The mutation causes a dysfunction that can make it harder for infants to adequately respond to hypoxemia, or low oxygen levels in the blood, the researchers said. It alters the shape of a "sodium channel" that maintains an electric current to stimulate muscle contraction.
"I think the evidence is pretty compelling that some cases of SIDS are caused by sodium channel mutations," said Dr. Michael Hanna
, a professor of clinical neurology at University College London and a leading author of the study.
"There must be a vulnerability, and what we're saying is that in some cases, the sodium channel is rendering them vulnerable."
Sudden infant death syndrome refers to the unexpected and unexplained death of a seemingly healthy infant between 1 month and 1 year of age, often while the child is asleep. The syndrome accounts for nearly 2,400 infant deaths every year in the US and is the leading cause of death in this age group in high-income countries, according to the National Institutes of Health
The phenomenon has long been known to be associated with sleeping positions, such as when babies sleep on their stomachs, and second-hand exposure to cigarette smoke, according to Hanna.
"There's a big campaign in America and in Europe called the Back to Sleep campaign that's been running for some years," he said. "Basically, just the act of putting a baby on their back to go to sleep instead of the front reduces the incidence of these deaths by about 60%."
But this study would be among the first to show that a dysfunction in the electrical activity of skeletal muscle could also be a contributing factor, says Dr. Stephen Cannon
, a neurologist and professor of physiology at the David Geffen School of Medicine at the University of California, Los Angeles, who was not involved in the research.
"It's a very convincing set of data," Cannon said. "In the preceding four or five years, there have been cases recognized where muscle defects cause breathing difficulties in (newborns) and young children, so it was kind of a logical extension that this might go on to progress to something like SIDS."
The researchers compared the genomes of 278 children in the United States and United Kingdom who died of SIDS with 729 ethnically matched controls. They found that an extremely rare mutation in a gene called SCN4A was present in four of the 278 cases of SIDS but none of the controls.
The SCN4A gene codes for a sodium channel responsible for maintaining the electrical current that stimulates skeletal muscles, such as those responsible for breathing. A disruptive mutation in this gene would normally be expected in fewer than one in every 100,000 individuals, according to Cannon.
"The odds of seeing four in a group of 300 is just astronomical. There's no way that's going to happen by chance," Cannon said. "The numbers are small, which is a challenge, but that's what happens with extraordinarily rare disorders."
A mutation in the SCN4A gene has been linked to skeletal muscle disorders in adults. These disorders are typically characterized by an inability to effectively stimulate or relax skeletal muscles, resulting in excessive muscle stiffness or weakness.
The shared genetic basis between these adult muscle disorders and some cases of SIDS could impact the screening and counseling of prospective parents with known skeletal muscle disorders, Cannon suggests.
"An interesting spin off to this study is whether the couple of thousand people who have these inherited muscle diseases in the United States should be advised and whether we should change the recommendations for how their infants are cared for," he said.
However, Hanna cautioned that the mutation was found in only 1.4% of the infants who died of SIDS, meaning the vast majority of cases are still probably caused by a host of other factors. "I think it's probably a major factor, but it's not a sole factor," he said. "And what the additional factor might be could be one of these environmental triggers," like smoke exposure.
Because the study looked at only one ion channel, future research may want to look at similar mutations in other channels, according to Hanna.
"The respiratory muscles probably have about a hundred different ion channels that are ultimately responsible for normal contraction and relaxation of respiratory muscles. We've just looked at one channel because that was where our hypothesis took us," Hanna said.
"The next step is to look at all the other channels," he added. "That obviously requires further research into all these other genes."
The study looked exclusively at children with European ancestry, so the results may not be generalizable to people from other ethnic backgrounds. African-Americans, for example, are known to have an increased risk of SIDS, which may or may not be attributable to this genetic mutation, Cannon said.
What this means for the future of SIDS prevention is unclear. But some medications, including sodium-channel blockers such as mexiletine, may play a future role in managing those infants at higher risk of SIDS, according to Cannon.
"There are already medications available that can inhibit or block sodium channels and could therefore be very beneficial to get the patient past the period of vulnerability," Cannon said.
"Just knowing it's in the family, you could also be more vigilant about monitoring or other preventative measures that have been used in SIDS and other cases -- for example, careful positioning of a baby's sleeping," he added.