Stammering is a common and often agonizing disorder, but scarcelylife-threatening. Known medically as logospasm, it affects one in ahundred people worldwide. Its cause is an enigma; its cure unknown.But eight out of 10 stutterers get over their verbal disabilityspontaneously.

Not so, another kind of stutter, this one at the molecular level, whichis life-blighting and eventually lethal.

It's the bizarre repetition _ tens, hundreds, even thousands of times_ of trinucleotide codons in the genomes of afflicted individuals.These triplets are the combination of three bases in the genetic codethat transcribe and express a given amino acid.

DNA's double helix is a necklace of four nucleotide bases _ adenine(A), cytosine (C), guanine (G) and thymine (T) _ strung on twospiral threads of sugars and phosphates.

An increasing number of neurodegenerative diseases turn out to bemarked by myriad trinucleotide stutters in their genes. Best knownare Huntington's disease, fragile X syndrome, myotonic dystrophyand Friedreich's ataxia.

The last of these, Friedreich's ataxia (FA), is perhaps less of ahousehold word, but FA is the commonest of all the ataxias, strikingone in 50,000 people, mostly children and adolescents.

Ataxia describes spinal cord degeneration, which affects muscularcoordination in the limbs, eventuating in paralysis. FA leads also toenlargement of the heart, often to diabetes. It usually puts its youngvictims into wheelchairs by their late twenties. Death intervenes inthe late thirties.

A Heidelberg physician, Nikolaus Friedreich, described the neuronaldefect that now bears his name in 1863. Since then, nothing has beenlearned of FA's etiology, nor anything found to slow its inexorableprogression.

Now, in today's Science, 27 researchers from France, Italy, Spainand the U.S. report: "Friedreich's Ataxia: autosomal recessivedisease caused by an intronic GAA triplet repeat expansion."

The co-authors, led by Massimo Pandolfo, of Baylor College ofMedicine in Houston, examined 184 FA patients, and tracked thoseaberrant nucleotide iterations to mutations on a newly discoveredgene they call X25, in a region of human chromosome 9's long arm.This gene encodes a protein they have named frataxin

"Reduced frataxin in spinal cord, heart, and pancreas is probably theprimary cause of neuronal degeneration, cardiomyopathy andincreased risk of diabetes," the Science paper surmised. "Functionalstudies on frataxin," it added, ". . . will hopefully generate newtherapeutic possibilities."

The triplet codon guanine-adenine-adenine (GAA) re-peats from 200to 900 times in the mutant genes of FA patients. Normal X25 genesharbor only seven to 22 repeats.

"Studying how X25 and frataxin function," Pandolfo said, "will helpresearchers understand the disease and design treatments for it."

FA is a maverick among known trinucleotide disorders, which are allinherited by a single chromosome from one carrier parent.Genetically, the FA mutation is a somatic recessive, which means achild must acquire two mutated copies of the gene, one from eachparent.

Another departure: FA is the first triplet-codon disease based onGAA repeats. Huntington's is one of half a dozen bearing expandedCAG. Fragile-X syndrome has CGG; myotonic dystrophy, CTG.

Moreover, again unlike the other known triplet repeat disorders,notably Huntington's, the number of junk-DNA expansions in FAbears no relation to the severity or age at onset. (See BioWorldToday, Aug. 2, 1994, p. 1.)

About one in 100 people, said the National Ataxia Foundation, areFA carriers, walking around, unaware, with one altered chromosome.This they can pass on to offspring, who become carriers in turn.When two carriers mate, FA results.

"Our discovery," Pandolfo observed, "allows accurate screening forcarriers of the disease, and may lead to the first effective treatments."

Still another oddball characteristic of the FA genome: Itstrinucleotide repetition is the first disease-causing mutation thatoccurs on a gene's intron rather than its exon.

Introns are the alternating DNA non-coding stretches in a gene; theyare clipped out of messenger RNA before these assemble proteins.Mutated X25 genes produce much less DNA, the paper reported.Until this discovery, introns had not displayed a genetic function. n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.