In 2012 we were able to announce that the first gene responsible for AHC (ATP1A3) had been found and confirmed! This is exciting news because over 70% of those suffering with AHC have this mutation. 

The paper describing this finding can be found here:
http://www.newswise.com/articles/gene-mutations-identified-as-cause-of-most-cases-of-rare-disorder-ahc

If you would like to know if your child has the ATP1A3 gene please contact sharon@ahckids.org and we’ll arrange for your family to be tested.

Tara Newcomb, who is a Licensed Certified Genetic Counselor and the Clinical Research Coordinator at the University of Utah, will check if your child’s DNA is already stored in the AHCF Biobank. It is possible your families’ DNA was previously collected and you are already part of the AHCF Clinical Research Registry. If not, she will explain the registry and have you fill out the required research and permission forms and then send a DNA kit or arrange with you to have your child’s blood drawn at their next Doctor visit.

Once the test is complete she will notify you of the results or you can have the genetics counsellor of your choice receive the results and discuss them with you. The testing and consultation are free. 

AHC Clinical Registry

All individuals with Alternating Hemiplegia of Childhood (AHC) are invited to join the AHC Registry coordinated at the University of Utah. This involves a one-page questionnaire that may be completed securely either online or over the phone.
We are encouraging you to enroll in the AHC Registry so that we may quickly and efficiently contact you in the future with information about new treatments for AHC, or about studies for which you may be eligible. Additionally, this will provide us with an accurate “head count” of all people with AHC.
The primary benefit to you is that you will be contacted as soon as we launch any AHC research study in which you may be eligible to participate, or as soon as we find a new treatment for AHC. The secondary benefit is that you will know that you are accounted for in the AHC Registry, which is our way of counting how many people have AHC. Knowing how many people have the disease is an important piece of information for obtaining funding of studies on AHC. Completing the AHC Registry form takes about 10 minutes.

Aim 1: Identify key genes and mechanisms causing AHC, ensure pathophysiologic studies to prove functional relevance of mutations identified, perform genotype/phenotype correlations, help ensure widespread dissemination of study results, identify potential therapeutic targets in AHC, and work closely with Dr. Reyna to identify appropriate mechanisms and efforts for clinical trials in AHC.

We have screened 181 affected individuals from our database for mutations in ATP1A3. Of those we have identified a mutation in 120 individuals. We have 10 samples in which we have ruled out a mutation in ATP1A3 and 51 samples that we are still screening. Recently we have begun to screen ATP1A3 in parents of affected children to determine if they carry the same mutations as their child. To date we have screened 173 parents and no ATP1A3 mutations have been identified in those parents.  We continue to receive new requests to enroll in our research study and have obtained additional samples to be included in the screening.

Analysis continued on the remaining familial and sporadic cases that underwent whole genome sequencing and did not have a mutation in ATP1A3. We currently have one strong candidate gene. Once an ATP1A3 mutation is ruled out for an affected individual we screen their sample for mutations in this new candidate gene.

We have begun to look for correlations between genotype and phenotype among affected individuals. We are currently updating the database to include new mutation information, which can then be used to identify correlations between symptoms, age of onset, and disease outcomes.

We have developed a protocol to provide informative study results to families and their local medical providers. The genetic counselor working with the team has contacted families who have requested results at this point. We plan to reach out to all families for whom we have updated contact information to provide results and counseling regarding of the meaning of those results, recurrence risks and the impact of these results on the individual’s prognosis and overall clinical care based on our current information. A letter will be sent to the family as well as any medical provider they wish to have the results. All genetic results are confirmed by verifying the mutation three times using repeated Sanger sequencing.  The families receiving these results are notified that these are research results. The families and their local providers, if applicable, are given contact information for a CLIA certified laboratory in the event that they wish to have the results independently confirmed.

Additional studies are being designed to look at the functionality of the genes identified. At this point we have developed a collaboration with Vanderbilt University. We have provided skin fibroblasts from patients identified to have the most common mutations identified in ATP1A3.

