Mar 15, 2019 New causative mutations reported for familial epilepsy

Scientists uncover links between epilepsy and repeats in non-coding regions of DNA

Brain tissue from autopsied patients with a homozygous mutation (left) and with heterozygous mutations (right)

Reproduced with permission from reference 1 © 2018 Springer Nature

Short, repeated stretches of DNA that do not code for proteins have been shown by researchers to cause an inherited but rare type of epilepsy found more often in Japan and China.

Non-coding repeats are implicated in many human diseases that arise from an abnormal increase (or expansion) in the number of repeats. Now, in a study published in Nature Genetics, researchers in Japan have shown that expansions of non-coding repeats cause benign adult familial myoclonic epilepsy (BAFME).

Patients with BAFME often suffer from hand tremors with jerky twitches, especially during posture changes or fine movements, as well as infrequent generalised seizures. Although worldwide incidence of BAFME is unknown, in a single region in Japan there is estimated to be one case in 35,000 people. Several studies confirm that, among rare disorders, BAFME is prevalent in Japan and China.

The expanded repeats consist of five nucleotides, TTTCA and TTTTA, which were found in a non-coding region of the SAMD12 gene and at least two other genes. The expanded repeats in SAMD12 were found in 82 individuals from 48 families.

The ‘culprit’ repeats appear to be involved “regardless of the genes in which the expanded repeats are located,” says corresponding author Shoji Tsuji, former director of the Medical Genome Center and professor at the Department of Molecular Neurology, The University of Tokyo Hospital.

An accumulation of abnormal RNA molecules containing expanded repeats (RNA foci) were observed in the brains of patients with BAFME.

Reproduced with permission from reference 1 
© 2018 Springer Nature

Seeking a possible mechanism behind BAFME, the researchers looked at patients’ brain tissues. “As no obvious neuronal loss was observed, we infer that neuronal dysfunction, but not neuronal degeneration, is a key feature of BAFME,” explains Tsuji.

The study suggests that also playing a critical role in disease progression is RNA-mediated toxicity, arising from the disruption of RNA-binding proteins by abnormal clumps of RNA containing expanded repeats (RNA foci).

“Since the molecular target for intervention is clearly defined, we hope the development of effective treatments for BAFME will proceed rapidly,” Tsuji says, adding that non-coding regions of DNA may yet harbour more clues to understanding and discovering other diseases.

The research team has confirmed new cases of BAFME in six families since the publication of the Nature Genetics paper, highlighting that there is still much to learn about this emerging disorder.

Tsuji notes that Japanese researchers have been able to establish many disease entities including BAFME, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), dentatorubral-pallidoluysian atrophy (DRPLA), and hereditary progressive dystonia (HPD) or Segawa disease.

“Further application of advanced molecular genetics approaches that complement neurological findings will be key to advancing our knowledge of intractable diseases,” he says.

The program-affiliated researchers contributing to this research are from The University of Tokyo Hospital, Japan.


  1. Ishiura, H., Doi, K., Mitsui, J., Yoshimura, J., Kawabe, M. et al. Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nature Genetics 50, 581–590 (2018). | Article

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