Those of you who attended this year’s NBIA Disorders family conference may recall Dr. Hayflick, Dr. Hogarth and Allison emphasizing how important it is to collect natural history data in order to get the NBIA community ready for any drug trials that may be coming down the pipeline. We are now taking the first step to making that goal a reality and are proud to launch PKANready! This is a five-year clinical study that will help us better understand the natural history of PKAN (how symptoms appear and change over time) and hopefully identify disease markers that can be used in future clinical trials. We will be starting with the PKAN community but this study will soon expand to the other NBIA disorders as well.
The NBIAcure team has exciting news to share! The Knight Diagnostic Lab at OHSU has launched a brand new panel that can test for all the NBIA disorders at once. This panel can be a useful diagnostic tool when an individual suspected of having NBIA has symptoms that don’t match just one NBIA disorder. Our understanding of the NBIA disorders is always evolving, and the spectrum of symptoms for certain disorders is expanding with each new diagnosis. Individuals who may not have been diagnosed based on our previous knowledge are now being identified using new technology, like this NBIA panel. Along these same lines, this new test can also be useful in cases when an individual suspected of having NBIA has already tested negative for one or two forms of NBIA. Rather than doing testing for each disorder one by one, which can be time consuming and expensive, the individual could be tested for all the NBIA disorders at once with a single test.
If you are a clinician, the link below will take you to the Knight Diagnostic Lab’s page for the NBIA panel. It includes additional information about the test and how to order it. Only a physician can order this test, so if you are interested in this test for yourself or a family member, please talk to your doctor.
Copyright © 2015 by NBIAcure.org. All rights reserved.
The Brain Bank at the University of Maryland has recently changed its name. It was formerly known at the NICHD Brain and Tissue Bank for Developmental Disorders, and it will now be called the University of Maryland Brain and Tissue Bank (UMB BTB) due to its expanded scope. The bank is now funded by three NIH Institutions, the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Mental Health (NIMH) and the National Institute of Child Health and Human Development (NICHD), instead of just the NICHD, as it was before. These institutes will receive tissues collected by all the banks in the NIH NeuroBioBank, a network that now includes the UMB BTB.
The mission of the UMB BTB is to advance the research of developmental disorders. According to their website, “the objective of this human tissue repository is to systematically collect, store, and distribute brain and other tissues for research dedicated to the improved understanding, care and treatment of individuals with developmental and neurological disorders.”
Our team at NBIAcure has worked with the UMB BTB many times over the years to coordinate the paperwork and logistics involved with brain or tissue donation by patients (or their families) after they have passed away. For more information about brain and tissue donation, please visit the UMB BTB Family website and/or our brain donation page.
Copyright © 2014 by NBIAcure.org. All rights reserved.
The process of gene discovery can be a difficult concept for many people to comprehend. Just trying to understand a genetic condition after receiving a diagnosis can be a challenge. However, understanding the science behind that condition can help patients and their families grasp what goes on behind the scenes and why research takes so many years to complete.
People unfamiliar with genetic research many imagine it involves scientists running around in lab coats, peering into microscopes and talking in complicated scientific jargon. However, the process of genetic research is actually more like solving a mystery through detective work. Researchers put together the clues, try to find the culprit (the disease-causing gene) and attempt to piece together what happened (how a change in that gene leads to the disease’s symptoms).
Here we will explore how we learned about BPAN—what separated it out from other types of NBIA, how we found the gene, and what we know about the symptoms. By the end of the story, genetic research will seem less like a foreign language and more like an episode of your favorite detective show.
What is the mystery that needs to be solved?
Research starts with an unanswered question. In the case of genetic disease research, that means starting with a patient who has symptoms that don’t fit any known disease. If doctors can’t figure out what disease an individual has, it becomes much harder to treat them and to prevent or slow down additional symptoms that might develop later.
Rare conditions like the NBIA disorders were extremely difficult to classify in the past because the individuals who had them were spread out across the world. Now, due to the widespread use of scientific journals and online databases, it’s easier for doctors to report and share patients who have unusual symptoms they’ve never seen before. Eventually, doctors and researchers who work on rare conditions may begin to notice patterns among certain patients with unknown diseases. Once they see a pattern forming, the detective work can begin.
In the case of BPAN, our starting point was a small group of patients with a few key findings that made them special. Unlike any other NBIA patients, they had developmental delay from an early age but were stable medically until young adulthood. Then, they developed parkinsonism and other movement problems that progressed over time. This was when they usually had a brain MRI, and iron was noticed. These patients were so similar to one another that we thought they must all share the same changed gene. And, although it took us a while, we eventually noticed that most of them were female, and none of them had affected brothers or sisters. So, the mystery that needed to be solved was figuring out what altered gene was causing their symptoms and what the range of symptoms looked like.
