Mo­tor neu­rone find ‘ smok­ing gun’

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

The Weekend Australian - Travel - - HEALTH -

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.

Pic­ture: Sam Mooy

Link: Re­searcher Ian Blair says a pro­tein link to mo­tor neu­rone dis­ease has been known for some time, but is still a mys­tery

Newspapers in English

Newspapers from Australia

© PressReader. All rights reserved.