound is identified.

Why does it take so long to develop a study?

We want to make sure that we take our time during the design process to ensure that these studies give us data that will actually be helpful moving forward. Our team’s expertise in this group of disorders and our extensive repository allow us to determine the data points that would create the most robust natural history study for each NBIA disorder. We have also learned lessons from the experience of each natural history to apply to the next one. BPANready will be launching soon and the design of that study was directly influenced by what we learned from PLANready, which was influenced by what we learned from PKANready. Each online study has helped us better focus on what data is most helpful and what design or format can get us that data.

We want to thank everyone who tested PKANready/PLANready and are currently testing BPANready because your feedback is invaluable. We also want to thank all the individuals and families who have continued participating in PKANready for the past three years. We understand how difficult it can be to find time in your busy lives to complete our questionnaires, but we can confirm that you are doing an invaluable service to the entire NBIA community.

What have we gained from these studies?

The data gathered over the past three years through PKANready directly impacted the FDA’s positive response to CoA-Z and our ability to progress so quickly to clinical trial. It probably doesn’t feel quick for all of you, but it absolutely is in comparison to how clinical trials usually progress (especially for rare diseases).

If you want to learn more about PKANready or PLANready, please visit one of the links below. We will make an announcement on our website and social media accounts as soon as BPANready launches.


PKANready Statistics

Participants with both classic and atypical PKAN can enroll in PKANready so this study includes individuals ranging from 3 years old to 60 years old. Due to the increased availability of whole exome sequencing, we’ve seen a dramatic increase in the number of individuals diagnosed before age 10.

Age ranges of PKANready participants

Number of participants from each country

Launch of the NBIAcure Newsletter

Our team will now be publishing a newsletter several times a year to update you on our research studies and let you know about upcoming projects. If you would like to join the mailing list to receive the pdf by email as soon as it’s released, please let us know by sending an email to

The newsletters will be archived on this website at the following page: and the first issue is currently available for download.

Introducing the Spoonbill Foundation

As promised, here are updates on the fundraising questions you had about CoA-Z, the possible treatment of PKAN that we are developing.

Our goal is to make CoA-Z available to everyone at the lowest cost possible so we have formed sister non-profit foundations in the Netherlands and US to further develop the compound. The link below contains information about CoA-Z, the steps pending to get it to human trial, the cost associated with each step, and how you can send donations to the foundation.

We need your help to raise additional funds to reach our goal! Learn more at the link below:

Spoonbill Foundation

Announcement About PKAN Treatment Research

Is it true that OHSU is working on a treatment for PKAN?
Many of you in the family community have heard rumors that the OHSU team is working on a new treatment for PKAN, and we know you are eager to learn more. We’ve been keeping very quiet about our work because we are caring clinicians and careful scientists: we want to give you hope, but only when we can be confident about the science on which it is based. We’re at that point now, and so are ready to share information about a new compound we are developing in collaboration with colleagues in Europe. It is called “CoA-Z” (pronounced ‘co-A-zee’), and we believe it holds great promise for PKAN.

Why do you think CoA-Z will help PKAN?

  • Until now, drugs in development for PKAN have only been tested in animals, such as fruit flies or mice treated with a toxin. Although these animal models can give us helpful information, they don’t necessarily mimic the human disease. Now, we have found a compelling new way of measuring signs of disease in the brains of mice that have mutations in the PKAN gene. These same signs of disease (“biomarkers”) are not present in healthy mice without PKAN. Even more exciting, these same biomarkers are present in cells from people with PKAN, and are not present in healthy people without PKAN. This is BIG NEWS, because it has finally given us a better way of testing treatments for PKAN and a way of monitoring response to these treatments in people with the disease.
  • When we feed CoA-Z to the PKAN mouse, it fixes all signs of disease in the brain (the biomarkers go back to normal levels).
  • When we feed CoA-Z to PKAN cells from humans, the abnormal biomarker levels change to match the cells from healthy people.
  • We need only tiny doses to completely fix the signs of disease in the mouse brain, and even very high doses of the compound show no bad side effects in the mouse.
  • We have met several times with the FDA, the agency that reviews and approves drugs, and have had very positive feedback about our fast-track plans to move the compound into humans.

