Rare genetic mutations associated with impairment of the breathing muscles are more common in children who have died from sudden infant death syndrome (also known as ‘cot death’) than in healthy controls, suggesting a possible genetic element of the disorder, according to a case-control study in the UK and USA published in The Lancet.
Typically, these mutations are either not found in controls or are very rare, and typically found in fewer than five people in every 100000. However, the study found mutations of this kind in four of the 278 children who had died of sudden infant death syndrome, compared to none of the 729 healthy controls.
The authors stress that more research will be needed to understand the link identified, and whether drug treatments might be suitable. They also highlight that this is not the sole cause of sudden infant death syndrome, and other elements also play a part.
Sudden infant death syndrome is the unexpected death of a seemingly healthy child. It is the leading cause of post-neonatal death in high income countries, but deaths are rare, and an individual baby’s risk is low. Typically, it affects children aged between 2-4 months, and accounts for 2400 deaths each year in the USA, and around 300 in the UK.
The cause of the disorder is unknown, but babies being unable to regulate their breathing is thought to be an important component. It is more common in male babies and those born prematurely. Putting babies to sleep on their back, and not sleeping in the same bed as a parent is known to reduce the risk.
The study looked at the prevalence of mutations in the SCN4A gene which codes for an important cell surface receptor (a skeletal muscle sodium ion channel protein). The expression of this cell receptor in breathing muscles is low at birth and increases over the first two years of life.
Mutations in this gene are associated with a range of genetic neuromuscular disorders, such as myotonia, periodic paralysis, myopathy, and myasthenic syndrome, and with life-threatening pauses in breathing, and spasms of the vocal cords that make breathing or speaking temporarily difficult.
The study included two cohorts of children of Caucasian European ancestry who had died from sudden infant death syndrome in the UK and USA, including 278 children overall (84 from the UK and 194 from the USA). All deaths were unexplained after thorough post-mortem investigations. These were matched with 729 adults who had no history of cardiovascular, respiratory or neurological disease.
Tissue from each group was used and their genes were analysed to identify whether they had a mutation in the SCN4A gene, and to confirm whether the mutations affected the cell surface receptor that the gene codes for.
While the study found general mutations in the SCN4A gene in six of the 284 infants who died, and in nine of the 729 controls, mutations that disrupted the cell surface receptor were only found in four of the children who had died of sudden infant death syndrome, and none of the controls.
The authors conclude that the disruptive variants are over-represented in this group, and could indicate a genetic element of sudden infant death syndrome.
The authors suggest that this may increase susceptibility to sudden infant death syndrome in some cases as the cell receptor becomes more commonly used. During this period, the mutation could potentially leave these children with weaker breathing muscles, and, if an external stressor impacts their breathing (such as tobacco smoke, getting tangled in bedding, a minor illness or a breathing obstruction), they may be less able to correct their breathing, cough or catch their breath in response.
They stress that the gene mutation is probably not the sole cause of death, however, and safe sleeping measures for babies are still essential to ensure safety.
In addition, since SCN4A variants are found in some adults with neuromuscular disease, it is evident that SCN4A mutations are not always lethal.
“Our study is the first to link a genetic cause of weaker breathing muscles with sudden infant death syndrome, and suggests that genes controlling breathing muscle function could be important in this condition. However, more research will be needed to confirm and fully understand this link,” says corresponding author Professor Michael Hanna, MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, UK. “While there are drug treatments for children and adults with genetic neuromuscular disorders caused by SCN4A gene mutations, it is unclear whether these treatments would reduce the risk of sudden infant death syndrome, and further research is essential before these findings can become relevant to treatment.”
Co-author Dr Michael Ackerman, Mayo Clinic, USA, says:
This international collaborative UK-USA study provides interesting new evidence for a possible link between respiratory muscle sodium channel dysfunction and SIDS; further research is needed to confirm these findings and to evaluate any potential clinical relevance.
The authors note some limitations, including that the study only included white people of European ancestry, and the results will need confirmation in other ethnicities. In addition, as the information from children who died from sudden infant death syndrome was anonymised there was limited other clinical data and other family members could not be tested. Prospective studies will be needed to confirm the link between the mutation and sudden infant death syndrome.
Writing in a linked Comment, Dr Stephen Cannon, UCLA, USA, says:
Sudden infant death syndrome (SIDS) remains a leading cause of infant mortality, despite a steadily decreasing incidence since the 1990s. The reasons for this decline are debated, but it could be due to methodological reasons (eg, changes in reporting or advances in diagnosis of specific diseases) or a reduction of risks, such as an increase in supine sleeping position for infants, as advocated by the Back to Sleep campaign. A better understanding of the causes of SIDS is needed to identify infants at high risk and to develop interventions and guidelines that will prevent SIDS for all infants… Overall, the evidence is compelling that variants of SCN4A with disruption of channel function are overrepresented in SIDS.