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.
- neurodegenerative disorders
- mental retardation
- paediatric epilepsy
- molecular genetics
- epilepsy and seizures
- headache (including migraine)
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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.