Gathering the evidence
Like all good detectives, genetic researchers begin by gathering the available evidence or clues. In the case of BPAN, this meant gathering data from our small group of similar patients—medical reports, brain images, and descriptions from their families. We had met many of them over the years, so we even had photos and videos from some. By including patients with the most similar symptoms in the study group, investigators can dramatically increase the odds of finding a common cause for those symptoms.
Finding the common link
We first recognized the similarities among this group more than a decade ago, and for many years we used different technologies to hunt for a common gene. When NBIA conditions were first being investigated, the process of gene discovery was like finding a needle in a haystack. Human DNA is made of thousands of genes, and it took years just to figure out which section of the DNA might contain the gene we were looking for. However, due to advances in technology, that process has now become simpler and much faster.
The gene responsible for BPAN was eventually discovered through a new process called whole exome sequencing. This process is like running a spell-check program on your DNA. Sequencing breaks down the DNA into individual genetic components, or “words and letters,” so a sophisticated computer program can see if there are any changes or “spelling mistakes.” When our group had their DNA analyzed, it was discovered that all but one had changes in the same gene, WDR45. This gene sits on the X chromosome, one of the 2 sex chromosomes.
To make sure WDR45 was really the responsible gene, researchers used a confirmation method. They selected a total of 60 individuals from the OHSU NBIA registry and other international NBIA registries. None of the individuals selected had a known NBIA gene. The WDR45 gene was sequenced to see if other patients a change in that gene. Sure enough, some more cases were found. In the end, all the patients with a WDR45 gene change were found to have similar symptoms and MRI findings. This was even better evidence that the mystery had been solved.
Finding the WDR45 gene solved some additional mysteries about BPAN. First, why does it usually affect girls? The WDR45 gene sits on the X chromosome, one of the 2 chromosomes that decide sex. Females have two X chromosomes, while males have one X and one Y. X-linked conditions often affect females more than males, because females have a “back-up” X that can help them tolerate the change. It is likely that most males with BPAN miscarry early in pregnancy because they don’t have this back-up system. Second, why does BPAN happen only once in a family? After the gene was found and the parents and siblings were checked, we discovered that the gene change is new in the affected individual. This type of new change is called “de novo.” De novo gene changes are not inherited from a parent. Instead, they occur spontaneously. This can happen in the sperm or egg that leads to a pregnancy, or it can happen during early embryo development.
Unanswered questions that remain
In detective cases, the motive is often the most difficult question to answer and often contains many holes. This is also true in the case of BPAN. Even though we’ve discovered what altered gene leads to BPAN, we still don’t fully understand how a change in that gene causes all the symptoms we see.
WDR45’s main job is to help the body’s cells break down some of their components and recycle the parts to form new components. This process is known to be damaged in many other neurodegenerative disorders, but we still don’t understand how it specifically leads to BPAN symptoms.
How can genetic research be applied to the real world?
Once a disease gene is discovered, the next step is figuring out how to use the information to help patients. The most immediate way a disease-causing gene discovery helps is by making it easier to diagnose that disease. The diagnosis process becomes faster, has less room for error, and often leads to earlier diagnosis with fewer unnecessary, invasive tests. In many cases, an earlier diagnosis leads to better outcomes because medication can be started sooner and doctors can monitor for symptoms that are known to develop later.
Gene discovery can also help the parents of the individual who was diagnosed with a genetic condition. If a couple has a child with a genetic condition, they often wonder what the chances are to have another affected child. For some genetic conditions, the chance can be up to 50%. In those cases, parents may chose to not have any additional children or may undergo genetic testing during pregnancy. In the case of BPAN, it was discovered that the gene change is new and not inherited, which is important information for the parents and siblings to understand.
Finally, we have also learned that many individuals with BPAN share symptoms with another genetic condition called Rett syndrome. This has led to a new study to investigate whether some patients with Rett syndrome actually have WDR45 gene changes.
- Visit our Learn section for more information about BPAN
- Visit our BPAN-Rett Project page to learn about the BPAN and Rett syndrome research study
- “Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation” by S. Hayflick and colleagues
Copyright © 2014 by NBIAcure.org. All rights reserved.
