All posts by Puneet Rai

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

“Best Practices in PKAN” is now published!

Our team is excited to announce that we and several of our collaborators have developed a set of guidelines called “Best Practices in PKAN.” These guidelines provide recommendations and instructions for taking care of a child or adult with PKAN. They will be a valuable resource for patients themselves and for any doctors they may see who are not familiar with PKAN.

The document has been published in a scientific journal and you can access it here:

Upcoming: The 2017 NBIA Scientific Meeting

This upcoming scientific meeting will allow researchers studying NBIA disorders to come together to share their findings, discuss potential therapeutics and plan projects/collaborations. The 6th International Symposium on NBIA & Related Disorders will taken place April 7th-8th, 2017 at Skamania Lodge in Stevenson, WA.

If you are a researcher studying NBIA and related disorders, please follow the link below to learn about registration, lodging, abstract submission and applying for an Early Career Investigators travel award.

Important deadlines:

Application for an Early Career Investigator travel award is due December 1, 2016
Early conference registration (discounted price) ends on December 31, 2016
Abstract submission is due January 16, 2017
Deadline for hotel reservations at discounted price is February 1, 2017

6th International Symposium on NBIA & Related Disorders

Note for NBIA families:
This conference was established for researchers and presentations/talks will be geared towards a scientific audience. However, if a non-researcher still wants to attend, we will not prohibit them from coming. Also, we will share important updates that come out of this scientific meeting at the NBIA Disorders Family Conference in 2017.

Summary of 2016 BPAN Research Meeting

A summary of the 2016 BPAN Research Meeting in Portland is now up on our website! Check it out to learn about what we did, see lots of pictures of the wonderful children and families who attended and read the research updates we shared at the symposium. We can’t say thank you enough to everyone who provided biological samples at the meeting. Those cells are hard at work in our research studies and with our collaborators in England. Have you ever been to London? Well now your children’s cells have!

In addition, our team learned there were many advantages to holding a research meeting in Portland so we will likely be replicating this type of meeting in the future for other NBIA disorders.


PKAN Best Practices Feedback Request

Last year at the family conference, Dr. Hayflick announced that work had begun on a set of guidelines called “Best Practices in PKAN” that would provide recommendations and instructions for taking care of a child or adult with PKAN. This project was funded by the NBIA Disorders Association, Hoffnungsbaum, e.V., and Associazione Italiana Sindromi Neurodegenerative da Accumulo di Ferro. After collaborating with knowledgeable specialists in various fields, such as neurology, nutrition, ophthalmology, and physical therapy, these guidelines are almost ready to submit for publication.

Before we submit this to a scientific journal, we would like to get input from you, the families who live with and manage PKAN every day. Your personal experiences will add valuable insight and help us create a set of gold standards for the diagnosis and management of PKAN.

You can request a copy of the best practices guideline by emailing Feedback is due back in 2 weeks on July 12th.

Announcement: 2016 BPAN Research Meeting!


Our team is excited to announce that we will be hosting a BPAN research meeting in Portland, Oregon from June 24th-26th! We are thrilled to welcome you to our hometown and have planned a variety of activities including research activities, social events, a mini-symposium, and individual appointments with Dr. Hayflick and Dr. Hogarth.

For more details, please visit the event page here:

Once you have made travel plans, please contact us directly ( and let us know when you will arrive and where you will stay. Then, we can schedule appointment times with you for the individual parts of the research weekend.

Ask Jeff: The Mouse Expert Replies

You may recall that back in September we asked if anyone had questions about the PKAN knock-in mice for our resident mouse wrangler, Jeff. We had one curious dad who submitted some very interesting questions (and a few amusing ones that gave our team a good laugh). So without further ado, here are some answers:

Q1. Is the defect identical on both genes or are there two different ones mixed together?

The mutation in both of their PANK2 genes is the same. This allows us to have consistency in their behavior. One can imagine that if one particular mutation is more damaging to the PANK2 gene than another that would make things quite confusing for testing.

Q2. How do you ensure there are no other genetic spontaneous or inherited conditions causing symptoms?

All mice are bred on a specific genetic “background”. Basically, that means that they’re all a standard breed of mouse, in the same way that Jack Russell terriers are a standard breed of dog. The mice are identical except for the PKAN-causing mutations. To make sure they stay that way, we periodically order certified mice of that breed from a company and mate them with our colony. That allows us to minimize any outside spontaneous genetic conditions.

Q3. How do you get your mice to fall over backwards if they have four legs?

When we evaluate humans with PKAN, we measure their balance and coordination by having them do tests like walking a short distance or standing with their eyes closed. However, with PKAN mice, we use a different method called the rotarod performance test. A rotarod is a rotating cylinder as seen in the image below. Basically, the mice are placed on the rotarod and we see how well they’re able to stay perched on that cylinder. Mice with movement disorders, like PKAN, tend to fall off quickly.
Image courtesy of

Q4. Do the mice get headphones in the MRI? What music do you play them?

