All posts by Puneet Rai

Update on BPAN

A scientific paper about BPAN recently published in the journal Autophagy has created some confusion within the community of BPAN families, friends, and caregivers. Entitled “WDR45, one gene associated with multiple developmental disorders,” the paper suggests that gene mutations in WDR45 lead to six separate disorders rather than just BPAN. As you can imagine, this suggestion could make parents question whether their child has the right diagnosis. This paper was written by a team that reviewed the available literature, but has limited clinical experience working with BPAN.

As the team that discovered the gene for BPAN and has deep clinical experience working with patients and running the largest natural history study, we want to reaffirm our strong belief that BPAN is the only disorder associated with gene mutations in WDR45. As you know, BPAN is complicated by several factors:

  • the gene is located on the X chromosome
  • patients have new, often unique changes that are rarely inherited from a parent
  • most patients are “mosaic” in some way, meaning they have some cells with the active gene change and some without, which can vary from tissue to tissue
  • All these factors lead to a very wide range of variation in BPAN. We see variation in age of onset, motor skills, intellectual function, language, presence or absence of seizures, seizure types, and more. However, equally important, we also see overlap among individuals with BPAN that link them all to their common gene. While a child with BPAN may have various descriptions used, such as “Rett-like” or “epileptic encephalopathy,” their primary diagnosis and the underlying cause of their disease is still BPAN.

    Unfortunately, this paper also has a significant error in describing a key MRI finding in BPAN. We sincerely hope the authors will take steps to rectify this with the journal so the community of readers can be notified.

    BPANready Update & Feb Newsletter

    This article and other news can be found in the latest issue of our newsletter which can be downloaded/viewed here: February 2021.

    In May, BPANready turned 2 years old! It has been the fastest enrolling of our natural history studies. We broke 100 participants in last February 2020! We have also received 69 research blood samples and there have been nearly 400 study visits. None of this would have been possible without the BPAN family community’s enthusiastic research participation, and the grant funding we received from the NBIA Disorders Association and the University of Pennsylvania’s Orphan Disease Center Million Dollar Bike Ride. While the number of participants is important for the strength of a natural history study, so too is the number of years of data for each participant. We encourage everyone enrolled to keep inputting their data! We know that it can seem repetitive, but that is exactly what we need so we can learn how BPAN changes over time. Only with that background knowledge will we be able to tell if future therapeutics are changing the course of the disease. We need to be “BPAN ready” for treatment trials! We are currently exploring how to fund the BPANready study going forward. Our preliminary data analysis from the first two years has told us we are on the right track with our approach, but we need to continue to collect your family member’s data and samples over time.

    The not-so-good news is that we are facing a funding crisis for BPANready. While we have some funding support for the PKANready and PLANready natural history studies, without further funding for BPANready, we will need to curtail our efforts on the study. This would have a detrimental impact on this important work, and while we are working hard to sustain this work, we need the family community’s support and funding. We have been exploring how to fund the BPANready study going forward, and will continue to do so. If families want to donate, they can do so here: Click HERE to Donate.

    COVID-19 Vaccination for kids and adults with NBIA

    Many families have asked us recently whether their children ages 16+ with NBIA should be vaccinated for COVID-19. Since the available vaccines have not yet been approved for kids under 16, it will not yet be a question for many of you. However, others with NBIA have already been offered vaccination or will be in the near future.

    The NBIAcure group has always supported vaccination for those with NBIA, including a regular pediatric vaccination schedule and annual flu shots. While vaccination has never been studied specifically in NBIA, the information we have available and our decades of experience with these disorders suggest that the benefit of COVID-19 vaccination will far outweigh potential risks. Some parents have specifically voiced concerns about their children who have seizures. If your loved one with NBIA has seizures or an increased risk for seizures, then mindfulness around potential fever is warranted. Mild fever, as well as headache and general achiness, is more likely after the second dose of vaccine, but can also happen after the first. These symptoms are an expected reaction to the vaccine, and are considered a good sign that the immune system is responding normally. Recommendations regarding pre-medication with a fever-reducing medication like acetaminophen (Tylenol, paracetamol) vary, but because of increased risk of seizures with fever, we encourage you to discuss this with your loved one’s healthcare provider. All the vaccines approved for use at the time of writing are a two-dose series. Although side effects are more common after the second dose, it is very important to follow through with the second dose as your loved one will not be fully protected without it.

    Our team has enthusiastically welcomed the advent of vaccination and feels it’s a huge step forward in our journey of the past 10 months. As a side note, the fact that the vaccines are based on basic tenets of genetics has been particularly exciting! While they are new, mRNA vaccines promise to be highly effective and will likely continue to be used in the future. They leverage the machinery our cells already have to read genetic messages and build proteins. In the case of the vaccine, a new instruction or “recipe” is provided and our cells are able to do the rest. These vaccines do not change the natural genetic material already within our cells and they do not cause COVID-19 infection. We hope this message offers the community some hope and reassurance. We look forward to being able to see you in person in the future.

    A paper from the Sibon lab reveals important insights into biochemical changes in PKAN and related disorders

    Dr. Sibon’s group in the Netherlands has published a paper that reveals important insights into the biochemical changes in PKAN and related disorders (CoPAN, MePAN and PDH-E2 deficiency). It reports work done largely by Roald Lambrechts (who just got his PhD yesterday!) and others in the Sibon lab. Dr. Sibon has also written a FAQs section explaining what the paper means.