Deferiprone is a medication that chelates, or binds, iron and removes excess amounts from the body. Unlike previous chelator drugs, deferiprone can enter the brain, remove iron from places where it is high, and “redistribute” it. It has been used for treatment of various diseases since 1994 in Europe and Asia. Deferiprone was approved by the FDA for treatment of thalassemia in 2011. It has not yet been approved for treatment of NBIA disorders.
When deferiprone first came out, it sounded like a miracle drug for individuals with NBIA. Unlike iron chelating drugs available in the past, deferiprone was able to get into the brain and could potentially remove accumulated iron. Patients and scientists both hoped that if deferiprone was able to flush out some of the excess brain iron, it could improve the symptoms of NBIA. However, like all the other iron chelating agents, there was also a possibility that deferiprone’s side effects could cause problems before it showed any benefits.
Previous deferiprone studies
So, what do we know about deferiprone in NBIA? Not very much yet! Two small studies have looked at the safety and effectiveness of deferiprone. The first was a pilot study that tested the medication in 6 individuals with NBIA. The second was another small study that tested the medication in 10 PKAN patients. There is a larger, international trial going on right now, but we don’t have the results yet.
Both of these small studies showed that deferiprone was safe and well-tolerated during the trial. They also showed that deferiprone was able to decrease the level of iron in the brain in some cases. How did they prove this? By using specialized MRI technology to measure the iron over time. However, these trials were very limited and they did not answer the biggest question of all: does deferiprone improve the symptoms of NBIA?
It is important to answer this question because even if deferiprone is able to remove iron from the brain, this may not matter if it cannot change a person’s symptoms. Many people believe that iron is the problem in NBIA, but what if it’s not? There may be brain tissue damage or other changes happening before the iron moves in that are causing most of the problems.
New long-term deferiprone study
One of the major criticisms of the previous deferiprone studies has been that they only followed patients for one year. A potential medication needs to be tested for a much longer period of time to get an idea of its safety and effectiveness.
There are still many unanswered questions about deferiprone:
- Deferiprone may be well-tolerated if only taken for a year, but will the side effects get worse the longer it is taken?
- How long does deferiprone need to be taken before it shows any improvement of symptoms?
- Can deferiprone actually improve symptoms at all?
- Are there only some NBIA symptoms that can improve due to deferiprone?
- Will the side effects of deferiprone cause too many problems before we are able to see any clear benefits of the medication?
The research team that conducted the first pilot study has now published a follow-up trial. The new study followed the patients from the original trial for an additional 3 years. So, they were able to report on the safety and performance of deferiprone over a 4-year period.
Out of the 6 patients who were in the previous pilot study, only 5 agreed to participate in this new long-term study. Therefore, 1 new patient was added at the start of the follow-up study. By the end of the study, 5 participants had taken deferiprone for 4 years and one participant had taken it for only 3 years.
Did deferiprone have any serious side effects?
The dosage of deferiprone used during the trial was well-tolerated and safe for continued use up to 4 years. Their medication dosage was determined by their weight. The deferiprone was taken by mouth twice a day. By the end of the study, the participants had no serious side effects.
Can deferiprone reduce iron levels in the brain?
Deferiprone was able to reduce the levels of brain iron in most cases. However, it was not effective in ALL cases. Of 6 patients studied, 4 showed reduced levels of iron, 1 patient’s brain iron levels stayed the same, and 1 patient’s brain iron levels increased.
More research is needed to understand why deferiprone can reduce brain iron levels in some individuals but not in others.
Can deferiprone improve the symptoms of NBIA?
Although deferiprone may be safe, and it appears to reduce brain iron levels in some cases, we still need to decide if it has any effect on the symptoms of NBIA. In this new long-term study, the researchers used a combination of two methods to evaluate if the symptoms had improved.
First, a group of neurologists who were experts in movement disorders used two rating scales to measure the severity of the patients’ symptoms. One was a general dystonia scale and the other was a scale used commonly for Parkinson’s disease. Both scales were used to measure symptoms every 12 months. It is important to keep in mind that these scales were developed for patients with Parkinson’s disease and general dystonia. Although some NBIA patients have symptoms that overlap with Parkinson’s disease and dystonia, these scales are not specific to NBIA.
Second, a different neurologist rated patient videos and gave brief overall assessments such as “unchanged,” “worsened,” or “improved moderately.” This method is less scientific and very subjective since it only includes the observations of a single neurologist.
