Two thousand years ago, two tribes of humans, now known as theFinno-Ugric People _ emigrated out of Asia, across the Uralmountains into Europe, and split up. The Ugrians headed south tosettle in Hungary. The Finns pushed northwest into present-dayFinland.
There and then, as related by Finnish molecular geneticist Anna-ElinaLehesjoki, the small band of pioneers must have acquired a genemutation that makes today's 5 million inhabitants of Finland theworld's most concentrated focus of progressive myoclonus epilepsy(EPM).
"There are seven of these EPM's," Lehesjoki told BioWorld Today,"all extremely rare. But among them, one type, Unverricht-LundborgEPM type 1, is the most frequent, particularly in Finland. During ourpopulation history," she explained, "there is historical evidence of agenetic bottleneck 2,000 years ago, so the population became quitesmall."
She went on, "We are all descended from those founders, and wehave lived in isolation, exchanging no genetic material with Russiaand other neighboring people."
In modern Finland, EPM1 strikes one in every 20,000 births,producing on average, three new cases per year. "Some 200 caseshave been diagnosed in our country," Lehesjoki said, "and about 100of them are alive."
EPM1 is a childhood disease, she related: "The patients are normalup to school age, six, seven years or a little bit later, and then theystart to have symptoms. Typically, the disease begins with gran malclonic-tonic seizures, which people usually think of as epilepsy _convulsions, loss of consciousness.
"The myoclonus," she explained, "develops a little later."
Myoclonus is uncontrolled twitching of the muscles. Moleculargeneticist Richard Myers of Stanford University described it thus:"When you're at a really boring talk, and you're about to fall asleep,you kind of jerk yourself awake. That sudden action is called amyoclonic jerk."
In affected children, Lehesjoki said, "the myoclonus is usually action-activated. Lying in bed, nothing. But when they start to move, dressthemselves or write something, they get these uncontrolled muscletwitches. You cannot read what they try to write, because they cannotcontrol their hands."
EPM1 is a lifetime affliction; the seizures get progressively worseand more frequent. A generation ago, death usually intervened beforeage 30, for a bizarre iatrogenic reason. At that time, the drug ofchoice to treat the common epilepsies was phenytoin (Dilantin). Butthe myoclonus epilepsies are uncommon, in a class by themselves.
EPM patients had no other medicament 20 or more years ago, soreceived phenytoin. "Maybe it killed some of their brain cells,"Lehesjoki speculated, "so that's why they had more severe symptoms.They were usually bed-ridden, and got infections, such as pneumonia,from which they usually died."
Nowadays, she added, "they receive better epilepsy drugs, so theirdisease doesn't progress so badly."
Family histories make it clear that EPM1 is an autosomal recessiveinherited disorder. Finnish families, by virtue of its high incidence,are a fertile source of genomic information for mapping its geneticetiology.
Lehesjoki is a career scientist at the University of Helsinki. RichardMyers directs Stanford's National Institutes of Health-funded HumanGenome Center. He is senior author, and she second author, of apaper in today's Science. Its title: "Mutations in the gene encodingcystatin B in progressive myoclonus epilepsy (EPM1)."
Known Gene _ Unknown Epileptogenesis
The two centers pooled their gene-hunting resources in 1991,searched the chromosomes of 30 Finnish families, and found amutation of the cystatin gene in all EPM patients but in no healthyindividuals.
"We happened to be lucky," Myers told BioWorld Today, "becausecystatin turned out to be a known gene, on human chromosome 21'slong arm, which had never been mapped before. It's a member of alarge gene family of protease inhibitors, and it's expressed invirtually every tissue of the body."
Its protein product, cystatin B, blocks certain cellular enzymes calledcathepsins, which degrade other proteins.
This raised a dilemma: "Here's a protein expressed everywhere,"Myers observed. "The mutations that we found are ones that knockout its functions, because it's a recessive."
Those mutations, found only in the EPM patients, leads to hisguesswork that "whatever this protease inhibitor is inhibiting, there'ssomething specific about the neurons or the brain that's probablygoing to give us clues as to why these defects cause this seizuredisorder."
Myers added: "This is the first time we've known that a proteaseregulation pathway is involved in epilepsy. That's something that we,and I think others, will be trying to explore. We have a hint now thatwe didn't have before, and that's probably the value of this kind ofresearch _ genetics tends to do this _ it opens up new insights intohow things might be going wrong, even in non-genetic forms ofepilepsy." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.