    The paper is now open for the public to read here:
    CoA‐dependent activation of mitochondrial acyl carrier protein links four neurodegenerative diseases

    What does the paper say?

    In order to develop a treatment for a disease, it is important to understand the symptoms of a disease. The manuscript by Lambrechts et al explains some of the characteristics of PKAN and explains why some symptoms of PKAN are comparable to symptoms of 3 other diseases. These other diseases are CoPAN, MePAN and PDH-E2 deficiency. The presence of similar symptoms suggests that the 4 diseases share comparable metabolic defects. The manuscript describes and explains these shared metabolic defects in a fruitfly model and in human cells. One of the key findings of the manuscript is that the protein mtACP is less active in PKAN. A defect in mtACP has never been considered nor investigated in relation to PKAN and this provides important insights why mutations in PANK2 gene cause the disease PKAN. A less active mtACP explains also the metabolic defects observed in cells of PKAN patients and the iron accumulation reported in the manuscript of the OHSU group in the PKAN mouse model. The results presented in the Lambrechts et al manuscript also explain why 4-phosphopantetheine corrects the metabolic defects in PKAN as elegantly demonstrated in the Jeong et al manuscript.

    What does it mean for people with PKAN?

    The manuscript further supports the findings of the OHSU group that the mouse model is a valuable model to understand PKAN and is in agreement with the findings of the OHSU group that 4-phosphopantetheine might help people with PKAN.

    What does it mean for people with CoPAN, MePAN and PDH-deficiencies?

    Based on the results of the fly model, the results suggest that 4-phosphopantetheine most likely is not promising for CoPAN, MePAN and PDH-E2 deficiency patients. For these diseases the manuscript suggests other treatment strategies. These strategies need to be further explored before they can be implemented in the clinic.

    A new paper explains the rationale behind the CoA-Z clinical trial

    This peer-reviewed paper authored by our OHSU team in partnership with our Dutch colleagues helps explain the rationale behind our proposed CoA-Z trial in humans. In addition to a link to the paper below, we also developed some Frequently Asked Questions that summarize key points and their relevance for PKAN families.

    The paper is now open for the public to read here:
    4′‐Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN

    What does the paper say?

    The paper by the OHSU team presents a mouse model of PKAN. This mouse is important because it is the only one in use that has the equivalent genetic change as human PKAN patients, and is the first to show a problem with abnormal iron accumulation in brain as well as other PKAN changes. When the mice were fed a vitamin metabolite called 4’-phosphopantetheine, the biochemical abnormalities in their brains resolved. The mice did not have any dystonia; they had only biochemical changes of PKAN. But all of the biochemical changes improved after taking 4’-phosphopantetheine by mouth for two weeks. After testing the mice, Dr. Jeong and team also tested for the same changes in skin cells from people with PKAN. The same biochemical changes were found, and when those cells were bathed in 4’-phosphopantetheine, the changes resolved. The idea of trying 4’-phosphopantetheine in the PKAN mice came from work done by the group of Dr. Ody Sibon in the Netherlands.

    What does this mean for people with PKAN?

    The combination of positive results using 4’-phosphopantetheine in the only true mouse model of PKAN and corroborating studies in PKAN human cells suggested that 4’-phosphopantetheine might help people with PKAN. The mouse experiments showed that 4’-phosphopantetheine is not degraded in the gastrointestinal tract and that it is able to cross the blood-brain barrier. These are important discoveries that disprove concerns raised by other scientists about 4’-phosphopantetheine. The mice showed no toxic side effects from taking 4’-phosphopantetheine, which is a naturally occurring compound that is present at low quantities in most foods. The results together suggest a very low risk for toxicity from 4’-phosphopantetheine. But don’t think that you can just eat the 4’-phosphopantetheine that you need to help your PKAN. The levels in food are so low that an adult would need to eat 100 lbs of meat every day in order to get enough 4’-phosphopantetheine.

    Is 4’-phosphopantetheine the same as CoA-Z?

    CoA-Z contains 4’-phosphopantetheine as one of its ingredients. The formulated compound is called CoA-Z, and the active ingredient is 4’-phosphopantetheine. CoA-Z contains other inactive ingredients as well.

    Where can I get 4’-phosphopantetheine?

    As far as we know, 4’-phosphopantetheine that is suitable for human use is not available anywhere for purchase; you should be wary of any product making such claims. Any 4’-phosphopantetheine that might be available to buy has not been synthesized in a way that makes it safe for human use, and it is very expensive. The 4’-phosphopantetheine that we synthesized for use in the human clinical trial is ultra-pure and was made following strict safety procedures. The synthesis of this special 4’-phosphopantetheine was funded by the Spoonbill Foundation, Stichting Lepelaar, and “ZZF”, the Dutch Foundation for rare diseases, using funds donated by families and other supporters. This high grade 4’-phosphopantetheine is only available to participants in the clinical trial and is not available for purchase.

    When will I be able to buy 4’-phosphopantetheine?

    The clinical trials must be completed and approval given by FDA before 4’-phosphopantetheine can be made available for purchase.

    When can you tell us more about the human clinical trial of CoA-Z?

    We will provide detailed information to the PKAN family community starting in the coming weeks. For families outside of the US and Canada, we will be providing updates on trials in other countries as progress is made and information becomes available. We know how eager you all are!

    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

    As of October 2019, BPAN is now the most common NBIA disorder. You can see an updated diagram with the distribution of NBIA disorders at THIS LINK.

    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