Using whole genome sequencing, a large group of scientists has identified a new genetic cause of progressive myoclonus epilepsy, one of the most devastating forms of epilepsy that emerges in early childhood and can result in early death.
The international team - including members from the University of Helsinki in Finland and the Universities of Melbourne and South Australia - report their findings in the journal Nature Genetics.
Progressive myoclonus epilepsies (PME) are severe, rare forms of epilepsy and frequently arise from hereditary metabolic disorders. Their core symptoms include epileptic seizures and debilitating involuntary muscle twitching. Muscle rigidity, unsteadiness and mental deterioration are often also present.
For the study, the international team recruited 84 patients with PME of unknown cause and used DNA sequencing to identify potential genetic causes of the disorder.
Modern DNA sequencing techniques have revolutionized genetic research of rare, severe diseases. In this case, the team used the technology to sequence the protein-coding elements of the human genome.
They managed to identify genetic causes in nearly a third of the PME patients (26 patients, 31%).
13% of PME cases had previously unknown mutation of potassium ion channel gene
Remarkably, the team found that a previously unknown mutation in a potassium ion channel gene - called KCNC1 - was present in 11 (13%) of the 84 patients and another two (7%) patients in a secondary cohort.
The authors note that the mutation was a "de novo" mutation - meaning it was not inherited from the patients' biological parents.
"De novo" or new mutations are errors that occur in cell division or in the copying of genetic material. They emerge in a germ cell of one of the parents, or in the fertilized egg. Every person has dozens of these new mutations, but they rarely cause disease.
The researchers estimate that this mutation occurs in about 1 in every 5.7 million conceptions, indicating that globally, at least hundreds of PME patients could have this mutation.
Corresponding author and principal investigator Professor Anna-Elina Lehesjoki, from the University of Helsinki and the Folkhälsan Institute of Genetics in Helsinki, says:
"The mutation site is an example of a 'mutation hotspot' of the genome - a DNA nucleotide which is more prone for alterations."
The KCNC1 mutation that the team identified stops a potassium ion channel in brain cells working properly. The channel - called KV3.1 - plays an important part in signal transmission in the brain.
Ion channels are how cells, including brain cells and muscle cells, translate their chemical messages into electrical signals.
The cell builds up a concentration of ions inside itself - different to the concentration in the cell's environment - and this creates a voltage difference. Then, when the time is right to send a signal, the cell opens an ion channel, and because of the voltage difference, ions travel out of the cell, embodying an electrical version of a chemical message.
The researchers suggest the effect of the mutation is to reduce inhibitory signals - making patients susceptible to epileptic seizures and myoclonus starting in childhood. The mutation also leads to degeneration of the cerebellum - a region of the brain that plays an important role in movement control - and subtle cognitive decline in some cases.
Drugs that restore function in this ion channel may already exist
Professor Lehesjoki says because the mutation occurs in a well-known ion channel, there is hope of developing therapy that can target this.
"There are anti-epileptic drugs in the market that target other similar ion channels and follow-up research aims to discover a way to rescue the function of the channel in PME patients," she adds.
In October 2014, Medical News Today learned how a team from Johns Hopkins University in Baltimore, MD, has discovered new clues about conditions that stem from faulty ion channels, such as cardiac arrhythmias, epilepsy and Parkinson's disease. The discovery relates to a common protein that the team says plays a different role than previously thought in the opening and closing of channels that let ions in and out of cells.