In the United States, Heinzen’s team used exome sequencing of seven AHC patients and their unaffected parents. De novo mutations in ATP1A3 were identified in all seven patients. Subsequent sequencing included another ninety-eight patients.
In Germany, the Rosewich team used whole-exome sequencing of 24 AHC patients. Twenty-one individuals affected with AHC were identified with disease-associated
mutations in ATP1A3.
In Japan, Ishii’s team used exome sequencing techniques to identify ATP1A3 mutations in ten patients, finding a much higher percentage (50%) of E815K patients.
In the United States, the AHC Foundation was instrumental in assisting the Heinzen team with the genetic discovery. Some of our contributions included:
- Providing funds won from the Pepsi Refresh Challenge ($250,000) to help with DNA cell line extractions.
- “The DNA samples for the seminal discovery were provided by the AHCF.” Dr. Erin Heinzen.
- Connecting investigators with AHC families.
- Funding family meetings in the United States and Canada.
- “Helping counsel families and provided hope to the families and to the researchers,” Dr. Kathryn Swoboda
- “Working with the AHC Foundation and other investigators worldwide, we were able to study the DNA from a much larger number of children with AHC that
allowed us to replicate our findings.” Dr. Erin Heinzen
The work of all three international teams confirmed that ATP1A3 mutations are the primary cause of AHC—a breakthrough that turned uncertainty into clarity and hope for families worldwide. The AHC Foundation is proud of the role we played in this pivotal achievement.
The citations to these three important studies follow:
Heinzen EL, Swoboda KJ, Sisodiya SM, Mikati MA, Goldstein DB, et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet. 2012 Sep;44(9):1030-4. doi: 10.1038/ng.2358. Epub 2012 Jul 29.
Ishii A, Saito Y, Mitsui J, Ishiura H, Yoshimura J, Arai H, Yamashita S, Kimura S, Oguni H, Morishita S, Tsuji S, Sasaki M, Hirose S. Identification of ATP1A3 mutations by exome sequencing as the cause of alternating hemiplegia of childhood in Japanese patients. PLoS One. 2013;8(2):e56120.
Rosewich H, Thiele H, Ohlenbusch A, Maschke U, Altmüller J, Frommolt P, Zirn B, Ebinger F, Siemes H, Nürnberg P, Brockmann K, Gärtner J. Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study. Lancet Neurol. 2012 Sep;11(9):764-73.
Despite the growing number of pathogenic variants described, the most extensive cohort studies conducted in various populations showed that three variants account for ∼60% of all cases.[1]
- p.Asp801Asn (D801N) variant is detected in 30–43% of all cases
- p.Glu815Lys (E815K) is responsible for 16–35% of cases
- p.Gly947Arg (G947R) is responsible for 8–15%.
[1] Cordani R, Stagnaro M, Pisciotta L, Tiziano FD, Calevo MG, Nobili L; I.B.AHC Consortium, De Grandis E. Alternating Hemiplegia of Childhood: Genotype-Phenotype Correlations in a Cohort of 39 Italian Patients. Front Neurol. 2021 Apr 8;12:658451.
