15.09.2003
By MARTIN JOHNSTON health reporter

New Zealand researchers have discovered a rare gene mutation responsible for progressively crippling three siblings in an Auckland family.

The Auckland University-Auckland Hospital team is using the breakthrough to treat two of them with an experimental osteoporosis drug.

The inherited bone-thinning disease gradually causes deformities in bones, spinal curvature and protrusion of the hip socket.

Children with the condition, hyperphosphatasia, often end up in a wheelchair by the age of 15, or as young as 3 in the most severe cases.

The two Aucklanders receiving the drug, who are young adults, are in wheelchairs; the third family member with the disease, a young teenager, has not reached that stage.

Doctors expect the drug will suppress the extreme overactivity of bone reabsorbing cells that the mutation causes.

The body continually makes and reabsorbs bone. The mutation greatly increases the reabsorption rate, outpacing bone-making and leaving bones weakened.

One of the research leaders, Associate Professor Tim Cundy, said last night he hoped the drug would halt the disease's progression, restoring density and strength to the bones.

The university's bone research group director, Professor Ian Reid, said the two people receiving the drug, a synthetic version of a bodily protein called osteoprotegerin, had shown the expected improvements in blood and urine tests, but it was too soon to expect any upturn in their physical condition.

Their younger sister, who had already started on another osteoporosis drug, "appears to be doing very well".

The family is one of about seven worldwide in which the mutation has been confirmed by gene analysis at Auckland Hospital after overseas physicians heard of Dr Cundy's work.

Professor Reid said Dr Cundy's team's findings, published in Human Molecular Genetics, were a major international advance.

He said osteoprotegerin (OPG), the protein for which the gene held the code, was previously known to have a role regulating bone function in animals. "But there's never been any human condition identified with it until now."

The discovery and other leading-edge work Professor Cundy was involved in provided important insights into bone regulation. This could lead to the discovery of new treatment targets for which drugs could be developed.

The research, and other bone projects, will continue under a $3.09 million, three-year grant to Professor Reid's group by the Health Research Council, announced this week as part of the council's $43.47 million in grants nationally.

Part of the work funded by the new grant would be trying to relate the severity of patients' symptoms to the location on osteoprotegerin molecules where the abnormality occurred.

"OPG is a big, long protein. Probably one end is most important for binding to its own particular receptors [on cells] and regulating bone-cell function.

"If you have an abnormality of OPG at the other end, it still seems to cause some problems, but not as much as if you've got the problem right down at the business end of the molecule, where you seem to have a much more severe [expression] in children."

These children suffered broken bones, deformities and loss of mobility in the first few years of life.

"It's a pretty severe disease, even in the Auckland family, but they are at the more mild end of the spectrum."

The seven families had no history of the disease, but as in other rare, inherited disorders it was more common in cultures where first cousins married, he said.

The parents of the Auckland family are first cousins.

* The other big winners from the research council grants are the university's diabetes research ($3.09 million), and Otago University programmes on chronic disease risks ($3.5 million), and cancer genetics ($3.07 million).

Bone disease

* Researchers have found a gene mutation that causes three-quarters of cases of a rare bone-thinning disease called hyperphosphatasia.

* About seven families worldwide, including one in Auckland, are known to suffer from the mutation.

* It increases the rate of re-absorption of bone cells, leading to fractures and deformity.

* Two Auckland patients have been put on an experimental osteoporosis drug, called synthetic osteoprotegerin, which is expected to normalise the re-absorption rate.

"All you have to decide is what to do with the time that is given you."
Gandolf the Gray