Squeak defects in mice could help treat human stutterers

The mystery of why some children begin to stutter in the first few years of life, and never fully recover from the speech impediment, may soon be solved with the creation of the world’s first “stuttering” mouse.

Scientists have generated laboratory mice with the same genetic mutations believed to be involved in triggering the speech disorder in humans in the hope that the genetically engineered animals will provide new insights into understanding and treating the condition in people.

The mice are currently undergoing tests to determine whether their high-pitched calls, which cannot be heard by the human ear, display any characteristic signs that could be linked with the mutations inserted into their DNA.

The researchers believe that the prospect of creating stuttering laboratory mice could revolutionise research into the human condition because it would allow scientists to make detailed studies of the chemical changes within the brain cells of individuals with a stutter.

Although not all stuttering is caused by genes alone, scientists have shown that a sizeable proportion of people who suffer from a stutter are likely to have inherited genetic mutations that predispose them to developing the condition, which usually begins between the ages of three or four.

“We know that about half the people who present themselves for stuttering therapy have a clear family history of the disorder. So a rough guess is that maybe half of stuttering is due to things that are inherited in a family, but we don’t know exactly,” said Dennis Drayna of the US National Institute on Deafness and Other Communication Disorders in Bethesda, Maryland.

“We’ve begun to find genes that contain mutations that do cause stuttering. It’s clear that they don’t cause all of the disorder, in fact a large fraction of the disorder is probably not genetic at all, but we have a piece of it,” Dr Drayna said.

“These genes are providing a lot of surprises. The genes we have found to date all control an aspect of cell metabolism that has been well known and studied by medical geneticists for 50 years but in a completely different context.

“These genes have been associated with very rare but lethal inherited diseases of children. So it was quite a surprise to see mutations in people who otherwise are completely normal, other than stuttering,” he said.

By generating mice with the same DNA mutations, the scientists hope to create the first animal “model” of human stuttering, which will be a vital tool both for understanding the speech impediment and for the development of potential drugs that could be used to treat it.

“Mice have an extremely rich vocal communication but it is extremely poorly understood right now – you can’t hear it because it’s too high pitched,” Dr Drayna said.

“What we are really looking for is an outward manifestation of the fact that these animals are carrying a mutation in these particular genes,” he told the American Association for the Advancement of Science in Washington.

“If we get some sort of alteration, then that opens up an enormous realm because the mouse is the standard mammalian laboratory organism, it is the standard model [for human disorders],” he said.

The genetic mutations, which are found in about 10 per cent of people with a family history of stuttering, were discovered by studies of extended families. These relatively minor mutations occur in three genes, which were already known to cause severe inherited disorders as a result of far more severe mutations that eliminate the gene’s function entirely.

“It’s just a hypothesis at this point but there is a class of cells in the brain, the neurons, that are exquisitely sensitive to this modest little metabolic deficit that is produced by these mutations and these neurons are dedicated uniquely to speech,” Dr Drayna said.

“Our goal is to find out what these cells are, what they are connected to, what their normal function is, and how that function goes awry when these mutations produce a relatively mild metabolic abnormality in those special cells,” he said.

Other studies by Dr Luc De Nil of the University of Toronto have shown higher-than-usual nerve activity in certain regions of the brain of people who stutter, which may be related to the genetic differences identified by Dr Drayna’s team.

“One very curious thing that people have been reporting is that while many of the areas of the brain are over-activated, there actually seems to be a deactivation or under activation of the auditory parts of the brain in people who stutter,” Dr De Nil said.

“I would be extremely surprised if some of the genetic research will not ultimately elucidate and clarify what we are finding,” he told the meeting.