Goal: Develop, populate, maintain, and analyze an online REDCap database for individuals with AHC in order to (1) describe natural history of AHC over time (useful for parents as well as for future trials), and to (2) correlate medical history (age at diagnosis, medications, therapy, episode type/frequency, comorbid conditions, etc.) with how well a child is doing (motor function, quality of life, activity level).

We have included over 230 entries in our REDCap database. Data that has been collected on children and adults with AHC over the past 12 years has now been entered into the database. Data is verified when possible with medical records. We continue to add new data to the database as it is collected.

4/16/2012 Interim Bridge Grant Update

Database

Since January 2012 we have created a database for Demographics, Medical History and Functional Outcome Data. We have entered 235 participants demographic information, 142 participants’ medical history data and 21 participants’ functional outcome measures. We are moving forward with the creation of forms in the database to store genetic testing information as well as physical exam and medical history update information.

Whole Genome

We received the data from CGI in late March 2012 on the sporadic cases. In preliminary analysis 12 of the 16 were found to have mutations in the ATP1A3 gene. Additional interpretation is currently ongoing of the other 4 cases to identify additional candidate genes. Analysis of whole genome data is extremely complicated so we have continued our collaboration with Lynn Jorde, Mark Yandell and Chad Huff on this analysis. Chad is actively working on this project.

Other

As we continue to look at the whole genome data for additional gene candidates we are currently screening the DNA we have from participants in our AHC study for mutations in the ATP1A3 gene.

Each project has taken a lot of man power and effort to get to this point. We are grateful for the bridge grant which has made this work possible, and will continue to move forward with each project.

The findings in the article are a direct result of the close relationships developed between AHC patients, families, foundations, practitioners, and researchers.  AHC patients contributed to databases and DNA banks.  Families raised money to fund research projects. Foundations worked to coordinate research projects and inform the public about AHC. Practitioners consulted with patients and their families when so few professionals knew much about AHC. And, researchers dedicated countless hours to the study of AHC and the genetics behind the disorder.

It would be our honor to post a full text copy of the article on our website.  However, copyright law prohibits us from doing so.  The following points provide a few details on the gene discussed in the article.

What is ATP1A3? It is the official name of this gene, “ATPase, Na+K+ transporting, alpha 3 polypeptide.”

What does the ATP1A3 gene do? The ATP1A3 gene provides instructions for making one part of a protein.  This protein uses energy from a molecule to transport charged atoms into and out of cells. Specifically, it pumps sodium ions (Na+) out of cells and potassium ions (K+) into cells. This is critical for the normal function of nerve cells in the brain.

 What does this mean? It means that researchers identified a mutation with the ATP1A3 gene as a cause of AHC in a majority of patients. The article also mentions that AHC patients with epilepsy have a greater chance of having this specific gene mutation than those without epilepsy.

How does this help AHC patients?  Processing the results of this research will take some time. However, since there is established research on this particular gene mutation, it helps us determine in which direction to begin research on creating treatment protocols for AHC patients.

How do I find out if my child has the mutation?   The Foundation created a process for testing AHC patients for the genetic mutation. Please contact our Medical Liaison, Sharon Ciccodicola at Sharon@ahckids.org and she will go over the instructions for DNA testing and genetic counseling.

What you’ll find on the internet.  The Foundation is mostly run by parents of children with AHC. Some of their children may have the mutation and some may not. We whole heartily recognize the need to find as much information as you can about ATP1A3 by searching on the internet. We ask that you exercise caution when doing so because the link between this mutation and AHC is so very new.  We encourage you to speak to your physicians and continue to check our website for more information.

What’s next?  Research and more research.  Now that one of the genes responsible for causing AHC has been identified, more research is needed. Researchers believe there are additional gene mutations that cause AHC and that they still need to be found.  Research also needs to be done on how to best treat AHC patients with the ATP1A3 mutation. So, the need to raise money to fund research is now more important than ever.

