Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS): Kindred disorders of autonomic regulation

Northwestern University Feinberg School of Medicine, Center for Autonomic Medicine in Pediatrics, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614, USA.
Respiratory Physiology & Neurobiology (Impact Factor: 1.97). 06/2008; 164(1-2):38-48. DOI: 10.1016/j.resp.2008.05.011
Source: PubMed


Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS) were long considered rare disorders of respiratory control and more recently have been highlighted as part of a growing spectrum of disorders within the rubric of autonomic nervous system (ANS) dysregulation (ANSD). CCHS typically presents in the newborn period with a phenotype including alveolar hypoventilation, symptoms of ANSD and, in a subset of cases, Hirschsprung disease and later tumors of neural crest origin. Study of genes related to autonomic dysregulation and the embryologic origin of the neural crest led to the discovery of PHOX2B as the disease-defining gene for CCHS. Like CCHS, SIDS is thought to result from central deficits in control of breathing and ANSD, although SIDS risk is most likely defined by complex multifactorial genetic and environmental interactions. Some early genetic and neuropathological evidence is emerging to implicate serotonin systems in SIDS risk. The purpose of this article is to review the current understanding of the genetic basis for CCHS and SIDS, and discuss the impact of this information on clinical practice and future research directions.

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    • "Two potential uniting principles in functional disease are the autonomic nervous system and energy metabolism. Aberrant autonomic function (dysautonomia) has been documented in migraine (Daas et al., 2009), IBS (Pellissier et al., 2010), CFS (Hoad et al., 2008), CVS (Chelimsky and Chelimsky, 2007), CRPS (Riedl et al., 2001), and SIDS (Weese-Mayer et al., 2008), thus an effect on autonomic pathways is a plausible mechanism of action of a common genetic factor. Aberrant energy metabolism (mitochondrial dysfunction) has been demonstrated in migraine (Sparaco et al., 2006), CRPS (Higashimoto et al., 2008), CFS (Myhill et al., 2009), CVS (Boles and Williams, 1999), and SIDS (Läer et al., 2014). "
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    ABSTRACT: About 20% of the population suffers from "functional syndromes". Since these syndromes overlap greatly in terms of co-morbidity, pathophysiology (including aberrant autonomic activity) and treatment responses, common predisposing genetic factors have been postulated. We had previously showed that two common mitochondrial DNA (mtDNA) polymorphisms at positions 16519 and 3010 are statistically associated with the functional syndromes of migraine, cyclic vomiting syndrome and non-specific abdominal pain. Herein, among individuals with mtDNA haplogroup H (HgH), the presence of these two mtDNA polymorphisms were ascertained in additional functional syndromes: chronic fatigue syndrome, complex regional pain syndrome, sudden infant death syndrome, and major depressive disorder. Polymorphic prevalence rates were compared between disease and control groups, and within each disease group in participants with and without specific clinical findings. In all four conditions, one or both of the polymorphisms was significantly associated with the respective condition and/or co-morbid functional symptomatology. Thus, we conclude that these two mtDNA polymorphisms likely modify risk for the development of multiple functional syndromes, likely constituting a proportion of the postulated common genetic factor, at least among individuals with HgH. Pathophysiology likely involves broad effects on the autonomic nervous system. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Apr 2015 · Mitochondrion
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    • "Fresh specimens were firstly collected from the brainstem, near the obex, and conserved in ethanol or in RNA-later reagent (AMBION, Inc; Austin, TX) for genetic studies of the serotonin transporter polymorphism that has been widely associated to SIDS [9], and of the PHOX2B gene, whose mutation causes a large decrease in the central chemoreflex responsible for the Congenital Central Hypoventilation Syndrome (CCHS) [10]. After fixation in 10% phosphate-buffered formalin, the brainstem, the spinal cord and cerebellum were processed and paraffin-embedded. "
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    ABSTRACT: To contribute to a more balanced assessment of the morphological substrates underlying unexplained perinatal death and SIDS. In-depth histological, immunohistochemical and genetic examinations were performed on the autonomic nervous and cardiac conduction systems in 95 unexpected perinatal deaths, 140 SIDS and 78 controls (44 infants and 34 perinatal death victims). The study revealed the localization and the nature of a variety of specific congenital abnormalities of the autonomic nervous system, central and peripheral, and of the cardiac conduction system that represent the morphological substrates of the pathophysiological mechanism of sudden fetal death and SIDS. The observation of similar anomalies of the autonomic nervous and the cardiac conduction systems in both unexplained perinatal deaths and SIDS indicates their common congenital nature. Therefore, the definitions of these deaths, currently nosographically distinct, should be unified.
    Full-text · Article · Mar 2011 · Early human development
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    • "This frequency was preserved among both Caucasian and African-American subgroups [34]. Kijima et al. also examined the PHOX2B gene in 23 Japanese SIDS cases for mutations associated with the congenital central hypoventilation syndrome, also similarly characterized by autonomic dysfunction [35,36]. They reported three variants not reported by Rand et al. but did not clarify if these were found in cases or controls, nor did they report the frequency of the polymorphisms reported by Rand et al. [35]. "
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    ABSTRACT: Sudden infant death syndrome (SIDS) is a major contributor to postneonatal infant death, and is the third leading cause of infant mortality in the USA. While public health efforts have reduced these deaths in recent years, the pathogenesis of SIDS remains unclear. Epidemiological data on SIDS-related deaths have suggested genetic factors, and many studies have attempted to identify SIDS-associated genes. This has resulted in a large body of literature implicating various genes and their encoded proteins and signaling pathways in numerous cohorts of various sizes and ethnicities. This review has undertaken a systematic evaluation of these studies, identifying the pathways that have been implicated in these studies, including central nervous system pathways, cardiac channelopathies, immune dysfunction, metabolism/energy pathways, and nicotine response. This review also explores how new genomic techniques will aid in advancing our knowledge of the genomic risk factors associated with SIDS, including SNPs and copy number variation. Last, this review explores how the current information can be applied to aid in our assessment of the at risk infant population.
    Full-text · Article · Nov 2010 · Genome Medicine
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