Alcohol, Timing, and One Molecule Contribute to Fetal Alcohol Syndrome

The path from a cell adhesion molecule in the brain to a cell phone in the hand may serve as a link between drinking alcohol during pregnancy and the technology to diagnose the development of fetal alcohol spectrum disorder (FASD) among offspring, says Michael Charness, M.D.

Charness presented the annual Mark Keller Honorary Lecture sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) last month in Bethesda, Md.

The link is the L1 neural cell adhesion molecule, said Charness, a professor of neurology and associate dean at Harvard Medical School and Boston University School of Medicine and chief of staff at the VA Boston Healthcare System.

“FASD is an umbrella term for a spectrum of disorders and is defined by a constellation of signs—facial dysmorphology, height, weight, head circumference, among others—only some of which are behavioral,” said Charness in an interview. In his work, he and his colleagues use the 1996 Institute of Medicine’s diagnostic guidelines, as modified and updated in the August issue of Pediatrics.

DSM-5 does not include fetal alcohol spectrum disorder as a diagnosis. The chapter “Conditions for Further Study” includes a “neurobehavioral disorder associated with prenatal alcohol exposure.” That description refers mainly to behavioral impairments but does not refer to physical abnormalities like facial dysmorphology.

L1 is involved with neural migration, neurite extension, axon fasciculation, growth cone motility and pathfinding, neuronal survival during development, as well as learning and memory in adults, said Charness. Most critically, L1 shepherds new nerve cells to their appropriate places within the brain.

L1 appears in the embryo as early as gastrulation, and there is a surge of expression when neurons undergo differentiation and synaptogenesis.

When mutated, the L1 gene can cause intellectual disability, hypoplasia of the corpus callosum, hydrocephalus, and cerebellar dysplasia. More than two decades ago, Charness and others noted the resemblance of brain abnormalities produced by those L1 gene mutations to fetal alcohol syndrome (FAS), suggesting that alcohol might cause FASD partly by disrupting L1.

Ethanol inhibits cell adhesion mediated by L1, and as little as one drink ingested by a woman at a sensitive moment during pregnancy may be sufficient to affect development, he said.

The critical periods for its effects arrive early. The face is developing rapidly on day 17 after conception, and exposure to alcohol during that narrow window may lead to the facial dysmorphology that characterizes full fetal alcohol syndrome.

At those critical times during gestation, ethanol can disrupt L1-mediated cell adhesion and cause teratogenesis or cell death in the embryo. Methanol, ethanol, propanol, and butanol are agonists and reduce adhesion, but longer molecular forms of alcohol act as antagonists and block the effects of ethanol.

Alcohol’s effects vary with timing and degree of exposure and can produce degrees of FASD, ranging from severe to mild. That diversity is reflected in the updated clinical guidelines published in Pediatrics, which also cover partial fetal alcohol syndrome, alcohol-related neurodevelopmental disorder, and alcohol-related birth defects.

In his talk, Charness also moved from the molecular to the global. Population-based studies in the United States have found rates of six to nine per 1,000 live births for FAS, and 2.4 to 4.8 percent of first graders diagnosable with FASD. Results of a forthcoming NIAAA study on the prevalence of FASD will likely be “stunning,” he predicted.

The incidence of FASD is likely to increase as the incidence of heavy episodic drinking expands around the world, now that modernization has produced cultural changes leading to increased drinking by women, he said.

The challenge to prevention and treatment is as much administrative as biological, said Charness. Treatment still is limited by a lack of facilities and specialists, as well as stigma that inhibits treatment seeking.

“Already there is a huge discrepancy in the options to diagnose and treat FASD because of geography, ability to pay, and numbers of therapists compared with the number of affected individuals.”

However, mobile technology may serve as a potential tool to improve access to diagnosis and treatment while at the same time reducing stigma and barriers to care, he said. “The technology takes advantage of the fact that the face is accessible, and the face is a window on the brain.”

Studies of three-dimensional images of thousands of faces of exposed and control subjects have resulted in algorithms that can detect symptoms of FASD and differentiate cases, said Charness. “Potentially, someone could transmit a cell-phone photo to a website that could automatically analyze the image to see if the subject had damage caused by exposure to alcohol in utero.”

Prospects for use in humans are a long way off, but Charness and his colleagues also are exploring agents that might block alcohol’s effects on L1 in rodent models. Two neuropeptides, NAP and SAL, appear to do just that, he said. NAP antagonizes the actions of ethanol without altering L1 expression. They also have reported that mitogen-activated protein kinase can modulate ethanol inhibition of cell adhesion by L1. Dephosphorylation at four sites on the L1 molecule renders it insensitive to alcohol, he said.

Of course, the best way to stop FASD is by avoiding alcohol during pregnancy, said Charness. “Alcohol is toxic to the nervous system throughout gestation.” ■

“Two Alcohol Binding Residues Interact Across a Domain Interface of the L1 Neural Cell Adhesion Molecule and Regulate Cell Adhesion” can be accessed here. An abstract of “Updated Clinical Guidelines for Diagnosing Fetal Alcohol Spectrum Disorders” is available here. “NIAAA Proposes Updated Guidelines for Fetal Alcohol Spectrum Disorders” is located here.