Article Text

Download PDFPDF
Original article
Novel mutations consolidate KCTD7 as a progressive myoclonus epilepsy gene
  1. Maria Kousi1,2,
  2. Verneri Anttila3,4,
  3. Angela Schulz5,
  4. Stella Calafato3,
  5. Eveliina Jakkula4,
  6. Erik Riesch6,
  7. Liisa Myllykangas1,7,
  8. Hannu Kalimo7,
  9. Meral Topçu8,
  10. Sarenur Gökben9,
  11. Fusun Alehan10,
  12. Johannes R Lemke11,
  13. Michael Alber12,
  14. Aarno Palotie3,4,13,14,
  15. Outi Kopra1,2,
  16. Anna-Elina Lehesjoki1,2
  1. 1Folkhälsan Institute of Genetics, Helsinki, Finland
  2. 2Haartman Institute, Department of Medical Genetics and Research Program's Unit, Molecular Medicine, and Neuroscience Center, University of Helsinki, Helsinki, Finland
  3. 3Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
  4. 4Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
  5. 5Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg, Germany
  6. 6CeGaT GmbH, Tübingen, Germany
  7. 7Department of Pathology, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland
  8. 8Department of Pediatrics, Hacettepe University Faculty of Medicine, Section of Child Neurology, Ankara, Turkey
  9. 9Department of Pediatrics, Ege University Medical Faculty, Izmir, Turkey
  10. 10Baskent University Faculty of Medicine Division of Child Neurology, Baskent, Turkey
  11. 11University Children's Hospital, Inselspital, Bern, Switzerland
  12. 12Department of Neuropediatrics, University Children's Hospital Tübingen, Germany
  13. 13Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
  14. 14Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland
  1. Correspondence to Professor Anna-Elina Lehesjoki, Folkhälsan Institute of Genetics, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), University of Helsinki, FIN-00014 Helsinki, Finland; anna-elina.lehesjoki{at}


Background The progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous disorders characterised by myoclonus, epilepsy, and neurological deterioration. This study aimed to identify the underlying gene(s) in childhood onset PME patients with unknown molecular genetic background.

Methods Homozygosity mapping was applied on genome-wide single nucleotide polymorphism data of 18 Turkish patients. The potassium channel tetramerisation domain-containing 7 (KCTD7) gene, previously associated with PME in a single inbred family, was screened for mutations. The spatiotemporal expression of KCTD7 was assessed in cellular cultures and mouse brain tissue.

Results Overlapping homozygosity in 8/18 patients defined a 1.5 Mb segment on 7q11.21 as the major candidate locus. Screening of the positional candidate gene KCTD7 revealed homozygous missense mutations in two of the eight cases. Screening of KCTD7 in a further 132 PME patients revealed four additional mutations (two missense, one in-frame deletion, and one frameshift-causing) in five families. Eight patients presented with myoclonus and epilepsy and one with ataxia, the mean age of onset being 19 months. Within 2 years after onset, progressive loss of mental and motor skills ensued leading to severe dementia and motor handicap. KCTD7 showed cytosolic localisation and predominant neuronal expression, with widespread expression throughout the brain. None of three polypeptides carrying patient missense mutations affected the subcellular distribution of KCTD7.

Discussion These data confirm the causality of KCTD7 defects in PME, and imply that KCTD7 mutation screening should be considered in PME patients with onset around 2 years of age followed by rapid mental and motor deterioration.

  • Myoclonus
  • mutation
  • neurodegenerative disorders
  • mental retardation
  • paediatric epilepsy
  • genetics
  • linkage
  • molecular genetics
  • neurology
  • epilepsy and seizures
  • headache (including migraine)
  • neurology

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • Funding This work was supported by the Center of Excellence in Complex Disease Genetics of the Academy of Finland, the Folkhälsan Research Foundation, the Epilepsy Research Foundation, the Biomedicum Helsinki Foundation and the Emil Aaltonen Foundation. VA was supported by the Häme Student Foundation.

  • Competing interests None.

  • Patient consent Patient consent to carry out the study was received from all participants. Separate consent for publication was not received though, as the presented data preserve patient anonymity.

  • Ethics approval This study was approved by an institutional review board of the Helsinki University Central Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.