We don’t use MRIs to evaluate the mice’s brain, but if we did, I imagine the “Mighty Mouse” theme song would be a favorite :)

Unexpected Family Ties

NBIA in Africa? We don’t often hear about new NBIA diagnoses in African countries. The NBIA disorders are not isolated to a particular race or ethnicity so we know individuals must be diagnosed in countries all over the world. Genetic testing is more widely used each year but having affordable access to it is still a barrier in many parts of the world. There are likely many individuals with NBIA in African countries who are still undiagnosed. Another reason we don’t hear as often about these individuals is that identified cases may not be getting published and shared with the global community. That is just one reason why this new study out of North Africa is so fascinating!

PLAN Testing in North Africa

In a study by Romani et al. (2015), seventeen patients (10 girls and 7 boys) from 13 unrelated families had genetic testing of the PLA2G6 gene. This testing was done because the children were all suspected of having infantile-onset PLAN (PLA2G6-associated neurodegeneration) due to their symptoms. The PLA2G6 gene is currently the only gene known to cause all the types of PLAN. The seventeen patients came from eleven families in Tunisia, one from Algeria and one from Libya. As the map below shows, these countries are located next to each other along the southern border of the Mediterranean Sea.


After completing genetic testing, the researchers discovered that five of the families from Tunisia and one family from Libya had the exact same mutation (p.V691del) in the PLA2G6 gene. By analyzing the size and location of the mutation and the number of families sharing the mutation, the study team estimated that this genetic change first occurred in a distant relative shared by these families at least 12 generations back! Assuming that women in each generation had children around 25-30 years of age, this common ancestor likely lived around the late seventeenth century (or even earlier).

In the case of many other genetic diseases, individuals who are affected may pass away before reproducing and this stops the mutation from reaching future generations. However, in the case of autosomal recessive conditions, like PLAN, individuals with just one mutation have no symptoms and that mutation can be passed through multiple generations without any individuals being affected. It is only when two individuals with mutations (the same mutation or different mutations) in the same gene have children together that an affected individual may first appear in the family.

Based on these facts, the study speculated that the one common ancestor of all these families, who lived somewhere around the Mediterranean Sea in the late seventeenth century, was the first to spontaneously develop the p.V691del mutation in their PLA2G6 gene and then passed it on to his/her children, who then passed it on to their own children, and so forth. This phenomenon is called a “founder mutation.”

What is a founder mutation?

It is a gene mutation that is observed with high frequency in a group that is or was geographically or culturally isolated, in which one or more of the ancestors was the first carrier of that mutation.

How do founder mutations occur?


In many cultures, especially in the older generations, marriage practices such as consanguinity and endogamy increased the prevalence of founder mutations in certain populations. Consanguinity is the practice of marrying within a family, such as first or second cousins getting married. Endogamy is the practice of marrying within a specific ethnic group, religion, class, or social group. These practices, along with population decrease, migration or geographical isolation, can increase the number of individuals within a population who carry (and pass on) the same founder mutation. In the case of the Tunisian and Libyan families with the same PLAN mutation, so many years had passed since the founder mutation first occurred that many of them had no idea they were related! After all, not many of us know our ancestry going back over four hundred years ago.

How common are founder mutations?

Founder mutations are actually fairly common among humans. There are many communities around the world in which multiple disease-causing founder mutations have been identified. Some well known examples include the Amish, French-Canadian and Ashkenazi Jewish. These communities have a high rate of founder mutations because they were established by a limited number of founders and tend to marry within their community.


The families in the 2015 study by the Romani et al., had genetic testing done to try to figure out the cause of their children’s symptoms. They never could have imagined the other surprising discovery made about their shared ancestry through this testing! Interestingly, the p.V691del in the PLA2G6 gene has also previously been identified in a family from Jordan and two families from Israel. Just how far does this family tree expand?


Source article: “Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort” by Romani et al. (2015).

Original map source:

Our PKAN mice have news to share

This has been an exciting month for our mice! In September, a new litter who we have been eagerly anticipating was born in the Hayflick lab.

As you may recall from one of the past NBIA Disorders Association newsletters, the Hayflick lab is developing a new mouse model for NBIA. This mouse has been genetically engineered to have a mutation in Pank2, the gene that causes PKAN, and mimics mutations seen in people with the disease.


Getting the mice to the point where they can be used for experiments has been a time-consuming process, but the good news is that we’re finally almost done! The last pairs of breeding mice were set up, and in the past week or so, they gave birth to experiment-ready mice. This is a very big step for our lab, not only for our personal efforts, but hopefully for developing new knowledge about NBIA in general.

Do you want to learn more about the PKAN knock-in mice? Do you have any burning questions about the process so far or what’s coming up in the future? You can now directly ask our resident mouse expert, Jeff! He has graciously agreed to answer questions submitted to our Facebook, Twitter or by email to Send in your mouse questions!


In about 1-2 weeks, we will make another post with Jeff’s answers for everyone to read.