The Daily Telegraph (UK)
02-June-2005

Genetic discovery offers new hope after family tragedy
By Roger Highfield, Science Editor

When Michael Salsbury discovered his baby daughter was dying in the same way that her two sisters had, he found himself comforting the weeping doctor who had given him the diagnosis.

The doctor knew that Gracie-Sophia had started the same mysterious decline that killed both her sisters before their first birthdays. He was crying with frustration because he could not offer Mr Salsbury and his wife, Gabriella, any explanation, prospect of treatment or hope of recovery.

The brain disease, known as Vanishing White Matter disease (VWM), gradually robbed all three daughters of their ability to stay alert, to move or eat as their brains disintegrated. But this story of despair has finally ended in hope, following the discovery a molecular cause for VWM.

Organ donation, detective work and studies of other affected families have revealed that the faulty genes responsible are all involved in a vital aspect of our biology, the translation of the genetic material RNA into proteins, the molecules that build and operate the body. "It has been quite a journey," Mrs Salsbury said yesterday.

The discovery has contributed to a broader realisation that this so-called faulty translation plays a role in many diseases.

In the case of the three Salsbury children, the disease caused them to lose the white matter in their brains, the "wiring" consisting of axons surrounded by a fatty material called myelin, that carries signals between the brain's nerve cells, its grey matter.

According to today's issue of the journal Nature, the new understanding of how this basic mechanism breaks down has much wider implications, and offers an insight into common diseases such as cancer and Alzheimer's.

For the Salsburys, who live in Santa Barbara, California, the discovery offers comfort to their two surviving children, their 15-year-old son and their seven-year-old daughter, who can now use genetic and prenatal testing to make sure they do not suffer the same fate.

"Our son has seen three of his sisters die," said Mr Salsbury. "We told him the other evening that when you get married and want kids, you will not have to wonder or worry 'are my kids going to die too?' "

It is still a mystery why two of the Salsbury's five children have not been struck down by VWM and so far they have not been tested to see if they are at risk. Having gone "as low as any family can probably get, three times", the discovery has helped the Salsburys to heal, his wife added. "We finally know what took the lives of our daughters."

The mysterious disease struck their second child, Stephanie, in 1993. At three months, she began to suffer seizures. Five months later, despite endless tests, she lapsed into a coma and died. Mrs Salsbury gave birth to Jennifer in 1995. Three months later she developed the same symptoms. Knowing that nothing could be done, the family refused intensive care. "We wanted to keep our baby at home and comfortable and love her for as long as we could," Mrs Salsbury said.

Studies have shown that the decline is triggered by a fever or a bang on the head. It can take anything between a few days to a few months for the disease to claim the victim's life. In the case of their third daughter, Gracie-Sophia, symptoms appeared while the family was travelling from Switzerland, where Mr Salsbury was working as a banker, to Santa Barbara where Gracie-Sophia was to be baptised.

The planned celebration "became a funeral", said Mr Salsbury. She abandoned any thought of having a bigger family and donated the girls' organs for research.

They were kept abreast of progress by Dr Hugo Moser, an expert in genetic disorders of the nervous system at the Kennedy Krieger Institute in Baltimore. Dr Moser was the inspiration for the doctor played by Peter Ustinov in the film Lorenzo's Oil. "We knew samples went all over the world," said Mr Salsbury. "But years went by when we did not hear anything."

More clues came, however, from the Netherlands, where there was an unusually high incidence of VWM, affecting one in 40,000 people and scans revealed how the disease operated.

Eventually, Dr Moser told the Salsburys that the cause had been found by Prof Marjo van der Knaap of the Free University Medical Centre, Amsterdam, who deduced how cases, clustered in the eastern Netherlands, probably shared a common ancestor. "The cause was found much quicker than we could dream," said the couple.

Prof van der Knaap's discovery linked the disease to mutations in any of the five genes responsible for a protein called eIF2B. "Whichever gene is mutated, the resulting disease is the same: vanishing white matter," said Prof van der Knaap.

A tell-tale mutation was also found in the organs of Mr Salsbury's daughters. "Each single daughter gave science a new piece of knowledge," he said. Both Mr Salsbury and his wife carry the faulty gene.

The eIF2B protein works with many others that form a molecular machine to translate RNA into proteins. The brain seems more affected by defects in this machine than other parts of the body.

"No cell in the body survives without eIF2B activity, so it is quite surprising that mutated eIF2B leads to a brain disease, and not a whole body disease," said the Dutch professor. "There must be a certain rest activity of eIF2B for cells to survive and apparently the threshold for brain cells is higher."

This mechanism has never before been implicated in such a dramatic illness and is making scientists re-examine the importance of translation in other diseases. The British researcher Prof Christopher Proud, now at the University of British Columbia, Vancouver, said the discovery had "triggered wider excitement".

In the case of cancer, a drug under development called Rapamycin, targets a protein involved in translation. In the long run it may be possible to develop similar drugs to help VWM patients too. The Salsburys have set up a charity to back this research, the Three Little Angels Pediatric Neurological Foundation.