Epileptic seizures are triggered by the abnormal, synchronised firing of neuron groups, resulting in a disruption to the central nervous system which causes spasms and convulsions.
The team led by Dr. Thomas Sander, from the University of Cologne in Germany, have discovered a missing segment of DNA which could be the culprit in unexplained seizures defined as "idiopathic", meaning that their origin is unknown.
The researchers focused on a region of chromosome 15, one of the packages of DNA found within the nucleus of every cell, which in the past been linked to mental retardation, schizophrenia, autism and epilepsy.
The discovery came about after the team genetically screened 647 people with idiopathic generalised epilepsy (IGE) and compared them with 1,202 healthy individuals and they found a deleted section of DNA on chromosome 15 in 1% of IGE sufferers who did not have mental retardation or a psychotic illness.
The deleted section contained at least seven missing genes including CHRNA7, which is responsible for regulating signalling at neuronal synapses, the junctions between nerves.
It is already known that mutations in other members of the same gene family cause a rare form of epilepsy, which suggests that the loss of CHRNA7 may account for the link between chromosome 15 and IGE.
The researchers say the deletion was "the most prevalent risk factor for common epilepsies identified to date."
The research is published in the journal Nature Genetics.
Mayo geneticists hypothesized that Perry syndrome may be caused by mutations within the same gene, even though families afflicted with this disorder are unrelated, and come from different continents. The disease is autosomal dominant, meaning that the chance of inheriting the disease is 50 percent if one parent carries a copy of a mutant gene. With the help and participation of eight families with Perry syndrome, the Mayo-led team set out to find the defective gene.
They determined that each family had one of five novel mutations in the DCTN1 gene, whose protein produces a large subunit of the dynactin complex known as p150glued. This protein is essential to the movement of cargo along the microtubule rails. "Curiously, the mutations all cluster in the p150glued cytoskeleton-associated protein glycine-rich domain and its 'GKNDG' binding motif," Dr. Farrer says. "This region acts like a parking brake, so Perry mutations in p150glued mean that this brake is affected. It would be analogous to driving that train with faulty brakes."
What amazed the researchers are the similarities that Perry syndrome shares with other neurodegenerative diseases. Perry mutations in DCTN1 are physically very close to a mutation previously reported in familial motor neuron disease, they say.
The deposits of TDP43 are also the same as found in motor neuron disease and in some forms of frontotemporal dementia, although they are in a different part of the brain. "With the discovery of mutations in Perry syndrome, researchers have a new means to explore the breakdown in the microtubule transport system in each of these diseases," says Dr. Farrer. "The insides of neurons are very dynamic. Molecules and organelles are constantly being moved to where they are needed, so it makes sense that these disorders, with aging, may be caused by a progressive breakdown in this transport system."
Understanding Perry syndrome may shed light on depression as well as metabolic syndromes, says Dr. Wszolek. Many of the patients have profound depression and about one-third of those commit suicide. Many of the patients also experience severe weight loss and sleep deprivation.
The study was funded by the Pacific Alzheimer Research Foundation of British Columbia, Canada, and the National Institute of Neurological Disorders and Strokes, which funds the Morris K. Udall Parkinson's Disease Research Center of Excellence at Mayo Clinic, Jacksonville.
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