Etiology and pathogenesis
Sudden unexplained nocturnal death syndrome is most likely caused by congenital cardiac conduction system abnormalities in conjunction with the autonomic discharge accompanying sleep terrors and nightmares. In subjects with a family history of sudden unexplained death syndrome, there is abnormal central modulation of autonomic outflow under physical stressors (16). Inappropriate respiratory control during sleep has also been postulated (based on eyewitness accounts) to play an etiologic role. Potassium deficiency has also been proposed as a contributing factor. Right bundle-branch block and precordial injury pattern in V1 through V3 is common in sudden unexplained nocturnal death syndrome patients and represents an arrhythmogenic marker that identifies patients who face an inordinate risk of ventricular fibrillation or sudden death. Pyrogenic toxins of Staphylococcus aureus have also been implicated in some cases. Nevertheless, environmental factors and seasonal factors may also be important. Studies have curiously shown a lack of atherosclerotic coronary disease among victims of this disorder (32).
Detailed postmortem cardiac examinations show cardiac conduction system anomalies, including mild or moderate fatty, fibrous, or fibrofatty tissue replacement, stenosis of node artery, and punctate hemorrhage in the node area (04). These can be anatomic substrates for sleep-related ventricular fibrillation, acute cardiopulmonary failure, and sudden death, which may be triggered by an overactivation of the sympathetic nervous system during sleep terrors or nightmares. Autopsies done in male sudden unexplained nocturnal death syndrome victims from the northeastern region of Thailand showed mild pulmonary congestion in 88.6%, but there were no cardiac or pancreatic abnormalities (22).
Researchers have identified 13 mutations of SCN5A and related genes, conferring instability on the voltage-gated cardiac sodium channels in victims, survivors, and family members of this disorder, specifically among the Han Chinese (12). A rare heterozygous variant VCL-M94I was found in a sudden unexplained nocturnal death syndrome victim who suffered sudden nocturnal tachypnea. He lacked pathogenic variants in known arrhythmia-causing genes, linking it to the loss-of-function of cardiac sodium channel in HEK293 cells and iPSC-CMs. This demonstrates a previously unknown functional interaction between VCL and SCN5A genes. D841H, another VCL variant, was detected in 8 of 120 sudden unexplained nocturnal death syndrome cases among the Han Chinese. This was also associated with loss of function of SCN5A under acidotic circumstances. The findings support the idea that nocturnal sleep respiratory disorders with acidosis may play a crucial role in triggering the deadly arrhythmia underlying sudden unexplained nocturnal death syndrome victims (05). Evidence of the influence of low pH was also demonstrated in the SCN5A mutation and R1512W with both extracellular and intracellular mild acidosis at pH 7.0 (33). These account for about 13% of all sudden unexplained nocturnal death syndrome cases (12).
A number of studies have shown that variants of another gene, SCN10A, have been associated with arrhythmias. However, a study has shown the presence of SCN10A VUS variant in cases of sudden unexplained death (06). The product of SCN10A is Nav1.8 sodium channel. In the study, Nav1.8 was found to be expressed in vagal fibers and intracardiac ganglia but not in cardiac myocytes. One of the functions of Nav1.8 is to modulate arrhythmias, which may explain its role in sudden unexplained deaths (06).
Although a mutation of SCN10A accounts for another 3% of sudden unexplained nocturnal death syndrome cases in this population, polymorphisms of the NOS1AP gene have also been associated with sudden unexplained nocturnal death syndrome among the Han Chinese, with some variations being protective and others conferring a higher risk for the condition (10; 29). Also, mutations of desmoplakin or the DSP gene seem to confer a higher risk for sudden unexplained nocturnal death syndrome in this population (30). A heterozygous mutation causing R1193Q polymorphism (amino acid substitution) has also been described (14). Mutations in the KCNQ1, KCNH2, KCNE2, SCN1B, CACNB2, CACNA1C, and AKAP9 amongst other genes have also been associated with sudden unexplained nocturnal death syndrome (28). A genetic linkage was found between sudden unexplained nocturnal death syndrome and another syndrome called Brugada syndrome. The common mutation underlying both conditions appears to be a variant of plakophilin 2, or PKP2 (08). SCN5A mutations have also been associated with more severe conduction abnormalities and a higher risk for future cardiac events in Brugada syndrome (26). Brugada syndrome is a related illness characterized by specific ECG changes and nocturnal ventricular fibrillation. Furthermore, a study demonstrated a pathological increase in collagen content in both ventricles in patients with Brugada syndrome, which may implicate fibrosis as a reason for the arrhythmias and sudden death encountered with the syndrome (15). It has also been demonstrated that the homeostasis of both magnesium and zinc is altered in sudden unexplained nocturnal death syndrome patients. LRRC10 could be genetically linked to sudden unexplained nocturnal death syndrome and Brugada syndrome among Chinese men (07). HCN4 variations could induce critical arrhythmias and contribute to the development of sudden unexplained nocturnal death syndrome. Researchers detected one missense variant and four synonymous variants of HCN4 in sudden unexplained nocturnal death syndrome cases in China (25).
Research has linked a novel nonsense mutation on the gene gap junction alpha 1 (GJA1) in sudden unexplained nocturnal death syndrome cases. The detected variant would decrease the expression of Conexin 43 (CX43) GJ channels, thus very likely causing electrical coupling disorder of cardiac muscle cells and leading to sudden death (24). In a postmortem study performed in Thailand, 28% of sudden unexplained nocturnal death victims had at least one potentially pathogenic variant in TTN that could cause or modify the risk of the disease (23).
A study that included the largest sudden unexplained nocturnal death syndrome cohort to date has found a new possible factor, XIRP, in the pathogenesis of sudden unexplained nocturnal death syndrome (09). The study demonstrated that in sudden unexplained nocturnal death syndrome and Brugada syndrome cases unexplained by genetic testing, variants in 39 known arrhythmia-susceptibility genes were abundant, with rare variants in XIRP1 and XIRP2. The study has further demonstrated that Xirp2 null hearts exhibit cardiac conduction defects such as A-V block and prolonged QT intervals. In addition, XIRP2 was associated with important cardiac ion channel components, Nav1.5 and Kv1.5. Also, XIRP1 and XIRP2 were found to function as scaffolding proteins that interact with components of actin cytoskeleton, N-cadherin-mediated junction, and ionic channel assembly. Thus, they play a role in the structure and function of cardiac myocytes and also in the surface expression of ion channels and action potential propagation. Further studies are needed on the role of XIRP in sudden unexplained nocturnal death syndrome; however, rare variants of XIRP may be the reason behind many unexplained cases of sudden unexplained nocturnal death syndrome and Brugada syndrome (09).
There is a hypothesis that sudden unexplained nocturnal death syndrome will only occur if three factors present simultaneously during nocturnal sleep: (a) carriers of genes that confer higher susceptibility to sudden unexplained nocturnal death syndrome, (b) stressors caused by environmental or social factors, and (c) disturbance in action potential production and propagation in nocturnal sleep (32).
