A Step Closer to Resolving Birth Defects

Scientists have made a landmark discovery that could help women minimize or even avoid the risk of having a baby born with congenital birth defects. The study is published April 5 in the international journal Cell.

The scientists, from universities in Australia, Japan, Canada and the United States, including Arizona State University, show for the first time how “nature” and “nurture” interact to increase the severity and likelihood of developing birth defects, including abnormalities in the heart, kidneys, brain, limbs and cranio‐facial regions (cleft palate).

They show how hypoxia, or a period of low oxygen during pregnancy, combined with a genetic risk factor of having only one functioning copy of a gene, dramatically increases the chances of a baby being born with congenital scoliosis, a malformation of the spine that affects around 1 in 1,000.

Sally Dunwoodie, head of the Embryology Laboratory at the Victor Chang Cardiac Research Institute in Sydney, Australia, a professor at the University of New South Wales and the senior author on the study, says the findings take us a step closer to understanding why some people in families develop diseases and others don’t, and, importantly, simple strategies that mothers could adopt to help prevent such defects occurring.

“We’ve long suspected that it is genes or our environment that cause birth defects, but up until now, the majority of these have been largely unknown,” says Dunwoodie. “This is the first time anyone in the world has shown that both ‘nature’ and ‘nurture’, in combination, are molecularly responsible for causing many birth defects.”

“This research is hugely exciting and will help us to genetically diagnose a whole range of birth defects, and give advice to women on how and when to avoid certain activities when pregnant,” says Dunwoodie. “We hope it will eventually lead to the development of therapeutics to stop these defects occurring in the first place.”

Hypoxia during pregnancy can be caused by a range of circumstances including poorly controlled sugar levels in diabetics, smoking, high altitude, prescription and recreational drug‐use, anemia or a poorly functioning placenta.

“Just as genetic studies of selected families led to the discovery of genes causing breast cancer, this study of the genetics and development of congenital scoliosis will lead to breakthroughs in finding the factors that cause scoliosis, a disorder affecting up to 3 percent of the general population,” says co-author Kenro Kusumi, an associate professor in the School of Life Sciences in ASU’s College of Liberal Arts and Sciences.

One of the largest genetic studies focused on congenital scoliosis was led by Kusumi’s group. Together with clinical collaborators in Philadelphia and Toronto, the group identified the first case of a patient with congenital scoliosis due to having a single defective copy of the HES7 gene. Previous studies in mice had established that disruptions in this gene could lead to spinal defects, and loss of both copies of this gene had been found in severe cases of spinal deformities. The type of defect found in the patient in the ASU study was shown by Dunwoodie’s group to clearly affect the ability of the protein to function normally. This finding meant that having just one, instead of two functioning copies of a known gene from either mother or father, was a major risk factor for causing the abnormal formation of vertebrae in embryonic development.

Dunwoodie’s group then went on to test the genetic risk factor in a mouse model combined with an environmental insult in the form of hypoxia. Surprisingly, they found a marked increase in spinal abnormalities in the offspring, when the mothers were exposed to only 8 hours of low oxygen during an entire 21‐day pregnancy.

“We found that the combination of the genetic risk as well as exposure to low oxygen, resulted in our subjects being up to 10 times more likely to develop congenital scoliosis, than those that only had the genetic risk factor,” says Dunwoodie.

“What this brief period of low oxygen essentially did was disrupt the pathway responsible for development of the spine, and we know that the same pathway is used in the development of limbs and many organs, including the heart, kidneys, brain and cranio‐facial region,” adds Dunwoodie.

Bob Graham, a professor and executive director of the cardiac research institute, says around 25 percent of patients with congenital scoliosis also have some form of congenital heart defect, indicating that a single environmental ‘insult’ such as hypoxia, can potentially affect the development of more than one organ in the body.

