Myotubular myopathy (MTM) is a rare and serious hereditary muscle disorder. It is also called X-linked myotubular myopathy (XLMTM) because it is passed down through a mutated gene on the X chromosome, so it mostly affects boys. If girls are affected, the condition is typically much less severe.
Perry Shieh, MD, PhD
People with MTM are missing or have low levels of a protein called myotubularin, which is essential for muscle development. Without enough of this protein, muscles are very weak. The weakness can cause life-threatening feeding and breathing difficulties in early infancy. With feeding and breathing support, infants with the disease can survive into childhood and, in some cases, into adulthood.
To better understand MTM, we spoke with Perry Shieh, MD, PhD, a neurologist and neuromuscular specialist at UCLA Health, an MDA Care Center.
What are the common symptoms of MTM?
Most boys with MTM are born with severe muscle weakness. From the start, they have trouble breathing, latching, and swallowing. Immediately after birth, they’ll need a feeding tube or some type of respiratory support. Many of them will have a tracheostomy in place and a ventilator when they leave the hospital.
They also have a difficult time coughing and clearing out secretions, so there’s a high risk for developing respiratory illnesses like pneumonia. That’s actually a common cause of death.
How prevalent is MTM?
MTM is exceedingly rare. Numbers we hear range from 1 in 40,000 to 1 in 50,000. Even in a clinic like ours, where we treat a lot of rare conditions, we may only see one or two cases of MTM a year.
When measures like respiratory support aren’t put in place very quickly, unfortunately, those children don’t survive long after birth. So MTM might be more prevalent than we realize because many of these babies may die shortly after birth without a diagnosis.
MTM is diagnosed through genetic testing, and the right testing has to be ordered to get an accurate diagnosis. Like many genetic conditions, MTM often isn’t diagnosed prenatally.
Can you explain the ASPIRO clinical trial and what researchers hoped it would achieve?
The ASPIRO study began in 2018 and tested a gene therapy designed for MTM. The therapy used an AAV8 viral vector — essentially a virus as a delivery vehicle — to carry a healthy copy of the MTM gene into the body. The idea was to replace the defective gene in boys with MTM through a single intravenous infusion.
There were both remarkable successes and devastating losses in this study. Some boys who received the therapy went from requiring ventilators, feeding tubes, and tracheostomies to running, climbing, and playing like typical children. Improvements often developed gradually over the first year or two as muscles strengthened and children learned how to use them.
Other boys benefited less but still saw some improvements.
Unfortunately, four boys died from complications. That clinical trial was placed on hold in 2020. Despite how amazingly transformative it was for the patients that did well, four deaths out of 22 patients is not acceptable, and the sponsor needed to figure out a safer way.
What have you learned about the complications?
The boys died from complications related to liver toxicity. During the ASPIRO clinical trial, researchers discovered that many boys with MTM also had an underlying liver condition called cholestatic liver disease that had previously gone largely unrecognized. In some patients, the gene therapy worsened the liver disease.
While devastating, those outcomes taught researchers critical lessons about the importance of liver health in gene therapy safety — not only for MTM, but potentially for many other diseases as well.
Using learnings from the ASPIRO trial, a new VALOR clinical trial began in spring 2026. The new approach uses engineered viral vectors — modified delivery systems designed to target muscle more efficiently while reducing how much of the therapy reaches the liver. The goal is to improve safety by “detargeting” the liver and improving muscle targeting. Researchers are also using lower doses because the liver toxicity appears to be dose dependent.
Another major change is patient selection. We now screen for underlying liver disease, which we didn’t know enough about during the first trial.
What makes you hopeful for future therapies?
We’ve learned a lot about gene therapy and liver toxicity because of the ASPIRO trial — there were a lot of take-home messages, not just about MTM therapy, but other disease therapies as well. It’s provided us with a path forward in treating MTM, and it facilitates hope that in the future we’ll have an effective and much safer gene therapy for this disease.
Michelle Jackson is a writer for Quest Media.
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