So…..what’s next?

  • Making large amounts of CoA-Z from scratch has proven more challenging than expected: this is the main thing that has been slowing us down. Although we now have two different methods of making CoA-Z, there are still some challenges to overcome before we are ready to give it to people with PKAN:
    • ∘ A recipe that works beautifully to make enough CoA-Z to feed to a mouse – even a lot of mice – doesn’t necessarily work when it is scaled up to the quantities needed for all the people with PKAN who will need it. Both methods (recipes) need to be tested for their ability to produce large quantities of CoA-Z.

      ∘ A compound that is to be given to humans has to be extra-pure and super-safe. We are working with companies that can produce CoA-Z to the high standards required by the FDA.

      We are committed to keeping the cost of CoA-Z as low as possible for families, but this work is very expensive. We are fundraising, writing grants, and donating our own funds to support this work. We welcome contributions at Donations will make the work go faster, since we will not need to spend as much time applying for grants.

  • We want you to know that we are working very hard to bring what we believe is a very promising, very safe compound to you as fast as we can. We plan to launch a clinical trial just as soon as we have enough CoA-Z and funding to do so, using a study design that allows you to participate from home, completing online assessments and blood draws at your local doctor’s office or lab.
  • We plan to publish our work soon and will keep you posted of our progress on the website, as well as via tweets, Facebook, and email alerts.

But wait….there’s more!

In addition to CoA-Z, findings in the PKAN mice have given us reason to believe that an existing FDA-approved drug may help PKAN. We are in the process of testing this drug in the mice. If it also fixes the PKAN mouse brain biomarkers, we may be able to launch a study even sooner. Stay connected to us at…

What can you do?
You can help now by enrolling in the PKANready study and completing your assessments on time. This online study will give us baseline information about how PKAN affects you or your child, so we can compare symptoms “before” and “after” any treatment.

Decades-long Search for Diagnosis Finally Reaches Conclusion

When Mike Cohn was 15 years old, his unique medical history was described in the well-known medical journal, Neurology. Mike had seizures as a baby, and he reached his motor milestones later than other kids his age. When he turned 8, he felt like his world was turned upside down. Walking became increasingly difficult due to spasticity and dystonia, although he can still do it with a walker. Speech and communication became a frustrating challenge as he approached 11, and his vision worsened. Early imaging studies suggested he had abnormal iron accumulation in his brain. Eventually, Mike connected with the NBIA community and became a champion for NBIA disorders, despite not having a specific diagnosis himself. We first learned of Mike in October of 1996—just over 20 years ago. Over the years, each time a new gene was identified, we thought “maybe this one will explain Mike’s disease,” and each time it tested negative.

In medical speak, we call this a diagnostic odyssey. A journey, sometimes over decades, searching for the cause of disease. Mike’s odyssey recently reached a conclusion. During his search, he has touched thousands of people and helped stimulate a research collaboration across 4 continents. Mike’s DNA, with his permission, has traveled across the Atlantic Ocean as part of his quest. Finally, this year, just shy of his 50th birthday, Mike got an answer.

It started when our team decided to apply to the University of Washington Center for Mendelian Genomics to support a new project. Newer technologies had become available to efficiently screen thousands of genes in a single swoop. This program, if they accepted our application, would screen several of the NBIA research subjects in our repository who still lacked a specific diagnosis. Our proposal was accepted, and we got to work preparing samples and information to send 173 miles north to the University of Washington, located in Seattle.

Several months later, Washington’s Center for Mendelian Genomics had generated so much data that we had to buy a sophisticated new external hard drive just to contain it all. While an expert analyst on the Washington team started to sift through the data, we did the same in parallel at OHSU. Of the 13 individuals submitted, we were able to make new diagnoses in 7 of them based on mutations found in genes that were already known to cause diseases. Of course, Mike was one of the remaining 6 individuals who still did not have an answer. However, we did find something suspicious. Actually, 2 things.

Mike’s DNA sample showed 2 different changes in a gene called MECR. This gene encodes a protein called “mitochondrial trans-2-enoyl-CoA reductase.” Those of you who have lived with NBIA, who have delved into the complicated literature, attended family meetings, and taken your loved ones to doctor appointments, will probably notice a few interesting things about this protein: the words “mitochondrial” and “CoA” made our OHSU team giddy with excitement. The pieces of the puzzle seemed to be coming together. This gene made sense; we thought it could explain Mike’s symptoms. However, it had never been associated with human disease.

