Jonathan C. Makielski

Chapter Outline

Linking Sudden Infant Death Syndrome and Arrhythmia

By definition, SIDS occurs in infants without diagnosed or suspected disease antemortem, and with no clear cause of death on routine postmortem examination. This lack of antemortem data has been an obstacle for the field overall and particularly for making the link to arrhythmia. Techniques to investigate the etiology of SIDS include analyses of epidemiologic data, studies of the parents and relatives of SIDS victims, and studies of infants who were considered to be at high risk for SIDS. Infants who came to medical attention before death, or who were resuscitated from an event (called survivors of SIDS, or designated as having near miss SIDS) also have been studied. These cases provide valuable insights into and proof of principle for etiologic factors in SIDS. The near-miss cases, however, do not fit the clinical and epidemiologic definition of SIDS, because the affected patients either had clinical manifestations detected antemortem or did not die. With the discovery that mutations in ion channels and associated proteins cause long QT syndrome (LQTS; Chapters 50 and 69) and other arrhythmia syndromes such as Brugada syndrome (BrS; Chapters 50 and 92) and catecholaminergic polymorphic ventricular tachycardia (CPVT; Chapter 53), it became possible to perform a “molecular autopsy”² for SIDS victims by screening candidate genes for mutations.

The study of cohorts of true SIDS cases that meet the rigorous definition of SIDS can give an estimate of how many cases can be explained by mutations in ion channels or related proteins (channelopathies) that cause altered electrophysiology. A certain semantic paradox occurs, however, because once a cause is established, an individual case should no longer be considered SIDS. This chapter focuses on recent studies showing that some cases previously considered to be SIDS can be explained by channelopathies, and it discusses the extent to which these discoveries and undiscovered channelopathies will lead to reclassification of SIDS cases as early deaths from channelopathies. The importance of making the diagnosis extends well beyond reclassification, because it leads to elucidation of mechanism, prevention, and possible therapy in individual patients.

It also is important to recognize that the presence of a mutation in a susceptible gene does not necessarily imply a link to causation, because mutations without functional significance can occur as common polymorphisms (affecting greater than 0.5% of the population) or as rare variants (affecting less than 0.5% of the population). The absence of the mutation in control panels provides supporting evidence for pathogenicity, but the possibility of discovering an incidental rare variant in SIDS increases as the number of genes screened increases. Traditional linkage studies in family kindreds are used to connect the genotype to the phenotype, but such studies are not possible in SIDS because the phenotype is death in infancy, and mutations can be de novo and are not present in the parents. When a mutation is found, biophysical function of the mutation can be investigated by expressing the mutated protein in heterologous expression systems, or even in myocytes, to demonstrate an abnormality consistent with known pathogenetic mechanisms for LQTS, BrS, CPVT, or other arrhythmia syndromes. If such a mutation is present, it provides strong but not conclusive evidence for pathogenicity. If it is absent, however, it does not prove nonpathogenicity because the mutation might not have been studied under the conditions necessary to elicit the dysfunction (e.g., reduced pH),4,5 or that the presence of the complete macromolecular complex present in myocytes but not heterologous cells is required to manifest dysfunction. To support the conclusion of a link between a genotype and an arrhythmic SIDS clinical phenotype, a mutation should cause biophysical dysfunction of an ion current under relevant environmental conditions that result in a cellular phenotype supporting an arrhythmogenic phenotype at the tissue and organ level (Figure 98-1).

Sudden Infant Death Syndrome and Long QT Syndrome

In the 1970s, Schwartz⁶ suggested that abnormalities of cardiac sympathetic innervation caused a disorder of the heart’s electrical rhythm known as LQTS, and that this can also cause SIDS.⁶ Maron et al.⁷ showed a longer QT interval in parents of SIDS victims and provided evidence for a role of LQTS in SIDS. In a prospective trial of electrocardiographic (ECG) screening in more than 34,000 infants that produced 24 SIDS cases,⁸ a long QT interval increased the risk of SIDS by a factor of 41. The proof of principle that congenital LQTS could cause SIDS came from two cases: a near-miss case⁹ in which the infant survived, and a case in which the patient died in infancy but LQTS was recognized antemortem.¹⁰ In both cases, a mutation in the gene SCN5A encoding the voltage-dependent cardiac sodium channel was found, and it had the characteristic biophysical phenotype of increased late sodium current associated with LQTS type 3 (LQT3). These cases, however, did not meet the formal epidemiologic definition of SIDS.

In 2001, Ackerman et al.¹¹ screened a cohort of 93 patients with defined SIDS for mutations in SCN5A and found two novel mutations that on expression in heterologous cells showed the increased late sodium current of LQT3. Additional studies in SIDS cohorts have found additional mutations in SCN5A associated with LQT3.^4,12 Most of these mutations were rare and novel, but one, S1103Y, was a common polymorphism with an allelic frequency of approximately 10% in the black population that had previously been shown to be associated with ventricular arrhythmia in adults.¹³ Plant et al.⁴ showed that homozygosity for S1103Y increased the risk of SIDS by 24-fold. Moreover, the biophysical abnormality of increased late sodium current depended on acidosis, linking the interaction of environmental influences with the genotype to produce the pathologic phenotype (see Figure 98-1). Subsequently, two other mutations were shown to require acidosis to produce the abnormal phenotype.⁵ Three novel mutations in caveolin-3 (encoded by CAV3), a channel accessory protein, were found in a SIDS cohort and were shown to cause late sodium current characteristic of LQTS.¹⁴ Four novel mutations in α-syntrophin (encoded by SNTA1), a scaffolding protein associated with SCN5A, were found in a SIDS cohort and were shown to cause increased late sodium current by a nitrosylation dependent mechanism.¹⁵ Novel mutations in the sodium channel–associated β-subunits β3 (encoded by SCNB3) and β4 (encoded by SCNB4) were found in the same SIDS cohort and shown to cause increased late sodium current.¹⁶ Thus, the abnormality of sodium current in LQTS as a cause of SIDS is not restricted to mutations in SCN5A.

Mutations in potassium channel genes KCNQ1¹⁷ (LQT1), KCNH¹⁸ (LQT2), and KCNE¹² (LQT6), which cause loss of function in potassium currents, have also been described in SIDS cohorts. The common KCNH2 polymorphism K897T was found to be strongly associated with two cases of SIDS in a singular family.¹⁹ Two other LQTS potassium channel genes, KCNJ2 (LQT7) and KCNE1 (LQT5), were screened in 201 SIDS cases,¹² but no pathologic mutations were found. Currently, approximately 80% of all genetic LQTS can be accounted for by mutations in the known genes (for LQT1 to LQT13),²⁰

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