Causes of Phenotypic Variability and Disabilities after Prenatal Viral Infections

Abstract

Prenatal viral infection can lead to a spectrum of neurodevelopmental disabilities or fetal demise. These can include microencephaly, global developmental delay, intellectual disability, refractory epilepsy, deafness, retinal defects, and cortical-visual impairment. Each of these clinical conditions can occur on a semi-quantitative to continuous spectrum, from mild to severe disease, and often as a collective of phenotypes. Such serious outcomes result from viruses’ overlapping neuropathology and hosts’ common neuronal and gene regulatory response to infections. The etiology of variability in clinical outcomes is not yet clear, but it may be related to viral, host, vector, and/or environmental risk and protective factors that likely interact in multiple ways. In this perspective of the literature, we work toward understanding the causes of phenotypic variability after prenatal viral infections by highlighting key aspects of the viral lifecycle that can affect human disease, with special attention to the 2015 Zika pandemic. Therefore, this work offers important insights into how viral infections and environmental teratogens affect the prenatal brain, toward our ultimate goal of preventing neurodevelopmental disabilities.

New Insights into Zika in Infants and Children

“…These issues are applicable in a presented case report of discordant clinical outcomes in a monozygotic dichorionic-diamniotic twin pregnancy, with one twin having severe Zika-associated birth defects and the other twin having none [12]. It is likely that genetic and intrauterine environmental factors contribute to the differing phenotypes described in this case report [9].…”

“…The manuscripts describe patients from Brazil, Colombia, Honduras, Thailand, the United States (U.S.) Virgin Islands, and from the World Health Organization's (WHO) Zika Individual Participant Data Meta-Analysis (IPD-MA), which includes data from 28 countries and territories [5]. The themes presented in this Special Issue include adverse pregnancy outcomes, such as birth defects [6], infant and child neurodevelopment [6][7][8], indicators of risk for adverse neurodevelopment [8,9], postnatal Zika virus infection [7], head circumference measurement [10], ocular findings [11], importance of data sharing [5], surveillance systems [5,6,10,12], and a health brigade care model [11,13].…”

“…In a review article, Drs. Kousa and Hossain describe how prenatal viral infection can lead to a spectrum of adverse neurodevelopmental conditions or fetal demise and how phenotypic variability between cases may arise following prenatal viral infections [9]. Their manuscript lays the groundwork for applications of this knowledge to other infectious agents that may pose a threat to the developing brain.…”

Building a growing genomic data repository for maternal and fetal health through the PING Consortium

“…Interactions between individual and populational factors are likely. 7,10,11 Today, the contributions of host genetic modifiers are unknown. 12 However, the information is critically needed because it can inform our basic and mechanistic understanding of prenatal viral infections and aid in identifying patients at highest risk of having an affected infant(s).…”

“…8 During a Brazilian epidemic, prenatal Zika virus infection was found to be associated with severe brain injury leading to microcephaly, a condition defined by an infant’s head circumference measuring two/three standard deviations below the mean for gestational age, sex, and ethnicity. 10 Novel viral mutations increased virulence and transmissibility, which likely increased pathogenicity during the epidemic. 16 Prenatal Zika infection was later identified as the cause of congenital Zika syndrome, a clinical condition associated with severe microcephaly, a partially collapsed skull, and limb, ocular, and hearing abnormalities.…”