A research team led by Children’s National Hospital faculty was able to “rescue” a pre-clinical model of fetal alcohol spectrum disorder (FASD) in juvenile models, reversing motor skill deficits with the help of a novel drug derived from scorpion venom.
The finding, in the Nature Neuroscience, could offer hope to an estimated 119,000 children born with this condition worldwide each year.
FASD, caused by alcohol consumption during pregnancy, causes numerous learning disabilities, including cognitive and intellectual deficits.
Motor skills problems can be an early indicator for these other issues, explains study leader Kazue Hashimoto-Torii, Ph.D., a principal investigator at the Center for Neuroscience Research at the Children’s National Research Institute.
Many parents and caregivers first notice a problem when babies show delays in achieving motor developmental milestones. Although these effects are well documented, Hashimoto-Torii adds, it’s been unclear what molecular mechanisms cause these deficits.
Hashimoto-Torii has been studying these effects ever since her postdoctoral training when, pregnant herself; she became interested in the consequences of environmental exposures on development.
Over the past several years, she and colleagues have published a series of papers toward understanding FASD’s molecular mechanisms.
In the most current paper, her team worked with a pre-clinical model of FASD in which gestating fetuses were exposed to alcohol at embryonic days 16 and 17, a period in which brain cells grow predominantly in the upper cortex, a brain region that plays a key role in motor abilities.
This embryonic period corresponds to early mid-gestation in human fetuses.
When the researchers tested these pre-clinical models 30 days after birth–in two exams designed to assess both large– and small-muscle motor skills–they showed significant deficits in both areas.
Searching for the molecular differences that might underlie this diminished performance, the researchers found that prenatal alcohol exposure immediately activated a signaling pathway known as “heat shock,” which causes cells to produce protective proteins.
These heat shock proteins were produced randomly in some cells, rather than uniformly throughout the cell population.
Using a pre-clinical model that allowed them to track the descendants of these rapidly dividing neurons, the team found differences in the expression of 93 genes. One gene in particular, known as Kcnn2, which encodes a calcium-activated potassium channel, was over-expressed in the cells that produced heat shock proteins.
This gene already has been implicated as playing an important role in learning and memory. Cells in which Kcnn2 was over-expressed showed abnormal firing patterns.
When the researchers administered a drug that blocks this channel, known as Tamapin, derived from Indian red scorpion venom, the affected cells’ firing patterns reverted to normal. The image is credited to Dinesh Valke.
When the researchers administered a drug that blocks this channel, known as Tamapin, derived from Indian red scorpion venom, the affected cells’ firing patterns reverted to normal.
More importantly, pre-clinical models that received this drug at 30 days of life showed marked improvements in both large- and small-muscle motor skills. The fact that the pre-clinical models could still show improvements long after the initial damage suggests that treatment for children with FASD with a similar agent might also be effective, says Hashimoto-Torii. To that end, she and colleagues have launched a biotech company to further investigate this drug to see if it might hold promise in humans.
“Usually investigators looking for the molecular mechanisms behind disease stop there, but we want to move forward to have a real impact on public health,” she says. “We really want to give patients the hope of having a better life through treating the neurodevelopmental problems caused by FASD.”
Other Children’s National researchers who contributed to this study include Shahid Mohammad, Stephen J. Page, Li Wang, Seiji Ishii, Peijun Li, Toru Sasaki, Aiesha Basha, Zenaide Quezado, Joshua Corbin, and Masaaki Torii.
Funding: Funding for this study was provided by the Scott-Gentle Foundation
Fetal alcohol syndrome is one of a spectrum of disorders under the umbrella term of fetal alcohol spectrum disorder (FASD). There is a total of five disorders that comprise fetal alcohol spectrum disorders.
They are fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND), a neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE), and alcohol-related birth defects (ARBD).
All of these fetal alcohol spectrum disorders are used to classify the wide-ranging physical and neurological effects that prenatal alcohol exposure can inflict on a fetus.
All of the conditions that comprise fetal alcohol spectrum disorders stem from one common cause, which is prenatal exposure to alcohol. Alcohol is extremely teratogenic to a fetus. Its effects are wide-ranging and irreversible.
Although higher amounts of prenatal alcohol exposure have been linked to increased incidence and severity of fetal alcohol spectrum disorders, there are no studies that demonstrate a safe amount of alcohol that can be consumed during pregnancy.