The Foundation is greatly appreciative to the families who started raising money over a decade ago to help get us to this day. We are also appreciative to the researchers and practitioners who worked for many years to support the AHC community. And, we are thankful for the collaborative efforts of geneticists around the world who made finding this gene mutation and the publication of the article in Nature Genetics possible.

Vicky Platt

Secretary, AHCF

AHC Foundation Press Release http://www.onlineprnews.com/news/249348-1343786507-parents-passionate-efforts-help-researchers-identify-cause-of-rare-disorder-affecting-800-worldwide.html

Duke Press Release    http://www.dukehealth.org/health_library/news/gene-discovery-set-to-help-with-mysterious-paralysis-of-childhood

Italian Association    Individuato il gene primario dell’Emiplegia Alternante, una malattia neurologica molto rara

Iceland Association http://www.ahc.is/en/2012/07/cause-of-alternating-hemiplegia-found-mutation-in-atp1a3/

Utah Press Release http://www.newswise.com/articles/gene-mutations-identified-as-cause-of-most-cases-of-rare-disorder-ahc

AHCF Press Release picked up by the following media http://bit.ly/PNV88t

UK press release http://www.ucl.ac.uk/news/slms/slms-news/neuroscience/12081301-alternating-hemiplegia

German Study and Press Release http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(12)70182-5/fulltext#article_upsell

Related Press Articles:

http://uspolitics.einnews.com/pr_news/108229177/parents-passionate-efforts-help-researchers-identify-cause-of-rare-disorder-affecting-800-worldwide

http://www.eurekalert.org/pub_releases/2012-07/dumc-gds072412.php

http://www.healthcanal.com/genetics-birth-defects/31168-Gene-Discovery-Set-Help-with-Mysterious-Paralysis-Childhood.html

http://euroepinomics.wordpress.com/2012/07/31/atp1a3-links-alternating-hemiplegia-of-childhood-with-genetic-dystonia-and-parkinsonism/http://www.sciencedaily.com/releases/2012/07/120729142243.htm

http://medicalxpress.com/news/2012-07-gene-discovery-mysterious-paralysis-childhood.html

http://www.ncbi.nlm.nih.gov/pubmed/22842232

http://www.bioportfolio.com/news/article/1122092/Researchers-Discover-Gene-Mutations-In-Patients-With-Alternating-Hemiplegia-Of-Childhood.html

http://www.news-medical.net/news/20120730/Researchers-discover-gene-mutations-in-patients-with-alternating-hemiplegia-of-childhood.aspx

http://www.business-standard.com/generalnews/news/gene-mutation-that-causes-childhood-paralysis-identified/38352/

http://www.sciencecodex.com/gene_mutations_linked_to_most_cases_of_rare_disorder_alternating_hemoplegia_of_childhood-95737

http://zeenews.india.com/news/health/diseases/gene-mutation-that-causes-childhood-paralysis-identified_18118.html

http://www.asianage.com/newsmakers/gene-mutation-causes-paralysis-found-415

http://www.medicaldaily.com/news/20120730/11157/genetics-paralysis-children-alternating-hemiplegia-of-childhood.htm

http://www.news-medical.net/news/20120731/ATP1A3-gene-mutations-responsible-for-alternating-hemiplegia-of-childhood.aspx

http://www.wral.com/lifestyles/healthteam/story/11372507/

 http://www.pslgroup.com/news/content.nsf/medicalnews/852571020057CCF685257A4B00697405?OpenDocument&id=&count=10

http://www.medwire-news.md/44/100842/Neurology/Gene_for_sporadic_paralysis_of_childhood_discovered.html

http://www.doctortipster.com/10162-new-discoveries-on-alternating-hemiplegia-of-chidhood.html

http://www.als.net/forum/yaf_postsm353587_Genetic-defects-in-ALS-and-relevance-to-PALS.aspx

http://finance.yahoo.com/news/parents-passionate-efforts-help-researchers-100500341.html

http://techzim.blogspot.com/2012/07/alternating-hemiplegia-of-childhood-ahc.html

We have just received the second installment of the Pepsi grant money which will be used to extensively analyze the massive amounts of data produced by the sequencing of each patient.  Patience will be critical, but we are hopeful that this round of testing will give us our best chance yet at finding the answer. We will eagerly await any news and will keep the AHC families apprised of any developments!

