Human Brain Abnormalities Associated With Prenatal Alcohol Exposure and Fetal Alcohol Spectrum Disorder

Abstract

Fetal alcohol spectrum disorder (FASD) is a common neurodevelopmental problem, but neuropathologic descriptions are rare and focused on the extreme abnormalities. We conducted a retrospective survey (1980–2016) of autopsies on 174 individuals with prenatal alcohol exposure or an FASD diagnosis. Epidemiologic details and neuropathologic findings were categorized into 5 age groups. Alcohol exposure was difficult to quantify. When documented, almost all mothers smoked tobacco, many abused other substances, and prenatal care was poor or nonexistent. Placental abnormalities were common (68%) in fetal cases. We identified micrencephaly (brain weight <5th percentile) in 31, neural tube defects in 5, isolated hydrocephalus in 6, corpus callosum defects in 6 (including some with complex anomalies), probable prenatal ischemic lesions in 5 (excluding complications of prematurity), minor subarachnoid heterotopias in 4, holoprosencephaly in 1, lissencephaly in 1, and cardiac anomalies in 26 cases. The brain abnormalities associated with prenatal alcohol exposure are varied; cause–effect relationships cannot be determined. FASD is likely not a monotoxic disorder. The animal experimental literature, which emphasizes controlled exposure to ethanol alone, is therefore inadequate. Prevention must be the main societal goal, however, a clear understanding of the neuropathology is necessary for provision of care to individuals already affected.

Global DNA Methylation and Histone Posttranslational Modifications in Human and Nonhuman Primate Brain in Association with Prenatal Alcohol Exposure

“…Ethics approval was obtained from the University of Manitoba Research Ethics Board (#HS1311 – H2011:213). Details of the full PNAE/FASD autopsy cohort ( N = 174) were described previously (Jarmasz et al., ). Because our hypothesis concerns epigenetic changes associated with PNAE, and because epigenetic changes can occur during postnatal life (Kundakovic and Champagne, ), we restricted our study to fetuses and infants <1 year.…”

“…Because our hypothesis concerns epigenetic changes associated with PNAE, and because epigenetic changes can occur during postnatal life (Kundakovic and Champagne, ), we restricted our study to fetuses and infants <1 year. Exclusion criteria were as follows: documented in utero alcohol consumption by the mother in the clinical history of the autopsy report (see Jarmasz et al., ; for more details), no availability of formalin‐fixed paraffin‐embedded (FFPE) brain sample(s), extensive autolysis of brain tissue, severe hypoxic damage, cases dated <1988 (inconsistent FFPE), known gene mutations or chromosomal abnormalities, major brain malformations, bacterial meningitis, and a postmortem delay (PMD) > 48 hours. In our recent study, a PMD of >48 to 72 hours in pig and mouse brain tissue had adverse effects on histone acetylation marks (Jarmasz et al., ).…”

“…In individuals diagnosed with FASD, neuroimaging studies (MRI) have demonstrated a wide range of brain abnormalities including micrencephaly, abnormal gyral patterns, corpus callosum abnormalities, cortical thinning, and reductions in regional brain volume (e.g., basal ganglia, diencephalon, and cerebellum; Donald et al., ; Jacobson et al., ; Moore et al., ; Nardelli et al., ; Norman et al., ). In our recent descriptive study of 174 human autopsy cases (fetuses, infants, children, teens, and adults) with PNAE or FASD, we identified 31 cases with micrencephaly, 6 cases with simple hydrocephalus, 6 with corpus callosum defects, 5 with neural tube defects, 5 with prenatal ischemic lesions, and 4 cases with heterotopias (Jarmasz et al., ).…”

“…To the best of our knowledge, PNAE‐associated epigenetic changes have not been directly assessed in human brain tissue. In this study, temporal lobe and hippocampus samples from 18 prenatal alcohol‐exposed fetuses and infants who had undergone autopsy (Jarmasz et al., ) were compared to age‐matched controls using immunohistochemical detection of 4 DNA cytosine modifications, 4 histone methylation modifications, and 6 histone acetylation modifications. In parallel, we studied the temporal lobes from macaque monkey infants that had been exposed in utero to alcohol (Clarren et al., , ).…”

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

“…Besides the craniofacial malformations exhibited by individuals with FAS, primary microcephaly can be frequently observed (Del Campo & Jones, ; Prapti Gautam et al, ; Jarmasz, Basalah, Chudley, & Del Bigio, ; Roussotte et al, ; Treit et al, ). In many instances, the microcephaly is accompanied by mental disability, reduced executive function, behavioral problems, and social difficulties sometimes involving social withdrawal (Gautam, Nuñez, Narr, Kan, & Sowell, ; Niccols, ; Roussotte et al, ; Spohr & Steinhausen, ).…”