Profound Autism: An Imperative Diagnosis.

Profound autism refers to a subset of individuals with autism spectrum disorder who have an intellectual disability with an intelligence quotient less than 50 and minimal-to-no language and require 24-hour supervision and assistance with activities of daily living. The general pediatrician will invariably work with autistic children across the spectrum and will likely encounter youth with profound autism. Awareness of profound autism as a real entity describing autistic children with concomitant intellectual disability and language impairment who require 24-hour care is the first step in developing a solid pediatric home for these youth.

A full semantic toolbox is essential for autism research and practice to thrive.

Individuals diagnosed with autism spectrum disorder (ASD) present with a highly diverse set of challenges, disabilities, impairments and strengths. Recently, it has been suggested that researchers and practitioners avoid using certain words to describe the difficulties and impairments experienced by individuals with ASD to reduce stigma. The proposed limitations on terminology were developed by only a subset of the autism community, and the recommendations are already causing negative consequences that may be harmful to future scientific and clinical endeavors and, ultimately, to people with ASD. No one should have the power to censor language to exclude the observable realities of autism. Scientists and clinicians must be able to use any scientifically accurate terms necessary to describe the wide range of autistic people they study and support, without fear of censure or retribution.

Beyond Genes: Germline Disruption in the Etiology of Autism Spectrum Disorders.

Investigations into the etiology of autism spectrum disorders have been largely confined to two realms: variations in DNA sequence and somatic developmental exposures. Here we suggest a third route-disruption of the germline epigenome induced by exogenous toxicants during a parent's gamete development. Similar to cases of germline mutation, these molecular perturbations may produce dysregulated transcription of brain-related genes during fetal and early development, resulting in abnormal neurobehavioral phenotypes in offspring. Many types of exposures may have these impacts, and here we discuss examples of anesthetic gases, tobacco components, synthetic steroids, and valproic acid. Alterations in parental germline could help explain some unsolved phenomena of autism, including increased prevalence, missing heritability, skewed sex ratio, and heterogeneity of neurobiology and behavior.

How family histories can inform research about germ cell exposures: the example of autism.

Throughout the scientific literature, heritable traits are routinely presumed to be genetic in origin. However, as emerging evidence from the realms of genetic toxicology and epigenomics demonstrate, heritability may be better understood as encompassing not only DNA sequence passed down through generations, but also disruptions to the parental germ cells causing de novo mutations or epigenetic alterations, with subsequent shifts in gene expression and functions in offspring. The Beyond Genes conference highlighted advances in understanding these aspects at molecular, experimental, and epidemiological levels. In this commentary I suggest that future research on this topic could be inspired by collecting parents' germ cell exposure histories, with particular attention to cases of families with multiple children suffering idiopathic disorders. In so doing I focus on the endpoint of autism spectrum disorders (ASDs). Rates of this serious neurodevelopment disability have climbed around the world, a growing crisis that cannot be explained by diagnostic shifts. ASD's strong heritability has prompted a research program largely focused on DNA sequencing to locate rare and common variants, but decades of this gene-focused research have revealed surprisingly little about the molecular origins of the disorder. Based on my experience as the mother of two children with idiopathic autism, and as a research philanthropist and autism advocate, I suggest ways researchers might probe parental germ cell exposure histories to develop new hypotheses that may ultimately reveal sources of nongenetic heritability in a subset of idiopathic heritable pathologies.

Heritable hazards of smoking: Applying the "clean sheet" framework to further science and policy.

All the cells in our bodies are derived from the germ cells of our parents, just as our own germ cells become the bodies of our children. The integrity of the genetic information inherited from these germ cells is of paramount importance in establishing the health of each generation and perpetuating our species into the future. There is a large and growing body of evidence strongly suggesting the existence of substances that may threaten this integrity by acting as human germ cell mutagens. However, there generally are no absolute regulatory requirements to test agents for germ cell effects. In addition, the current regulatory testing paradigms do not evaluate the impacts of epigenetically mediated intergenerational effects, and there is no regulatory framework to apply new and emerging tests in regulatory decision making. At the 50th annual meeting of the Environmental Mutagenesis and Genomics Society held in Washington, DC, in September 2019, a workshop took place that examined the heritable effects of hazardous exposures to germ cells, using tobacco smoke as the example hazard. This synopsis provides a summary of areas of concern regarding heritable hazards from tobacco smoke exposures identified at the workshop and the value of the Clean Sheet framework in organizing information to address knowledge and testing gaps.

