Myotubular Myopathy
A dark past gives way to a bright future
by Dan Stimson |
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Searching for a Cure
Because muscle weakness is the most common, most devastating complication of MTMX, researchers are primarily concerned with what effect the disease has on muscles and how to diminish that effect.
RESEARCH ON MTM TAKES FLIGHT
MDA-funded researcher Peter Harte is probing the causes of X-linked myotubular myopathy (MTMX) by studying a creature that most people would squash without much thought -- the fruit fly. Commonly used by biology teachers to teach genetics, the fruit fly is also used by scientists to explore the genetic origins of complex biological processes, including disease.
About two years ago, Harte identified a fruit fly gene that he's confident is the fly's equivalent of MTM1, the gene that's defective in human MTMX. By studying flies that are mutant for this gene, "we might be able to provide some basic insights into the process that's defective in myotubular myopathy," says Harte.
The mutant flies, says Harte, die shortly after embryonic development. They have muscle defects, as well as defects in other tissues, he says. By examining exactly what goes wrong in the mutants, Harte expects to learn about the normal functions of the myotubularin protein (the product of the MTM1 gene).
Harte also says he's recently identified groups of proteins that interact with fly myotubularin, which could lead to a better understanding of myotubularin function.
But are fruit flies too different from humans to reveal useful information about human myotubularin and its involvement in MTMX? "The differences are as instructive as the similarities," says Harte. "The superficial differences provoke you to scratch your head and say 'Gee, what do these things have in common?'"
With Harte on his way to answering that question, we should soon have a better grasp of what myotubularin does, how its loss causes MTMX and how to compensate for that loss. |
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Based on clinical findings, researchers have long believed that all three forms of MTM result from an interruption of muscle development (see illustration). Normal muscles are composed of cells called muscle fibers, and the formation of these fibers is well understood. During embryonic development, primitive muscle cells called myoblasts fuse together to form large, tube-shaped cells filled with many nuclei (tiny compartments that house the chromosomes). These cells, called myotubes, ultimately mature into muscle fibers.
When a myotube becomes a muscle fiber, the nuclei shift to the cell's outer edges, giving the mature muscle fiber a distinct appearance. In the affected muscles of someone with MTM, some fibers retain centrally located nuclei and thus resemble myotubes (hence the two names for the disease).
This immature appearance of muscle fibers has made muscle biopsy (removal and examination of a piece of muscle tissue) the method of choice for diagnosing MTM.
Researchers don't know exactly how muscle fiber maturation is impaired in MTM, but in 1996, they discovered that MTMX is caused by defects in a previously unknown gene. That gene is now called MTM1, and the protein it makes is called myotubularin.
Now that myotubularin defects are known to cause MTMX, genetic testing for the disease is available (on a fee-for-service basis from University of Chicago Genetic Services, www.genes.uchicago.edu). Moreover, the identification of myotubularin has opened up possible avenues to treatment.
"If we knew a little more about what the basic [muscle] defect is, MTMX could be an excellent candidate for gene therapy," says Herman.
She also points out that the nonmuscle complications of MTMX suggest myotubularin has important functions in many different tissues.
Researchers have some clues about those functions. When they identified the MTM1 gene, they immediately noticed that myotubularin resembles proteins called phosphatases. These proteins perform many important functions in cells simply by snipping off attachments (called phosphates) found on proteins and lipids (the main components of fat).
So, researchers suspect that myotubularin must normally carry out this snipping action to trigger essential events during the development of muscles and other tissues.
"The big question is, what are the other proteins or molecules targeted by myotubularin?" says MDA grantee Peter Harte, a geneticist at Case Western Reserve University in Cleveland.
Some researchers have evidence that myotubularin removes phosphates from proteins that turn genes on and off. Still others have evidence that it removes phosphates from lipids that control the transport of nutrients within cells.
Harte and others are trying to decipher myotubularin's precise functions with hopes that their work will one day lead to treatments for MTMX (see "Research Takes Flight").
When that day comes, children with MTMX will be able to rely less on their parents' persistence and ingenuity, and more on advanced medicine. Until then, the parents will continue to push for more research and better care for their children.
"These kids are sort of like small businesses," says Scoggin. "The more you put into them, the more you'll get out of them." 
RARE FORMS OF MTM
Myotubular myopathy (MTM) is most commonly inherited as an X-linked disease (MTMX), but it also exists in two autosomal forms. (This means that the disease-causing genetic flaw occurs on a chromosome other than the X or Y chromosome, so a roughly equal number of males and females are affected by the disease.)
One autosomal form is inherited as dominant (a child inherits the gene defect from just one parent), and the other is recessive (a child inherits the defect from both parents). Often, the autosomal forms of MTM are called centronuclear myopathy.
The autosomal forms of MTM cause muscle problems similar in quality to those of MTMX, but the dominant form is considered mild and the recessive form intermediate. Age of onset follows a similar trend, with the dominant form appearing sometime during childhood to adulthood, and the recessive form appearing sometime during infancy to early adulthood.
The autosomal MTMs -- and our state of knowledge about them -- differ from MTMX in other significant ways. First, autosomal MTMs are progressive, meaning that the muscle problems grow worse with age. Also, while MTMX can have effects on nonmuscle tissue, similar effects haven't been reported in autosomal MTMs. Finally, while MTMX is known to be caused by defects in the MTM1 gene, the genetic flaws underlying the autosomal MTMs remain to be identified.
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Centronuclear myopathy has not stopped Paul Kahn from having a productive career as a writer. |
Paul Kahn, 55, began experiencing symptoms of MTM during early childhood, and was diagnosed with centronuclear myopathy in his 30s. Kahn's neurologist indicated that his symptoms were consistent with autosomal recessive MTM, but couldn't define the type of MTM with certainty. (Distinguishing among the three types of MTM will be difficult in isolated cases, says geneticist Gail Herman, until genetic tests are available for the autosomal forms of the disease.)
Kahn, who lives in Auburndale, Mass., has used a wheelchair most of his life, and has progressive respiratory problems, which prompted him to get a tracheostomy 13 years ago. But he's always maintained an independent, active life. He's a successful writer and playwright, and for three years, he's led an MDA support group for adults with neuromuscular disorders. "I'm able to be out in the world, and work and play, and do all the things that people do," he says.
As a child, Kahn wasn't always certain what to expect from MTM. "This is such a rare disability that it was difficult for anybody to predict what was going to happen [to me]," he says. When Kahn was 6 years old, his 9-year-old brother died from respiratory complications of MTM. On top of his personal loss, Kahn dealt with fear that his condition would follow a similar course. He says he's hopeful that increasing knowledge about MTM will have a positive impact on future generations of young people.
Geneticist Gail Herman says that a group of European researchers is currently attempting to track down the genes responsible for the autosomal MTMs. The best candidates, she says, are the MTM-related genes (MTMRs) -- a group of eight genes that look very similar to MTM1. |
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