Editorial: Updates on the Neuropathology of Sudden Unexplained Perinatal Death and Other Neurodevelopmental Disorders

Perinatal mortality includes both fetal demises (stillbirths) and deaths in the first week of life. Worldwide, there are over 6.3 million perinatal deaths a year, almost all of which occur in developing countries (1). Stillbirths and neonatal deaths have many common determinants, such as maternal diseases, adverse prenatal exposure, inadequate care or complications during pregnancy and delivery, and genetic mutations. The first few hours of postnatal life are also particularly sensitive, as this is a critical time for a successful transition from intrauterine to extrauterine life wherein newborns are less responsive and more vulnerable to stressors. In case of sudden perinatal death, an important first step is the post-mortem examination since it can reveal the pathology underlying the possible causes of this inauspicious event (2). However, no unique etiology can be determined in most preand post-natal deaths, even after accurate autopsy investigations. Detailed examination of the autonomic nervous system can often reveal subtle developmental alterations, potentially providing a plausible explanation for sudden death (3, 4). Other neurodevelopmental disorders characterized by profound dysautonomia caused by single gene mutations may also lead to sudden unexplained death in perinatal life and infancy. Some of these syndromes are also thought to involve a state of “immaturity” of autonomic control systems. They include Rett syndrome, Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder, Pitt-Hopkins syndrome, Congenital central hypoventilation syndrome (CCHS), and GRIN1-Related Neurodevelopmental Disorder (5–9). The primary rationale for this Research Topic has been to advance the state of knowledge and expertise for investigating the neuropathology of unexplained perinatal deaths and, in particular:

Perinatal mortality includes both fetal demises (stillbirths) and deaths in the first week of life. Worldwide, there are over 6.3 million perinatal deaths a year, almost all of which occur in developing countries (1). Stillbirths and neonatal deaths have many common determinants, such as maternal diseases, adverse prenatal exposure, inadequate care or complications during pregnancy and delivery, and genetic mutations. The first few hours of postnatal life are also particularly sensitive, as this is a critical time for a successful transition from intrauterine to extrauterine life wherein newborns are less responsive and more vulnerable to stressors. In case of sudden perinatal death, an important first step is the post-mortem examination since it can reveal the pathology underlying the possible causes of this inauspicious event (2). However, no unique etiology can be determined in most pre-and post-natal deaths, even after accurate autopsy investigations. Detailed examination of the autonomic nervous system can often reveal subtle developmental alterations, potentially providing a plausible explanation for sudden death (3,4). Other neurodevelopmental disorders characterized by profound dysautonomia caused by single gene mutations may also lead to sudden unexplained death in perinatal life and infancy. Some of these syndromes are also thought to involve a state of "immaturity" of autonomic control systems. They include Rett syndrome, Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder, Pitt-Hopkins syndrome, Congenital central hypoventilation syndrome (CCHS), and GRIN1-Related Neurodevelopmental Disorder (5)(6)(7)(8)(9).
The primary rationale for this Research Topic has been to advance the state of knowledge and expertise for investigating the neuropathology of unexplained perinatal deaths and, in particular: • contribute to the identification of the pathogenic mechanisms underlying these deaths (especially if known gene mutations are absent), in the context of interactions with environmental risk factors (e.g., early exposure to smoking, air and water pollution, pesticides, food contamination) and neuropathological findings. • facilitate the development of evidence-based prevention and management strategies to decrease the incidence of these inexplicable and devastating deaths.
Another aim of this proposal was to deepen knowledge regarding developmental brain dysfunctions that can manifest later in life as neuropsychiatric symptoms, impaired motor function, learning, language, or non-verbal communication behaviors such as crying, or autism spectrum disorders (10)(11)(12). A related goal was to inform literature on the role of early life experiences, often associated with pre-or peri-natal environment exposures, in shaping the developing brain and vulnerability for the later neurodevelopmental outcome. This Research Topic presents a series of articles and reviews written by leading authors and covering most aspects of state-ofthe-art research on the neuropathology of fetal and infant sudden death and other neurodevelopmental disorders.
The These authors point out that the underlying death mechanism reported in many studies is highly controversial. Using machine learning tools, they emphasize the existence of three distinct groups of SIDS, each with a unique peak age of death, and specific epidemiological and extrinsic risk factors. of the PHOX2B gene with these two pathologies, suggesting that CCHS, ALTE, and SUID/SIDS might be members of the same group of respiratory autonomic disorders of infancy. • Ke and Chen report a rare case of a heterozygous nonsense mutation in the CTNNB1 gene in a 15month-old girl with a complex phenotype (dysmorphic features, microcephaly, hypotonia, development delay, retinal detachment, and polydactyly) associated with a neurodevelopmental disorder with spastic diplegia and visual defects. tobacco and alcohol consumption during pregnancy on autonomic function in a wide population of fetuses at ≥34 weeks gestational age, by quantifying heart rate, heart rate variability, movement, and heart rate-movement coupling. The results of this study contribute to identifying new biomarkers and understanding the mechanisms underlying risk for adverse outcomes. • The serious consequences of cigarette smoke and alcohol absorption in pregnancy are also the focus of the contribution by Vivekanandarajah et al. Through a multicenter longitudinal study and by using autoradiographic methods to highlight the nicotinic receptor binding in the brainstems of infants dying of SIDS, the authors provide evidence that developmental factors paired with changes in nicotinic receptor binding are related to the cause of death as well as exposure to maternal cigarette smoking.

2) Neuropathology of Other Neurodevelopmental Disorders
• Rett syndrome is caused by the loss of function of the transcription factor methyl CpG-binding protein 2 (MeCP2) (13 Together, these publications expand current knowledge on the neuropathology of sudden unexplained perinatal/infant death and other neurodevelopmental disorders, such as the Rett syndrome and CCHS, thus allowing the broadening of the diagnostic criteria and preventive strategies. As editors of this Research Topic, we express our sincere gratitude to the authors who accepted the invitation to participate and for their significant efforts in identifying interesting approaches that explain the pathogenesis of these conditions. We would also like to thank the reviewers for their significant comments, elevating the quality of the submitted articles. Finally, we thank Frontiers and, in particular, the editorial office for essential support.

AUTHOR CONTRIBUTIONS
AL, AA, and WF: the editors of this Research Topic, together wrote the editorial that summarizes the contents of all the 13 published articles. All authors contributed to the article and approved the submitted version.

FUNDING
AA was funded by the International Rett Syndrome Foundation (#3803).