The AHC online registry and participants enrolled in the Pediatric Motor Disorder study has continued to grow with 58 families now enrolled! We are also glad to report that 26 families have completed our AHC medical questionnaire, which is an increase from 17 completed last year. The AHC registry and medical questionnaire, have proven to be valuable tools in gaining a better understanding of the characteristics of AHC and in being able to contact families in the future about new treatments for AHC or studies for which they may be eligible. For more information about the AHC registry and Medical Questionnaire please visit our website at: http://medicine.utah.edu/neurology/research/swoboda/ahc/registry.htm

The search for the genetic basis for AHC received a significant boost with the award of the Pepsi Refresh grant. As genetic analysis continues to be more and more advanced, the new grant has allowed us to use the latest genetic sequencing technology available. With prior studies into AHC, we have attempted to do targeted analysis, looking for mutations in genes that have been identified in other better-understood diseases, as well as comparative genome and single nucleotide polymorphism arrays that could determine if an abnormal number of copies of a gene or highly variable (but not clearly abnormal) nucleotides are shared in children that have AHC. As yet, no answers have been found, despite extensive investigation. With the current technology, complete sequencing is finally available. As a result, we will have unparalleled resolution of each subject’s genome. Theoretically, this should prevent any genetic mutation from being concealed (within the 3 billion nucleotide pairs in the human genome) and give us the best chance to find the cause (or causes) of AHC. However, the sequencing of each patient will generate massive amounts of data, which will take extensive analysis. Patience will be critical, but we are hopeful that this round of testing will give us our best chance yet at finding the answer.

We greatly appreciate your support and dedication to our efforts in moving AHC research forward.

We also have 17 families who have completed our updated AHC medical questionnaire! The primary benefit of these questionnaires is knowledge gained regarding the characteristics of AHC in children and adults. There is no immediate personal benefit for participating in completing the AHC Questionnaire, however, we hope that information gained will help us in our search for effective therapies in AHC. The questionnaire can also be found on the above website and faxed back to our research office (fax: 801-587-9346). If possible, please complete the online registry before completing the questionnaire.

And last, but not least, our clinical trial of Sodium Oxybate in children with AHC is well underway and making progress. We currently have four participants enrolled and two in the screening process. For this pilot study, our total participation is capped at six. Three of the four participants have completed their six weeks on Sodium Oxybate and are in the follow-up stage of the study. The fourth participant is currently in the six-week initial drug phase. If our last two participants meet all inclusion and exclusion criteria we, hope to have them start the medication soon as well! This will provide us with the 6 participants we were aiming for.

We want to thank all the families who have participated in our studies. We greatly appreciate their time and dedication to AHC research. We also would like to invite all families who have not yet registered with our AHC Registry or filled out the updated medical questionnaire to please do so at http://medicine.utah.edu/neurology/research/swoboda/ahc/Ongoing%20Research%20Studies.htm

The search for genetic causes of any disease is vital, but it is also slow and painstaking. Many millions of dollars must be raised and many scientists must be engaged. Because AHC is both rare and complex, genetic research is especially challenging. Our work at the University of Utah, in collaboration with researchers at Harvard and UCLA, is promising, and it will continue. In an exhaustive search of 50 candidate genes, we have identified at least three families with specific mutations, 1 in the CACN1A1 calcium channel gene, and 2 in the ATP1A2 gene. However, to date, we have found that fewer than 5% of our AHC patients have one of those mutations. Thus, this work will continue, using newer more sophisticated gene chip techniques to help scan the entire genome for possible small changes in the genetic code that makes up our DNA.