Identifying these gene mutations was a huge hurdle we had just jumped, but we still faced several more. In order to truly prove that mutations in a gene cause a certain disease, it’s necessary to find them in multiple patients with similar symptoms. In other words, we needed to build our story a little more. But Mike was one of a kind! How could we try to find others like him, when MECR wasn’t even known to cause disease? As luck would have it, there is a match-making service for genes. Sort of an eHarmony for pairing up investigators studying the same rare gene changes. It’s called GeneMatcher. With the hope of identifying another patient somewhere in the world, we created an entry in GeneMatcher and asked any investigators who found a change in MECR to contact us.

While we waited to hear back from GeneMatcher, we continued to build the story with another approach. Although MECR wasn’t known to cause human disease, a small group in Finland had been studying it as part of a biochemical pathway for several years. Dr. Hayflick reached out to investigators at the University of Oulu, Finland, to share our findings and engage their team in better understanding our discovery. They agreed to use cell models in their lab to try to prove that Mike’s gene changes would knock out the function of the MECR protein. Many months later, as the work in Finland progressed, we got exciting news: GeneMatcher had made a match! We were contacted by a physician investigator in Israel who had a patient with mutations in MECR. Even better, this patient shared a mutation in common with Mike. Although it hadn’t seemed significant until that moment, Mike happens to be of Jewish ancestry, just like the patient in Israel. Now the puzzle pieces were really coming together. As we and our collaborators continued to work and build the story, with the goal of publication, we eventually identified patients in Italy and Australia as well.

On December 1, 2016, a new paper was published in The American Journal of Human Genetics entitled “MECR mutations cause childhood-onset dystonia and optic atrophy, a mitochondrial fatty acid synthesis disorder.” Mike is the oldest individual described in the paper, although a few others are close. The youngest is only 7. Mike has a name for his medical condition now: MEPAN. It stands for a long string of complicated words: mitochondrial enoyl CoA reductase protein-associated neurodegeneration. Based on what we know about MEPAN, we even have a few ideas about potential therapies. Oddly, MEPAN doesn’t technically fall under the umbrella of NBIA disorders. The few patients to date, including Mike, have disease in the same brain regions and similar symptoms to NBIA, but newer, better MRI technologies have shown us that there is a different type of tissue damage involved, rather than iron accumulation. However, the biochemical pathway involved in MEPAN intersects with NBIA, and the medical management is similar.

Mike is a son, brother, friend, disability awareness consultant, author, playwright, and dancer. Now, he can also say he has MEPAN. He has given an incredible gift to the family of the youngest MEPAN patient—learning of Mike’s sharp mind, wit, and ongoing achievements has created a new world of hope for their young child with this diagnosis. This summer, he will turn 50 years old. We should all raise our glasses to Mike and celebrate his personal accomplishments and his recent, important contributions to science. We can’t wait to see what he does with the next 50 years.

Additional thoughts from Mike Cohn:

MINNSPIRATIONSgal040316+003Finding out the true name of what the medical world now calls MEPAN has had a different impact for them than for me, Michael Miller Cohn. I have had to teach the world at large–doctors, nurses, and family friends –who I am and what I can do. Not having a name that people know makes life a very challenging way to live/die.

I have to still teach even after getting tagged with the name MEPAN. Personally, I still feel alone in this world. No one has come before me. No one can ever share what I see or know what I go through in life day to day. Not having medical pain or organ trouble–just a brain that runs 100,000,000 different ideas.

Some nights I go to sleep wondering, will I wake up? Every day is a TRUE gift. Open eyes, share love and friendship, smell the roses like each day is a new one! Last thing is, I hope some people want to see Mike Cohn the dancer. Yes, dance is a LARGE part of my life. How can a man with a medical tag see life as a dancer? Answer: no labels or tags. Art people do not look for names.

–Mike Cohn, February 18, 2017

You can watch Mike dancing on his Youtube channel:

Photo courtesy of Tom Wallace at the StarTribute