2012 Bridge Grant Updates

1/8/2013 – Final Report

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


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.


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.

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