These results confirm what we already knew: gene analysis must continue, because it provides important clues to helping AHC patients, but we cannot wait for its completion before we begin the hard work needed to identify more effective treatments. We must figure out what we can do to improve the symptoms of AHC as we search for genetic causes. Thus, our new phase of research will expand into design of clinical trials that will test likely treatments. We have already begun plans to initiate the first clinical trial in this program, which will enroll a total of twelve patients. Our next step is to take this plan to the FDA and the institutional regulatory agency for approval. We hope to enlist the support of the pharmaceutical industry in these efforts, and to enroll the first patients by later this year.

But the move to clinical trials to treat the devastating symptoms of AHC is not the only exciting news. All of us involved in the AHC community know that we need to increase awareness of AHC among pediatric neurologists and related specialists. We need to educate the medical and scientific communities to the importance of studying the disorder and providing optimal treatment. Thus, I am happy to announce that we have formed a fellowship program that will enable focused attention on AHC-related projects. Under my supervision and with the aid of a full-time study coordinator, each fellow will work exclusively on AHC. He or she will be actively involved in our clinical trial program and will also launch a specific mentored research project. The publications that ensue will further promote attention to AHC and help to generate enthusiasm and funding for future projects. Our first fellow is Dr. Matthew Sweeney. Dr. Sweeney received his bachelor’s degree in engineering at the University of Nebraska in 1997 and a master’s degree in bioemedical engineering at the University of Minnesota in 2000. He received his M.D. from the University of Oklahama in 2004. He has just completed his pediatric residency in June, 2007, and is committed to begin formal training in pediatric neurology in July of 2008. Thus, his background and interests make him ideally suited to contribute to advancements in our understanding and treatment of the complex problems faced by individuals with AHC. We are excited and fortunate for the opportunity to have him join us this year.

We are confident that the continuing expansion of our research program to focus not only on genetic research but on clinical trials to help advance treatment options will prove fruitful and enhance our mission. The AHC foundation’s help in establishing funding for career-development fellowships is a big step in our battle against this terrible disorder. We believe that working together with families to explore new directions is our best hope for future success.

Kathryn J. Swoboda, M.D.

Principal Investigator
AHC Project

As mentioned in the previous report, we have established two important collaborations with other research laboraties, one at Harvard in Boston with Dr. James Gusella, and the other with Drs. Jen and Baloh at the University of California Los Angeles. We continue to work together with them, and taking advantage of resources at both of those institutions as well as at the University of Utah, to work together to better increase our chances of identifying a genetic cause of AHC as soon as possible.

Our work with the Gusella laboratory and Dr. Kim Hyung-Goo in Boston has focused on two major areas: 1) we have some indications that there may be a “position effect” of a specific chromosome abnormality rather than a direct disruption of a single gene. What this means is that instead of a simple error in the genetic message, the chromosome breakage may actually be interfering in a different way with the normal function of genes in the general area. 2) we continue to work to check every single gene in the region by more standard techniques to decode the message to look for any small errors that could be interfering with the function of one or more genes in the region. Thus, we have applied different approaches to move forward using the strengths of this particular laboratory.

As mentioned also in our last report, Drs. Jen and Baloh from UCLA have recently identified a new gene candidate, a glutamate transporter, which they determined to be causing the disorder in a single child in California. The symptoms in this child are very similar to that seen in AHC, and include episodes of alternating hemiplegia. This has given us an entirely new direction in evaluating a whole new group of gene candidates which could play a role in AHC. We continue to work together with our colleagues at UCLA to sequence gene candidates (decode the genetic map dictating how these genes are made into proteins) and also to use newer techniques to identify small and difficult to find changes in these gene candidates which could prove critically important.

As Dr. Reyna has indicated in a recent conversations with both the AHC Foundation President and Medical Liason, approximately two weeks ago the lab specialist who has been working closely with me for the past five years on this project unexpectedly moved. This provides us the opportunity to hire someone with experience in new areas we would like to pursue for the AHC project. We have been actively interviewing new candidates, and have tentatively identified a young scientist with excellent credentials to replace her. She has a PhD, and would bring a number of new skills to the project. We propose to dedicate 60% of her time to the AHC project. Our former laboratory specialist, Justine Johnson, was extremely organized, and we foresee no difficulty in continuing work uninterrupted.

