All posts by Puneet Rai

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.

http://nbiacure.org/get-involved/events/2016-bpan-research-meeting-summary/

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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 PKANready@ohsu.edu. Feedback is due back in 2 weeks on July 12th.

Announcement: 2016 BPAN Research Meeting!

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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: http://nbiacure.org/get-involved/events/2016-bpan-meeting/

Once you have made travel plans, please contact us directly (info@NBIAcure.org) 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.
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Image courtesy of www.measuringbehavior.org

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.

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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?

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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.

Summary

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?

References

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

Original map source: http://www.mapsofworld.com

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.

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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 info@NBIAcure.org. Send in your mouse questions!

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

PKANready Launches!

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.

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OHSU Launches New NBIA Testing Panel

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.

The NBIA Panel

Copyright © 2015 by NBIAcure.org. All rights reserved.

A Name Change for University of Maryland’s Brain Bank

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 Case Of The Mysterious BPAN Gene

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.

Resources

Original Article

Copyright © 2014 by NBIAcure.org. All rights reserved.