Stillbirth versus SIDS. Pathology of the autonomic nervous system and DNA polymorphisms in SIUD and SIDS

Pathogenesis of sudden intrauterine unexpected death (SIUD) and sudden infant death syndrome (SIDS) seems to privilege, in most cases, autonomic nervous dysfunction. Neurogenic factors are interplaying in all the driving pathogenic hypotheses (the cardiac, the respiratory, and the visceral dyskinetic), as well as in the cardiac-arrhythmogenic one, in which the conduction system is subject to strict autonomic control. Therefore, histological substrates for SIDS should be looked for in a wild field of neuropathology, which include the autonomic nervous system, central and peripheral, and the cardiac conduction system. The studies we have conducted on a large series of victims of SIDS, of unexpected neonatal and late fetal deaths, revealed analogous and frequent lesions of the autonomic structures that control the respiratory activity, as well as the cardiovascular, upper digestive and arousal functions. The research upheld a new approach to SIDS by analogical link with late fetal stillbirth which has a six-fold greater incidence than SIDS. The common denominator of all these deaths was the absence of neurological symptoms, generally associated with the presence of congenital anomalies and in some cases of acquired lesions. Particularly frequent is the hypoplasia and/or agenesis of the arcuate nucleus involved in the central chemoreceptors, observed with the incidence of about 50% both in stillbirth and in SIDS victims. In stillbirth this anomaly is frequently associated with hypoplasia of the reticular formation, lung hypoplasia and chronic hypoxia. Hypoplasia of the parabrachial Kölliker-Fuse complex was detected in about 50% of our term fetuses and neonates dying suddenly and unexpectedly. Congenital anomalies are detected also in other nuclei (solitary tract, hypoglossus, vagus nuclei) as well as astrogliosis and functional alterations of the neurotransmitters, such as catecholamines in the locus coeruleus. Regarding the cardiac conduction system, accessory atrio-ventricular pathways (mainly Mahaim fibers) were seen in 30% of SIDS cases. Under particular conditions and autonomic neuronal stimulation, these accessory pathways can trigger potentially lethal arrhythmias, generally due to junctional reentry. The chronic prenatal exposure to cigarette smoke was significantly associated with brainstem and cardiac conduction abnormalities, as well as early coronary lesions. The research was extended to the detection of DNA mutations and polymorphisms potentially involved in SIDS etio-pathogenesis. Analysis of SCN5A and MCAD genes allowed exclusion of LQTS and deficiency of fatty acids b-oxidation in our samples, while detection of the promoter long (L) allele of 5-HTT gene resulted more frequent in SIDS infants (75%) than in controls (30%).