By the end of this 4-year study, 3 out of the 6 patients had symptoms that improved or stabilized according to both the clinical rating scales and the video rating. Two of the patients were said to have mildly worse symptoms by the video rater, but their clinical rating scales were unchanged or mildly improved. One patient had worse symptoms according to both the clinical rating scores and the video evaluation. However, it is important to note that 1 of the patients in the “improved or stabilized” category was the patient who took deferiprone for only 3 years. By the end of the three years, this patient’s clinical ratings were starting to mildly worsen. Therefore, it is unclear whether this patient would have continued to worsen or ended up stabilize/improved if she had taken deferiprone for 4 years like the other patients in the study.
The patient who worsened while on deferiprone had developed NBIA symptoms at the youngest age (11 yrs) out of the group and was one of the most disabled at the beginning of the study. Patients who develop symptoms at an earlier age tend to have more severe symptoms and may progress at a faster rate. It is possible that this patient did not respond as well to deferiprone because she was more severely affected. The research team used this patient’s results to suggest that deferiprone may be most effective if it is started right after diagnosis, when symptoms are less severe. However, there is no additional data to back-up this suggestion, and more research needs to be done.
While this new study is an improvement compared to previous studies of deferiprone, it still has several problems.
What did this clinical trial do right?
1.) Long-term follow up
The biggest improvement in this new trial is that the researchers followed the patients for an additional three years. By analyzing the effects of deferiprone for a longer period of time, the results provide a clearer picture of how the medication affects patients.
2.) Two methods of symptom evaluation
The use of two different methods to evaluate symptoms is important because it gives a broader picture of how the patient is doing.
What were the limitations?
1.) Small number of patients
Since the study only evaluated 6 patients, it is impossible to predict if the NBIA population in general would have similar results. A larger group of patients needs to be studied.
2.) Including one participant who took deferiprone for a shorter amount of time
This patient’s results were used to draw conclusions about the effectiveness of deferiprone, even though she had taken it for less time than everyone else in the study. It is unknown if the patient’s results might have changed if she had been evaluated after taking deferiprone for another year.
3.) Using clinical rating scales that are not specific to NBIA
The researchers used general dystonia and Parkinson’s disease scales to evaluate symptoms of NBIA. Although some patients with NBIA have parkinsonism and many have dystonia, others do not. Also, many patients with NBIA have other symptoms, like spasticity or motor tics, which can make it difficult to use these scales accurately.
4.) Not all of the 6 patients were confirmed to have PKAN
In this study, only 5 out of the 6 patients had their PKAN diagnosis confirmed by genetic testing. One individual had idiopathic NBIA (idiopathic means a genetic change known to cause NBIA was not found, but the individual has symptoms consistent with NBIA). Non-PKAN results should not be grouped together with those from PKAN patients. What if individuals with different forms of NBIA react differently to deferiprone?
Implications and a new upcoming study
Deferiprone continues to be well-tolerated among patients after 4 years of use, and it is able to reduce levels of brain iron in some individuals. However, the ability of deferiprone to improve NBIA symptoms is still unknown.
A new study underway since 2012 may provide the answer to this question. This new study was funded by the European Commission and is currently being carried out in five centers around the world: Munich (Germany), Warsaw (Poland), Milan (Italy), Newcastle (United Kingdom) and Oakland, California (USA). The study is placebo-controlled, randomized, and double-blinded. This means that some of the patients in the study will be taking a placebo* instead of deferiprone. In order to make it randomized, a computer program selects at random which patients receive the placebo and which receive deferiprone. Since it is double-blinded, neither the patients nor the study investigators will know which individuals received the placebo and which ones received deferiprone until after the study is completed.
Some of the improvements in this new study compared to previous studies include:
- A larger group of patients (90 total)
- Patient follow-up for 18 months (with a possibility for continuation)
- All patients are genetically confirmed to have PKAN
- Patients will range from ages 4 to adult
- Randomized, placebo-controlled, double-blinded analysis
*A placebo is something that looks exactly like the medication being tested in the study but it does not contain the same main ingredient(s) as the real medication. A placebo is sometimes called a “sugar pill” because it contains nothing useful but also nothing harmful. A placebo is used to create a patient group that can be compared to the group taking the medication being tested.
- “Efficacy and safety of deferiprone for the treatment of pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA): Results from a four years follow-up” by G. Cossu, G. Abbruzzese, G. Matta, D. Murgia, M. Melis, V. Ricchi, et al.
- “A pilot trial of deferiprone for neurodegeneration with brain iron accumulation” (2011) by G. Abbruzzese, G. Cossu, M. Balocco, R. Marchese, D. Murgia, M. Melis, et al.
- “Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial” (2011) by G. Zorzi, F. Zibordi, L. Chiapparini, E. Bertini, L. Russo, A. Piga, et al.
Copyright © 2014 by NBIAcure.org. All rights reserved.