Motor neurone find a 'smoking gun'

Australian researchers have uncovered a likely root cause of motor neurone disease, writes Lynnette Hoffman | April 26, 2008

IT was a twitch in Richard Quinn's leg that first tipped him off that something wasn't quite right. He was becoming uncharacteristically unsteady, tripping over.He might have ignored the symptoms had his neighbour not noted they were curiously similar to those her late husband had experienced in the early stages of motor neurone disease.

There were no such twitches for former nurse Margaret Lane. For her, it began with pain in her right thumb, enough to disturb her tennis game as she lost fine motor control and struggled to grip things properly. Gradually her thumb began to waste away. It was no longer puffy, but grew wrinkly and thin.

Both Lane and Quinn were subsequently diagnosed with the disease that had killed Quinn's neighbour. Known in many countries as amyotrophic lateral sclerosis (ALS) and in the US as Lou Gehrig's Disease, motor neurone disease is a rare but serious disease that attacks motor neurones, the nerve cells that control the movement of voluntary muscles which allow you to move, speak and breathe.

About 1300 Australians are living with the disease, and close to 500 die from it each year, often because they can't get enough oxygen to breathe.

With no nerves to activate them, muscles gradually weaken and waste away and paralysis ensues. Along with muscle twitches and weakness in hands and feet, early signs can include slurred speech, difficulty swallowing and cramps. But the disease often differs dramatically from person to person.

Despite a number of famous sufferers, including the American baseball player Lou Gehrig, jazz musician Charles Mingus, and professor Morrie Schwartz, subject of the bestseller Tuesdays With Morrie, the disease has remained mysterious.

There is no cure and only one approved medication to treat it, a drug called riluzole -- sold in Australia as Rilutek -- that delays the progression of symptoms by about three months. That's not much, but it's not as inconsequential as it may sound since MND often progresses very rapidly. The average person dies two to three years after learning their diagnosis, though some far exceed that. Quinn, for example, was diagnosed a decade ago.

But while little is known about the disease or the mechanisms by which it attacks, a paper published by Australian and British researchers in the journal Science last month provides new insight into a possible cause. The findings hinge on a protein known as TDP-43, found in about 98 per cent of MND patients.

The link itself is nothing new -- scientists first discovered the "aggregates," or clusters of the protein, in the spinal cord neurones of MND patients several years ago -- but they had no way of knowing whether the proteins were a cause or an effect of the disease, says Ian Blair, a co-author of the study and researcher at the ANZAC Research Institute in Sydney.

"We didn't know whether these proteins were a cause of the disease or a by-product of cells dying -- or even something the cell was trying to do to rescue itself," Blair says.

Then in 2006 scientists discovered mutations of the protein in a single Australian family with the inherited form of the disease. By far the majority of cases of MND, at least 90 per cent, occur sporadically. That means there is no known genetic link or family history of the disease. Just 5 to 10 per cent of cases are "familial" -- running in families

In the Australian case the family had English relatives who also had the disease, and mutations were found in those family members as well. Meanwhile, members of the family who did not have the disease had no mutations. It was that combination of factors that led the study's authors to conclude the protein was the likely cause.

"The mutations that we found in the family represent the proverbial 'smoking gun', if you like. Those mutations tell us for certain now that when it's abnormal, TDP-43 causes motor neuron disease," Blair says.

He adds that the findings provide strong evidence that the clusters of TDP-43 found in most MND patients are also playing a major role in causing the disease.

The researchers at ANZAC are optimistic that their discovery could lead to new, more effective drugs that target the protein. Still, other experts say it's important not to promise too much too soon.

In 1994, for example, scientists discovered a gene called superoxide dismutase, SOD-1 for short, linked to about 2 per cent of cases of familial MND. They were understandably ecstatic at the possible implications of such a finding, claims neurologist Dominic Rowe, head of the MND clinic at Sydney's Royal North Shore Hospital.

"But 14 years later there's still no specific therapy to treat it," Rowe says. He cautions that the outcomes of the new research could well be similar. "It's very important work, but it doesn't necessarily mean it's applicable to every patient with MND. The jury's still out."

Rowe quickly adds that the new findings could help scientists identify and test drugs for MND: "But is it going to translate to a proven therapy in the near future? Probably not, but if we understand the biology there's a greater chance we'll be able to slow the development of the disease."

Carol Birks, chief executive director of Motor Neurone Disease Australia, agrees the research is very encouraging: "It's another building block, another piece of the jigsaw puzzle."

In the short term, however, MNDA has launched a "living better for longer" campaign to push for better access to best-practice care and improved support for people with MND and their carers.

MND can be extremely expensive, note Birks and Rowe. Patients need access to carers, visiting nurses and nutritional supplements to make up for the nutrients they are no longer able to get through a normal diet.

They also need so-called adaptive devices to help with communication, mobility, feeding and breathing. That includes equipment such as motorised wheel chairs and non-invasive ventilators to help them breathe through the night. Factoring in additional costs such as hospital admissions, Rowe estimates the cost of the final year of illness is more than $150,000.

What's more, Birks says, access to equipment and support services is "patchy," especially in rural and regional areas. Patients in states with smaller populations -- and therefore fewer people suffering from MND -- may have to pay the brunt of the costs of the essential equipment themselves or wait until it becomes available through government services.

In Victoria and NSW, for instance, the state governments contribute significant amounts of funding to state MND associations. The associations then purchase equipment, such as light readers that allow patients to read books without turning pages and special lifters to help carers move patients more easily. The associations also provide expensive equipment such as wheel chairs and non-invasive ventilators which may only be needed for a short period of time -- tragically because the disease often progresses rapidly to death. In South Australia though, the Government provides no financial assistance to the MNDA.

Early diagnosis is also critical. That allows patients to make the most of their health while they've got it, to take advantage of medication that's available and to plan ahead.

But right now the criteria for a diagnosis are so stringent that patients may be missed in the early stages, says Rowe, adding that there's also a lack of awareness within the medical community because so few people develop the deadly disease: "A typical GP might only see one or two cases in their entire practice."

It's little wonder, then, that Richard Quinn ignored his unco-operative leg and an ironic stroke of luck that his neighbour didn't.

http://www.theaustralian.news.com.au...-23289,00.html