“This study provides a new paradigm for the interaction between our genes and environment, and may account for a lot of diseases that we haven’t understood before, such as many different forms of congenital heart disease, and conditions like hair‐lip or cleft palate,” says Graham.

Kusumi points to a recent genetic study of over 50,000 identical twins that emphasizes that the risk of developing disease arises from the environment acting together with a person’s unique genome. “For scoliosis, our study highlights how environmental conditions, such as lack of oxygen reaching the developing embryo, could interact uniquely with each individual’s genetic differences to increase the risk of birth defects,” said Kenro.

“It may not necessarily be a lack of oxygen that allows the underlying gene defect to be revealed, it could be a lot of other environmental factors, such as anemia or lack of folate. But the message is, if you have family history of disease or you know you have a defective gene, mums need to be extra careful during pregnancy,” adds Graham.

The team of researchers has begun working on similar studies in congenital heart defects, which affect around 1 in every 100 babies born world-wide every year.

Autism: Defective Genes May Explain Uncontrolled Brain Growth

As a baby grows inside the womb, its brain does not simply expand like a dehydrated sponge dropped in water.

Early brain development is an elaborate procession. Every minute some 250,000 neurons bloom, squirming past one another like so many schoolchildren rushing to their seats at the sound of the bell.

Each neuron grows a long root at one end and a crown of branches at the other, linking itself to fellow cells near and far.

By the end of the second trimester, neurons in the baby's brain have formed trillions of connections, many of which will not survive into adulthood—the least traveled paths will eventually wither.

Sometimes, the developing brain blunders, resulting in "neuro-developmental disorders," such as autism.

But exactly why or how early cellular mistakes cause autism has eluded medical science. Now, Eric Courchesne of the University of California, San Diego, thinks he has linked atypical gene activity to excessive growth in the autistic brain.

With the new data, he has started to trace a cascade of genetic and cellular changes that he thinks define autism.

Although intrigued by Courchesne's work, other researchers caution that explosive neural growth is not necessarily a defining feature of all autistic brains.

Since 1998 Courchesne has been searching autistic brains for unusual structural features.

His studies suggest that while in the womb, the autistic brain sprouts an excess of neurons and continues to balloon during the first five years of life, as all those extra neurons grow larger and form connections.

Sometime after age four or five, Courchesne has also found, autistic brains actually start to lose neural connections, faster than typical brains.

In a study published November 2011 in JAMA, The Journal of the American Medical Association, Courchesne reported that children with autism have 67 percent more neurons in their prefrontal cortex (PFC) than typical children.

Located in the area of the brain just behind the eyes, the PFC is responsible for what psychologists call "executive functions"—high-level thinking, such as planning ahead, inhibiting impulses and directing attention. In his 2011 study Courchesne sliced up brain tissue from six autistic children and seven typical children who had passed away and counted the number of cell bodies in the sections to estimate the total number of neurons in their PFCs.

Now, Courchesne and his colleagues have analyzed DNA and RNA in 33 cubes of brain tissue from people who passed away, 15 of whom were autistic (nine children and six adults) and 18 who had typical brains (seven children and 11 adults).

Looking at the order of DNA's building blocks reveals whether individual genes have mutations; measuring levels of RNA indicates how often those genes were translated into proteins.

Such gene expression, Courchesne and his colleagues found, varied between autistic and typical brains.

In brain tissue from both autistic children and autistic adults, genes coding for proteins that identify and repair mistakes in DNA were expressed at unusually low levels.

Additionally, all autistic brains demonstrated unusual activity levels for genes that determine when neurons grow and die and how newborn neurons migrate during early development.

Some genes involved in immune responses, cell-to-cell communication and tissue repair, however, were expressed at unusual levels in adult autistic brains, but not in autistic children's brains.

The results appear in the March 22 issue of PLoS Genetics.

You can also Read More of this article here at Scientific American: The Ballooning Brain

Dyslexia and Language-Processing by Dr Sally E. Shaywitz

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