Thus, we report the following progress, and continue to pursue the following goals.

Specific Aim 1. Genome wide linkage analysis and further characterization of resulting gene regions of interest in selected families with more than one affected child:

Simply put, genome wide linkage analysis is a method in which we utilize families with more than one affected individual to help us zero in on a particular area. Newer and better techniques are continually being identified to achieve this task, even using small families, because the tools to perform such work has become better and better in the last year or two. We are actively using a newer strategy, known as SNP analysis (or single nucleotide polymorphism analysis) that takes advantage of unique changes between individuals that occur throughout our genetic map to help identify subtle clues as to how those with AHC may be different than those without within families. Using this technique we are narrowing on focus on at least 3 different areas that could have critical genetic changes causative in AHC.

Specific Aim 2. Analysis of “gene candidates” which cause similar symptoms to those seen in AHC patients, or have an important function that has been implicated as possibly affected in these patients.

All three laboratories have been working on this effort. As a result, we have identified a calcium channel mutation in one of our families with two affected children with AHC. Neither parent seems to carry the mutation, leading us to assume the mutation could have newly occurred in either the eggs or sperm of one of the parents without he or she actually being affected by the disease. We are currently working on additional studies to better understand what this mutation is doing. In addition, we have redoubled our efforst in looking at this and other calcium channels as potential cause of AHC in other children within the database. If the PhD we mentioned above agrees to take the position, then we will have her focus her efforts on this front over the next few months, as it seems particularly promising.

In addition, we have been pursuing new directions with regard to regions within the genetic map holding genes in the following categories: the ATPases and glutamate transporters, using the families with more than one affected child to help us determine whether these additional candidate genes may be important to examine.

3) Cytogenetic analysis of AHC patients without a family history of the disease.

Cytogenetic analysis involves using techniques in which we isolate cells from the blood (we can use cells we’ve previously banked from our database) and then use a variety of chemicals to fix the chromosomes in place that hold all the genetic information in the cell together. We have used older techniques to screen patients in the past, but newer tools now provide improved power to identify very small missing pieces of chromosome. These small missing pieces are known as “microdeletions”. Disorders like Angelman syndrome, which has many symptoms in common with AHC, have been found to be due to such microdeletions, and we continue to try to use better and better techniques to help us find answers. To use an analogy: suppose you were to fly a plane over New York City, and instead of identifying entire missing buildings from the air, you could identify the equivalent of a broken window in one of the buildings….such techniques that dramatically improve our ability to detect changes among the 30,000 candidate genes are coming on line. So far, we have used high resolution karyotyping and fluorescent in-situ cytogenetic techniques to investigate a subgroup of AHC children. Tests performed in this screen include high resolution karyotype (to the 650 band level), and telomere FISH studies. We hope to use even higher resolution techniques in the months ahead to further explore this possibility.

Summary

I hope this above report outlines our progress for the committee in sufficient detail to assure them of our continued dedication and progress in trying to identify the genetic cause or causes or AHC. It increasingly appears from our data that more than one gene may be involved. So far, we and colleagues have identified mutations in 3 separate genes in association with AHC symptoms: ATP1A2, CACNA1A, and now the glutamate transporter SLC1A3. This represents considerable progress over the past three years as we approach the end of our current funding cycle, and provides new directions for identifying abnormalities in all AHC patients. Mutations in the SLC1A3 gene are directly responsible for our pursuit of a new therapeutic direction, since we can more specifically expand our focus to medications known to impact on glutamate related processes. We continue to be optimistic that with time, we will make progress in treating this disease by better understanding the genetics and biochemistry underlying symptoms in these children. I apologize for the previously highly technical report, and will make every effort to make our work more understandable in future reports.

AHCF Progress Report Swoboda Neurogenetics Laboratory