Journal of Neurology

, Volume 262, Issue 1, pp 187–193 | Cite as

Genome sequencing identifies a novel mutation in ATP1A3 in a family with dystonia in females only

  • Robert Wilcox
  • Ingrid Brænne
  • Norbert Brüggemann
  • Susen Winkler
  • Karin Wiegers
  • Lars Bertram
  • Tim Anderson
  • Katja Lohmann
Original Communication


Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements or postures. Several genetic causes of dystonia have been elucidated but genetic causes of dystonia specifically affecting females have not yet been described. In the present study, we investigated a large dystonia family from New Zealand in which only females were affected. They presented with a generalized form of the disorder including laryngeal, cervical, and arm dystonia. We found a novel, likely disease-causing, three base-pair deletion (c.443_445delGAG, p.Ser148del) in ATP1A3 in this family by combining genome and exome sequencing. Mutations in ATP1A3 have previously been linked to rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and CAPOS syndrome. Therefore, we re-examined our patients with a specific focus on typical symptoms of these conditions. It turned out that all patients reported a rapid onset of dystonic symptoms following a trigger suggesting a diagnosis of RDP. Notably, none of the patients showed clear symptoms of parkinsonism or symptoms specific for AHC or CAPOS. The ATP1A3 gene is located on chromosome 19q13.2, thus, providing no obvious explanation for the preponderance to affect females. Interestingly, we also identified one unaffected male offspring carrying the p.Ser148del mutation suggesting reduced penetrance of this mutation, a phenomenon that has also been observed for other RDP-causing mutations in ATP1A3. Although phenotypic information in this family was initially incomplete, the identification of the p.Ser148del ATP1A3 mutation elicited clinical re-examination of patients subsequently allowing establishing the correct diagnosis, a phenomenon known as “reverse phenotyping”.


Dystonia Female Next-generation sequencing ATP1A3 



This study was supported by intramural funding from the University of Luebeck.

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical standards

All patients and controls provided written informed consent and the local ethics committee approved the study which has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Supplementary material

415_2014_7547_MOESM1_ESM.mp4 (10.7 mb)
Video legend: The video demonstrates the presence of generalized dystonia in L4007. Spasmodic dysphonia slightly improves due to a sensory trick. The patient is mainly affected by dystonia of the upper half of the body (MP4 10931 kb).


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Robert Wilcox
    • 1
  • Ingrid Brænne
    • 2
  • Norbert Brüggemann
    • 3
  • Susen Winkler
    • 3
  • Karin Wiegers
    • 3
  • Lars Bertram
    • 4
    • 5
  • Tim Anderson
    • 6
  • Katja Lohmann
    • 3
  1. 1.Department of NeurologyFlinders Medical CentreAdelaideAustralia
  2. 2.Institute of Integrative and Experimental GenomicsUniversity of LübeckLübeckGermany
  3. 3.Institute of NeurogeneticsUniversity of LübeckLübeckGermany
  4. 4.Department of Vertebrate GenomicsMax Planck Institute for Molecular GeneticsBerlinGermany
  5. 5.Faculty of Medicine, School of Public HealthImperial CollegeLondonUK
  6. 6.Department of NeurologyUniversity of OtagoChristchurchNew Zealand

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