General anesthesia, germ cells and the missing heritability of autism: an urgent need for research.

Agents of general anesthesia (GA) are commonly employed in surgical, dental and diagnostic procedures to effectuate global suppression of the nervous system, but in addition to somatic targets, the subject's germ cells-from the embryonic primordial stage to the mature gametes-may likewise be exposed. Although GA is generally considered safe for most patients, evidence has accumulated that various compounds, in particular the synthetic volatile anesthetic gases (SVAGs) such as sevoflurane, can exert neurotoxic, genotoxic and epigenotoxic effects, with adverse consequences for cellular and genomic function in both somatic and germline cells. The purpose of this paper is to review the evidence demonstrating that GA, and in particular, SVAGs, may in some circumstances adversely impact the molecular program of germ cells, resulting in brain and behavioral pathology in the progeny born of the exposed cells. Further, we exhort the medical and scientific communities to undertake comprehensive experimental and epidemiological research programs to address this critical gap in risk assessment.

Pregnancy drugs, fetal germline epigenome, and risks for next-generation pathology: A call to action.

Drugs taken during pregnancy can affect three generations at once: the gestating woman (F0), her exposed fetus (F1), and the fetal germ cells that confer heritable information for the grandchildren (F2). Unfortunately, despite growing evidence for connections between F0 drug exposures and F2 pathology, current approaches to risk assessment overlook this important dimension of risk. In this commentary, we argue that the unique molecular vulnerabilities of the fetal germline, particularly with regard to global epigenomic reprogramming, combined with empirical evidence for F2 effects of F1 in utero drug and other exposures, should change the way we consider potential long-term consequences of pregnancy drugs and alter toxicology's standard somatic paradigm. Specifically, we (1) suggest that pregnancy drugs common in the postwar decades should be investigated as potential contributors to the "missing heritability" of many pathologies now surging in prevalence; (2) call for inclusion of fetal germline risks in pregnancy drug safety assessment; and (3) highlight the need for intensified research to ascertain generational impacts of diethylstilbestrol, a vanguard question of human germline toxicity. Only by fully addressing this important dimension of transplacental exposure can we responsibly evaluate safety of drug exposures during pregnancy and convey the full scope of risks, while also retrospectively comprehending the generational legacy of recent history's unprecedented glut of evolutionarily novel intrauterine exposures. Environ. Mol. Mutagen. 60:445-454, 2019. © 2019 Wiley Periodicals, Inc.

Bugs in the program: can pregnancy drugs and smoking disturb molecular reprogramming of the fetal germline, increasing heritable risk for autism and neurodevelopmental disorders?

In a seeming paradox, the prevalence of autism spectrum disorder (ASD) has surged, while at the same time research has pointed to the strong heritability of this neurodevelopmental pathology. Here an autism research philanthropist suggests a biological phenomenon of exogenously induced 'gamete disruption' that could reconcile these seemingly contradictory observations. Mining information from her own family history and that of her fellow autism parents, while also engaging with the scientific community, she proposes that a subset of the autisms may be rooted in a variety of molecular glitches in parental gametes induced by certain acute exposures during the parents' own fetal or neonatal development. These exposures include but are not limited to synthetic hormone drugs, tobacco, and general anesthesia. Consistent with this hypothesis, animal models have demonstrated adverse neurobehavioral outcomes in grandoffspring of gestating dams exposed to hormone-disrupting compounds, tobacco components, and general anesthesia. A recent epidemiological study showed a link between grandmaternal smoking and risk for ASD in grandoffspring through the maternal line. Given the urgency of the autism crisis, combined with the biological plausibility of this mostly unexplored paradigm, the writer contends that questions of nongenetic inheritance should be a priority in autism research.