Have you ever heard of MASA syndrome? How about CRASH syndrome? Both of these acronymic infantile disorders produce brain lesions similar to FAS - Fetal Alcohol Syndrome.

FAS pretty well spells out its meaning to women who flout the capital-letter label on bottles of booze in the U.S. To wit: GOVERNMENT WARNING: ACCORDING TO THE SURGEON GENERAL, WOMEN SHOULD NOT DRINK ALCOHOLIC BEVERAGES DURING PREGNANCY BECAUSE OF RISK OF BIRTH DEFECTS.

MASA stands for "Mental Retardation, Aphasia (impaired comprehension), Shuffling gait, Adducted thumbs." Now try CRASH syndrome: "Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus"

These two rap sheets add up to some of the salient birth defects hinted at by that label. As for FAS itself, the offspring of women who imbibe to excess during pregnancy might be born with mental retardation, microcephaly, irritability, growth deficiency and facial dysmorphisms.

FAS is estimated to occur in 0.3 to 2.2 births per 1,000 in the U.S, so it's by no means a rare disease. Maternal consumption of ethanol (alcohol) degrades the mental and physical endowments of at least three in every 1,000 infants born in the U.S. - about 12,000 each year. Elsewhere in the Western world, the toll is one in 300.

What sets FAS apart from that global disorder is that it is due to embryotoxicity from an exogenous toxin, namely, ethanol, and is therefore preventable - if not as yet curable. New research sheds light on the molecular mechanisms underlying Fetal Alcohol Syndrome, and might point toward eventual preventative treatment for FAS.

One leading investigator in the field is clinical neuroscientist Michael Charness. He is chief of staff at the Veterans Administration Boston HealthCare system, with affiliations to Harvard Medical School and Boston University. Charness is senior author of a paper in the Proceedings of the National Academy of Sciences, (PNAS) Early Edition, dated June 9-13, 2003. Its title: "Differential effects of ethanol antagonism and neuroprotection in peptide fragment NAPVSIPQ prevention of ethanol-induced developmental toxicity."

NAP, L1 Are Key Adjudicators Of FAS

"I think the overall finding of this article," opined Charness, "is that the peptide we studied, NAP, has at least two different mechanisms of action. One seems to protect embryos from alcohol toxicity by specific mechanisms - NAP's ability to be an ethanol antagonist and inhibitor of cell adhesion, mediated by the L1 adhesion molecule. The second is its ability to broadly protect neurons from many toxins.

"We demonstrate a structure-activity analysis of this NAP peptide's mechanism of action, which we developed in 1999, and showed it to be protective against a variety of neural insults, including beta amyloid (the toxin in Alzheimer's disease), excitotoxicity, stroke, brain injury and so on. But finding that it protects fetuses against alcohol could be that it's working only because alcohol, like many other toxins, activates a series of pathways that lead to cell death.

"So we found something different. We were able to discover derivatives of NAP that had no ability to protect neurons from a toxin. So we found derivatives that had no capacity, no effectiveness in preventing against the lethal puffer fish petrobotoxin on NAP's parent compound, but still was a very potent antagonist on ethanol's specific action against L1.

"We have been studying L1 for a decade," Charness related, "because we noticed that a particular neurological syndrome caused in kids who carry mutations in the gene for L1 produced brain lesions similar to those we see in children with FAS. This led us to ask whether the alcohol produces neurotoxicity in the developing embryo by interacting with L1, because the lesions are so similar. And we showed, by taking human genes to L1 and expressing them in cells that normally are not sticky, that the cell adhesion molecule is inhibited by low concentrations of ethanol and that the ethanol inhibitor can be reduced in derivatives of different alcohols. Then we were able to show that the same derivatives also retained their ability to protect embryos against the toxicity of ethanol. So this appears to demonstrate that ethanol is active on L1 as the target for NAP's protective effect in embryos.

"NAP," Charness told BioWorld Today, "is an active fragment of a peptide called activity-dependent neuroprotective protein.' It's an eight-amino-acid fragment of a much larger molecule. This larger parent compound, ADNP, is released by glial cells in the nervous system. It was the discovery of its protective role that led to the isolation of the active component, NAP. NAP is not released constitutively but was derived from a separate analysis to see what components of that activity could be retained in a small piece of the parent compound."

Ethanol Antagonist, Clue to Incurable FAS Cure?

"An extraordinary peptide in its potency," Charness went on, "NAP's breadth of activity led us to ask whether it was just a general neuroprotective agent that protected embryos against ethanol, or was it a specific ethanol antagonist. Our PNAS paper shows that it's the latter - also at very low concentrations that appear to endow its protective effects on embryos.

"Mutation in L1 brings about a neurological disorder that shares certain similarities with FAS - some of the brain lesions. And that is what connected our dots to L1 and FAS. FAS may occur in part because alcohol interferes with the function of L1, which is critical for normal development. Both L1 mutations and FAS are associated with mental retardation.

"We did three in vitro experiments," Charness recounted. "The first took NAP with its eight amino acids and replaced each aa, one at a time, with an alanine. That produced a series of seven different compounds, which we tested in three different assays. The first assay looked at their ability to block the effects of alcohol on L1. The second set of experiments tested the ability of those peptides to prevent toxicity in neurons. The third tested selective derivatives for their ability to prevent birth defects in embryos.

"In ongoing work, we would like to see ultimately if NAP or some other drug could be developed to possibly prevent FAS in humans. At present," he concluded, "this is at its nascent stage."