Discovery of gene mutation which causes epilepsy and mental retardation - but only in women

An Australian and British research team have discovered a gene mutation that causes epilepsy and mental retardation but only in women.

The condition, known as Epilepsy and Mental Retardation limited to Females (EFMR), is found only in particular families and only among women.

With EFMR girls with the condition appear normal at birth but start having seizures at around one year of age; there is then a slowing down of their development and with the combination of epilepsy and mental retardation, they grow up to be intellectually disabled, some quite severely so.

Their discovery is particularly quirky because it has revealed an unusual reversal of a genetic phenomenon that as a rule only affects men.

The PCDH19 gene is found on the X chromosome, and genetic mutations on this chromosome usually only cause disease in males.

Because females have two copies of the X chromosome this generally protects them against X-linked mutations because they have a healthy back-up that can compensate - they can be carriers of genetic conditions and pass them to their children, they are not themselves usually affected.

Males usually have only one X chromosome and one Y chromosome and have no back-up for genetic errors on the X, which can therefore trigger severe diseases such as Duchenne muscular dystrophy and haemophilia.

The international team, led by Dr. Leanne Dibbins of the University of Adelaide, discovered that the PCDH19 mutation reverses this usual pattern and causes EFMR only when a defective copy is inherited by women on one of their X chromosomes, while men who inherit the same mutation on their solitary X chromosome are not affected.

The scientists suspect that the male Y chromosome is somehow capable of compensating for the damage to the X, while the second female X chromosome cannot.

The researchers say how the unusual disease is caused and why it is particularly expressed in women rather than men, remains unclear but they are closer to understanding the mystery.

Dr. Dibbens says this is the first time this type of gene has been found to be involved in epilepsy and the fact that women in families affected by EFMR carry both a 'good' gene and a 'bad', mutated gene, while the men carry only the bad gene but remain unaffected by the condition, is one of the most important discoveries they have made.

Dr. Dibbens says the suspicion is that this may have something to do with the male Y chromosome and the genetic damage that the mutation causes results partly from having a mixture of brain cells with defective and normal genes.

It appears that in women, one copy of the X chromosome is randomly switched off in every cell, while in men, the same X is active in all of them - however more research will be needed to find out exactly how or why.

The researchers also say there is the possibility that a gene found on the male Y chromosome, but not on the X, can compensate for the problems caused by the PCDH19 mutation and they suggest as a candidate the related gene called PCDH11Y which while it has a similar counterpart on the X called PCDH11X, it is slightly different and may not work in quite the same way.

The findings came as a result of a study of seven families from Australia, the United States, Israel and Ireland, where it was found that in one family, 23 women across five generations have suffered from EFMR.

The results also suggest the implication of the PCDH family of genes in other brain conditions, including autism and obsessive-compulsive disorder as well as prompting further investigation into epilepsy.

Dr. Dibbens says with 100 related proteins involved in this particular family of protocadherins genes, the study could lead to many new areas of research.

Dr. Dibbens says their discovery will enable families affected by EFMR to benefit from genetic counselling, including screening for the genetic mutation at pregnancy and hopefully a cure for the condition using gene therapy.

The research is published in the journal Nature Genetics.