There is also no safe time during pregnancy in which alcohol can be consumed without risk to the fetus. Alcohol is teratogenic during all three trimesters. In summary, any amount of alcohol consumed at any point during pregnancy has the potential cause of irreversible damage that can lead to a fetal alcohol spectrum disorder.
- Women more than age 30 with a long history of alcohol are more likely to give birth to an infant with fetal alcohol syndrome
- Poor nutrition
- Having one child with fetal alcohol syndrome increases the risk for subsequent children
- Women with genetic susceptibility may metabolize alcohol slowly may be at a higher risk
Prenatal alcohol exposure is the leading cause of preventable congenital disabilities. Because the presentation of fetal alcohol spectrum disorders can vary so widely, and because of recent changes to the diagnostic criteria that define these conditions, the exact prevalence is difficult to determine.
Across the United States, in the 1980s and 1990s, fetal alcohol syndrome was estimated to occur in the range of 0.5 to 2 cases per 1000 live births. However, it is widely accepted that these studies underreported the problem as the other conditions that comprise fetal alcohol spectrum disorders were not defined at the time and thus not recognized.
Using the more recent definitions of fetal alcohol spectrum disorders that take into account the wide range of effects that prenatal alcohol exposure can elicit, recent studies in the United States have shown that currently, fetal alcohol syndrome ranges from six to nine cases per 1000.
Fetal alcohol spectrum disorders range from 24 to 48 cases per 1000. The higher ends of these ranges are seen in high-risk populations such as those with low socioeconomic status and those of racial and ethnic minority populations.
American Indians have some of the highest rates overall. The prevalence of fetal alcohol syndrome has been reported to be as high as 1.5% among children in the foster care system.
In many cases, prenatal alcohol exposure is unintentional because women continue their normal drinking patterns before they know they are pregnant. Most women stop drinking alcohol once made aware of their pregnancy.
Despite this fact, 7.6% of women report continued drinking during pregnancy.
When evaluating a patient for fetal alcohol spectrum disorders, each of the five conditions that comprise fetal alcohol spectrum disorders has specific diagnostic criteria.
Fetal alcohol syndrome (FAS) is diagnosed by the presence of all of the following criteria: two of the three characteristic facial features (short palpebral fissures, thin vermillion border, and a smooth philtrum), growth retardation (prenatally and/or postnatally), and central nervous system defects.
Because all of these criteria are met for diagnosis, fetal alcohol syndrome does not require documentation of prenatal alcohol exposure.
Partial fetal alcohol syndrome (pFAS) has two of the characteristic facial features plus, depending on where alcohol exposure was documented, varies in its other criteria.
Alcohol-related birth defects (ARBD) is the term used to describe those with the physical defects secondary to known fetal alcohol exposure, but who do not have neurobehavioral deficits.
On the opposite end of the spectrum, alcohol-related neurodevelopmental disorder (ARND) describes those with neurobehavioral impairment in the setting of documented prenatal alcohol exposure but have minimal to no physical findings and cannot be diagnosed before three years of age. Neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE) is very similar to alcohol-related congenital disabilities but may involve some physical features.
Because of the wide-ranging presentation and large overlap with other genetic and environmental etiologies such as illicit drug and tobacco use, a primary care provider cannot make a definitive diagnosis of fetal alcohol spectrum disorders.
Once a primary care provider has a strong suspicion for fetal alcohol spectrum disorders, their patient should be referred to a team of specialists to rule out other possible conditions and make a definitive diagnosis.
The composition diagnostic team varies based on the age of the patient. In general, the diagnostic team includes a pediatrician and/or physician who may have expertise in fetal alcohol spectrum disorders, an occupational therapist, speech language pathologist, and psychologist.
Treatment / Management
Given that the CNS damage from prenatal alcohol exposure is permanent, there is no cure for fetal alcohol spectrum disorders. However, treatment to mitigate the effects of fetal alcohol spectrum disorders is available.
Given the extensive variation in presentation and damage that prenatal exposure to alcohol can cause, treatment for fetal alcohol spectrum disorders is often tailored and specific to individuals.
One of the most common treatment approaches is using the medical home to coordinate developmental and educational resources. This treatment modality takes into account the fact that fetal alcohol spectrum disorders disrupt normal neurobehavioral development and that each person can have different manifestations of those disruptions.
This treatment methodology seeks to tailor specific therapies to reinforce and address any delays or deficiencies with additional education, practice, and reminders. In summary, when it comes to fetal alcohol spectrum disorders, as is true of most conditions in medicine, the best treatment is prevention.
Children’s National Hospital