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Rare gene variant linked to SIDS



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  • A specific genetic variant has been observed more frequently in infants who died of sudden infant death syndrome (SIDS) compared to controls.
  • NaV1.4 is a skeletal muscle voltage-gated sodium channel encoded by The gene SCN4A and the study found rare SCN4A variants that directly alter the function of NaV1.4 in infants who died of SIDS ,

A specific genetic variant was more commonly observed in infants who suddenly died of infant death syndrome (SIDS) compared with controls in a small case-control study, although the variant was still rare.

Four out of 278 infants who died of SIDS had a functionally disruptive SCN4A variant, while none among 729 ethnically matched controls had this variant ( P = 0.0057), reports Roope Männikko, MD, University College London (UCL) and colleagues.

Inherited neuromuscular diseases caused by variants in ion channel genes have an estimated Preval described in Lancet .

The authors described how variants in NaV1

.4, a voltage-gated sodium channel of skeletal muscle, can lead to varying degrees of severity. On the grounds that these "fatal and life-threatening airway phenotypes SCN4A " are compatible with SIDS and that these variants are "over-represented" in infants who died of SIDS

Cases and controls included in the study, from the US and UK, had no history of cardiovascular, respiratory or neurological disorders.

Männikko and colleagues defined SIDS "as the sudden death of a seemingly healthy infant who, despite a thorough investigation of the scene and circumstances, remained unaccounted for death, a comprehensive autopsy study including microbiology and histopathology performed by a pathologist or forensic physician with pediatric training, and a multiprofessional review of available information. "

Researchers identified rare alleles in the SCN4A gene in six infants who died of SIDS and nine of the ethnically-matched controls. However, it was found that four of the SIDS cases had a "functionally destructive [MISSENSEvariant SCN4A " compared to none of the controls.

Männikko's group concluded that the data suggest that these SCN4A variants are "a genetically and mechanistically plausible risk factor for SIDS."

However, the authors warn that these results suggest only a link between the two, and there is still a long way to go before they can be applied to any type of meaningful therapy

"Our study is the first which links a genetic cause for weaker respiratory muscles to sudden infant death syndrome, and suggests that genes that regulate respiratory muscle function may be important in this condition. " Michael Hanna, MD, of the UCL Department of Neurology and National Hospital of Neurology and Neurosurgery, said in a statement. While there are drug treatments for children and adults with genetic neuromuscular disorders that are caused by SCN4A gene mutations, yet it is unclear whether these treatments would reduce the risk of sudden infant death syndrome may become relevant to the treatment "

Co-author Michael Ackerman, MD, of the Mayo Clinic in Rochester, Minn., Characterizes the results as" interesting new evidence for a possible linkage "between these functionally disruptive variants and SIDS, but that" Further research is needed. " to confirm these results and to evaluate possible clinical relevance. "

An accompanying editorial by Stephen C. Cannon, MD, of the University of California Los Angeles, characterizes this as "compelling" evidence that these variants are at least over-represented in SIDS and hypothetical about the potential clinical application of these findings.

"A clinical implication of this study is that pharmacokinetics with sodium channel blockers during the time of developmental risk could prevent SIDS, as these drugs can do for laryngospasm, stridor, and myotonia," he wrote. "Should we be more alert to SIDS in children with non-dystrophic myotonia, and are SIDS cases in this population undervalued?"

Cannon also encouraged future research and wrote that it is particularly important to determine whether laryngeal and respiratory muscles are particularly prone to even slight disturbance of sodium channel function during the first year of life, thereby causing [apnea] and increased risk of SIDS

Study restrictions included the restriction to white Europeans. The study should be replicated in other ethnic groups, according to the authors, adding that because of the anonymity of the samples, little clinical data was available and family members were not tested.

The study was supported by UK Medical Research Council, the Wellcome Trust, National Institute for Health Research, the British Heart Foundation, Biotronik, Heart Risk in Boys, UK College Finance Council, Dravet Syndrome UK, Epilepsy Society, Eunice Kennedy Shriver National Institute for Child Health & Human Development and the Mayo Clinic Windland Smith Rice comprehensive Sudden Cardiac Death Program.

Männikko and co-authors revealed no relevant relationship with the industry.

Cannon reveals support from Strongbridge Biopharma, the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Muscular Dystrophy Association

  • Reviewed by
    Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

2018-03-29T12: 00: 00-0400


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