Scientists discover new gene for devastating form of epilepsy

Date: Nov-18-2014 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 team found that a previously unknown mutation in a potassium ion channel gene - called KCNC1 - was present in 13% of the PME patients and 7% of patients in a secondary cohort.

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.

Mutations (lightning bolts) in 13 unrelated cases hit the same DNA nucleotide in KCNC1 gene and disrupt the function of a potassium ion channel, which causes a severe form of epilepsy.
Image credit: Lehesjoki Lab

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.

Written by Catharine Paddock PhD

Not to be reproduced without permission.

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Courtesy: Medical News Today Note: Any medical information available in this news section is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional.