International collaboration uncovers mosaicism, a condition in which cells within the same person have a different genetic makeup, as a cause for pediatric seizures
Newswise — Epilepsy is present in 4% of the population, and is among the most common brain disorders in children. Modern medicine can prevent most seizure recurrences, but approximately 20% of patients do not respond to treatment.
In these cases, the reason may originate in patches of damaged or abnormal brain tissue known as “malformations of cortical development” (MCD), which results in a diverse group of neurodevelopment disorders. Surgical resection or removal of the patch can cure the seizures, and epilepsy surgery to improve neurological outcomes is now a key part of the modern medical armamentarium, but what causes the patches has largely remained a mystery.
Writing in the January 12, 2023 issue of Nature Genetics, researchers at University of California San Diego School of Medicine and Rady Children’s Institute for Genomic Medicine, collaborating with an international consortium of more than 20 children’s hospitals worldwide, report a significant breakthrough in understanding the genetic causes of MCD.
Members of the Focal Cortical Dysplasia Neurogenetics Consortium investigated 283 brain resections from children across a range of MCD types, with parental consent, looking for potential genetic causes. Because most brain tissue in these children is normal, the scientists focused on mutations present in a small subset of brain cells, a phenomenon termed genetic somatic mosaicism.
“This was a decade-long journey, bringing specialists together from around the world, to recruit patients for this study,” said senior study author Joseph Gleeson, MD, Rady Professor of Neuroscience at UC San Diego School of Medicine and director of neuroscience research at the Rady Children’s Institute for Genomic Medicine. “Until recently, most hospitals did not study resected brain tissue for genetic causes. The consortium organized a biobank to store tissue for high-throughput mosaicism analysis.”
Previous research by Gleeson and colleagues had shown that genetic somatic mosaicism in the mTOR signaling pathway was a contributing factor, said co-first author Changuk Chung, PhD, a postdoctoral fellow in the Gleeson lab.
“But most patients remain undiagnosed, which hinders treatment. We tested for hidden mutations, detectable only by greatly expanding the cohort size and improving methods so that the results could be meaningful. We collaborated to solve technical and logistical bottlenecks. The pieces fell into place, but it took 10 years.”
The team conducted intensive genomic discovery using state-of-art somatic mosaic algorithms developed by the National Institutes of Health-sponsored Brain Somatic Mosaicism Network, of which UC San Diego is a member.
“We tried our best to detect mutations in as little as 1 percent of cells,” said co-first author Xiaoxu Yang, PhD, a postdoctoral scholar in Gleeson’s lab. “Initially we failed. To solve these problems, we needed to develop novel artificial intelligence methods to overcome barriers in sensitivity and specificity.”
The team ultimately identified 69 different genes carrying somatic brain mutations, the majority of which have never previously reported in MCD.
“We can draw parallels with the cancer field because these mutations disrupt cellular function and need to be resected,” said co-first author Chung. “However, unlike cancer cells, brain cells mostly do not divide so these cells misbehave by stimulating epileptic seizures. The question that arose was whether the newly found gene mutations were sufficient to cause MCD disease.”
Gleeson said the scientists found that the genes converged on calcium signaling, gene expression and synaptic functions, and noted that when the mutations were introduced into a mouse model, abnormalities similar to those seen in patients were observed. The study authors suggest the findings could be used to improve diagnosis and develop cures for MCD disease.
“The MCD genes in patient brains have demonstrated critical roles during cortical development,” said Gleeson. “These findings could lead to new molecular classifications for MCD, and ultimately to personalized therapies for epilepsy.”
For a complete list of co-authors, see full study.
Funding for this research came, in part, from the National Institutes of Health (grants NIMH U01MH108898 and R01MH124890, NIA R21AG070462, NINDS R01NS083823), the San Diego Supercomputer Center and UC San Diego Institute of Genomic Medicine.
FDA Announces Action Levels for Lead in Categories of Processed Baby Foods
Today, the U.S. Food and Drug Administration is announcing draft guidance for industry on action levels for lead in processed foods that are intended for babies and children under two years of age, to help reduce potential health effects in this vulnerable population from dietary exposure to lead. The proposed action levels would result in significant reductions in exposures to lead from food while ensuring availability of nutritious foods. Today’s action is part of Closer to Zero, which sets forth the FDA’s science-based approach to continually reducing exposure to lead, arsenic, cadmium and mercury to the lowest levels possible in foods eaten by babies and young children.
“For more than 30 years, the FDA has been working to reduce exposure to lead, and other environmental contaminants, from foods. This work has resulted in a dramatic decline in lead exposure from foods since the mid-1980s.The proposed action levels announced today, along with our continued work with our state and federal partners, and with industry and growers to identify mitigation strategies, will result in long-term, meaningful and sustainable reductions in the exposure to this contaminant from foods,” said FDA Commissioner Robert M. Califf, M.D. “For babies and young children who eat the foods covered in today’s draft guidance, the FDA estimates that these action levels could result in as much as a 24-27% reduction in exposure to lead from these foods.”
Foods covered by the draft guidance, Action Levels for Lead in Food Intended for Babies and Young Children, are those processed foods, such as food packaged in jars, pouches, tubs and boxes and intended for babies and young children less than two years old. The draft guidance contains the following action levels:
- 10 parts per billion (ppb) for fruits, vegetables (excluding single-ingredient root vegetables), mixtures (including grain and meat-based mixtures), yogurts. custards/puddings and single-ingredient meats.
- 20 ppb for root vegetables (single ingredient).
- 20 ppb for dry cereals.
The FDA considers these action levels to be achievable when measures are taken to minimize the presence of lead and expects that industry will strive for continual reduction of this contaminant. The baby foods have differing action levels, to account for variances in consumption levels of different food products and due to some foods taking up higher amounts of lead from the environment. Action levels are one regulatory tool the FDA uses to help lower levels of chemical contaminants in foods when a certain level of a contaminant is unavoidable, for example due to environmental factors. To identify the action levels for categories of foods, the agency considered, among other factors, the level of lead that could be in a food without dietary exposure exceeding the FDA’s Interim Reference Level, a measure of the contribution of lead in food to blood lead levels.
Just as fruits, vegetables and grain crops readily absorb vital nutrients from the environment, these foods also take up contaminants, like lead, that can be harmful to health. The presence of a contaminant, however, does not mean the food is unsafe to eat. The FDA evaluates the level of the contaminant in the food and exposure based on consumption to determine if the food is a potential health risk. Although it is not possible to remove these elements entirely from the food supply, we expect that the recommended action levels will cause manufacturers to implement agricultural and processing measures to lower lead levels in their food products below the proposed action levels, thus reducing the potential harmful effects associated with dietary lead exposures. Although not binding, the FDA would consider these action levels, in addition to other factors, when considering whether to bring enforcement action in a particular case.
“The action levels in today’s draft guidance are not intended to direct consumers in making food choices. To support child growth and development, we recommend parents and caregivers feed children a varied and nutrient-dense diet across and within the main food groups of vegetables, fruits, grains, dairy and protein foods,” said Susan Mayne, Ph.D., director of the FDA’s Center for Food Safety and Applied Nutrition. “This approach helps your children get important nutrients and may reduce potential harmful effects from exposure to contaminants from foods that take up contaminants from the environment.”
As part of our approach, as laid out in 2021 when the FDA released Closer to Zero, the agency is committed to assessing if action levels should be lowered even further, based on evolving science on health impacts and mitigation techniques, and input from industry on achievability. We expect the draft action levels announced today, along with the draft action levels for lead in juice announced in 2022, will result in even lower levels of lead in the U.S. food supply. Moving forward, the agency will continue to gather data and collaborate with federal partners to establish the scientific basis for establishing Interim Reference Levels for arsenic, cadmium and mercury. Additionally, the FDA is considering the more than 1,100 comments it received in November 2021 during the “Closer to Zero Action Plan: Impacts of Toxic Element Exposure and Nutrition at Different Crucial Developmental Stages for Babies and Young Children” public meeting to inform its strategy moving forward for future planned action on contaminants and fostering engagement, education and sharing of public data and information.
The FDA will host a webinar to provide an overview of the draft guidance and answer stakeholder questions. More details on the webinar will be announced shortly.
- Action Levels for Lead in Food Intended for Babies and Young Children
- FDA Issues Draft Guidance to Industry on Action Levels for Lead in Baby Foods
- Releases Action Plan for Reducing Exposure to Toxic Elements from Foods for Babies, Young Children
- Lead in Food, Foodwares, and Dietary Supplements
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Managing Birth Defects for a Lifetime
(Family Features) An estimated 1 in 33 babies is born with a birth defect, according to the Centers for Disease Control and Prevention (CDC). While some require minimal intervention after birth, many birth defects affect the individual, parents and families across a lifetime.
Birth defects are structural changes present at birth that can affect almost any part of the body. They may affect how the body looks, works or both. They can cause problems in overall health, how the body develops or how the body works, and may range from mild to serious health conditions.
Awareness of birth defects across the lifespan helps provide affected individuals, parents and families the information they need to seek proper care. Learn more about birth defects at each stage of life from the experts at March of Dimes:
Before and During Pregnancy
Not all birth defects are preventable but protecting a mother’s health before and during pregnancy can help increase the likelihood of a healthy baby. Having adequate folic acid for at least one month before getting pregnant and throughout the pregnancy can prevent major birth defects.
Other important steps include receiving proper prenatal care from a doctor, preventing infections, avoiding alcohol and drugs, controlling conditions like diabetes and avoiding getting too hot.
Babies who are diagnosed with a birth defect during pregnancy or at birth may need special care. Similarly, monitoring for certain birth defects can help pinpoint a potential problem and ensure the baby begins receiving supportive care for better survival rates and quality of life. Examples include newborn screenings for critical congenital heart defects and monitoring bladder and kidney function in infants and children with spina bifida.
For children born with heart defects and conditions like spina bifida, muscular dystrophy or Down syndrome, early intervention services and support can make a significant impact on a child’s success in school and life. They can help children with learning problems and disabilities; school attendance; participation in school, sports and clubs; mobility adaptations; and physical, occupational and speech therapy.
Many adolescents and young adults who have birth defects begin working toward a transition to a healthy, independent adult life in their later teen years. This may involve insurance changes and switching from pediatricians to adult doctors.
Other areas of focus might include medications, surgeries and other procedures; mental health; social development and relationships within and outside the family; physical activity; and independence.
Certain conditions, such as heart defects, can cause pregnancy complications or affect sexual function. Talking with a doctor about your specific condition can help you understand your risk.
In addition, every pregnancy carries a 3% risk of birth defects, even without lifestyle factors or health conditions that add risk, according to the CDC. Women who have had a pregnancy affected by a birth defect may be at greater risk during future pregnancies.
Talking with a health care provider can help assess those risks. A clinical geneticist or genetic counselor can assess your personal risk of birth defects caused by changes in genes, as well as your risk due to family history.
Find more information about birth defect prevention and management at marchofdimes.org/birthdefects.
Common Causes of Birth Defects
Research shows certain circumstances, or risk factors, may make a woman more likely to have a baby with a birth defect. Having a risk factor doesn’t mean a baby will be affected for sure, but it does increase the chances. Some of the more common causes of birth defects include:
The things that affect everyday life, including where you live, where you work, the kinds of foods you eat and how you like to spend your time can be harmful to your baby during pregnancy, especially if you’re exposed to potentially dangerous elements like cigarette smoke or harmful chemicals.
Some health conditions, like pre-existing diabetes, can increase a baby’s risk of having a birth defect. Diabetes is a medical condition in which the body has too much sugar (called glucose) in the blood.
Taking certain medicines while pregnant, like isotretinoin (a medicine used to treat acne), can increase the risk of birth defects.
Smoking, Drinking or Using Drugs
Lifestyle choices that affect your own health and well-being are likely to affect an unborn baby. Smoking, drinking or using drugs can cause numerous problems for a baby, including birth defects.
Some infections during pregnancy can increase the risk of birth defects and other problems. For example, if an expectant mother has a Zika infection during pregnancy, her baby may be at increased risk of having microcephaly.
Women who are 34 years old or older may be at increased risk of having a baby with a birth defect.
Photos courtesy of Getty Images
March of Dimes
A Deepening Partnership: How CHLA and Macedonia Baptist Church Are Tackling Health Inequities in South L.A.
As the lead pastor of Macedonia Baptist Church, Rev. Dr. Shane B. Scott is accustomed to hearing from parishioners. But on one occasion, the words spoken by a 98-year-old woman struck a particular chord.
A children’s hospital and a church host a health fair to combat health disparities. They were joined by CHLA injury prevention experts, hospital therapy dogs and an expanded vaccination clinic that offered COVID-19 boosters and the flu shot. “A ZIP code should not determine the life expectancy nor the diseases that we get,” says Alejandro “Alex” Guerrero, Executive Director of the Macedonia Community Development Corporation
Newswise — As the lead pastor of Macedonia Baptist Church, Rev. Dr. Shane B. Scott is accustomed to hearing from parishioners. But on one occasion, the words spoken by a 98-year-old woman struck a particular chord.
“She told me she wasn’t planning to get vaccinated, but because we had it here at the church, she decided to do it and thought that saved her life,” says Rev. Scott. “That’s not just help—that’s hope.”
The church, located in the Watts area of South Los Angeles, was the site of four COVID-19 vaccination clinics staffed by clinical team members from Children’s Hospital Los Angeles in early spring 2021. The events made accessing the vaccine more convenient for early childhood educators and residents in the neighborhood, and also helped to break down hesitancy around getting the shot.
“Disenfranchised communities across this city have not always been treated well, so I think partnering with faith groups brings in a certain level of trust,” says Rev. Scott. “There are times when I get a phone call and I want to say, ‘But, wait, why are you calling me? You should be calling the doctor.’ But because they don’t trust the health care system, they call their pastor instead.”
Over the last century, South L.A.’s landscape has changed, but there has been one constant throughout the years: Macedonia Baptist Church. Founded in 1908, it was the first Black Baptist church—and today the oldest—in Greater Watts. Its longstanding history and deep roots have made it a prime partner in helping to address health disparities in the region.
“The church is often a central figure in African-American communities,” says Alejandro “Alex” Guerrero, Executive Director of the Macedonia Community Development Corporation, which serves as the church’s outreach entity. “It’s the honest broker, and in a place where there are multiple gangs, it’s also seen as neutral territory.”
Jennifer Baird, PhD, RN, Director of Clinical Services Education and Research at Children’s Hospital Los Angeles, who helped coordinate the COVID-19 vaccination clinics, attended a service at Macedonia Baptist Church. “I was really inspired by the strong role the church plays and how it can be a mechanism for promoting health equity as an anchor institution in the community,” she says.
“Our hospital’s commitment to supporting families across L.A. County really connects with what they’re trying to do,” she adds.
At one of the COVID-19 vaccination clinics, Dr. Baird and Rev. Scott began talking about ways the two organizations could continue working together. A family-friendly fair quickly came to mind. The COVID-19 vaccine would once again be available, but so would numerous other resources. A few months later, the inaugural Family Health and Wellness Fair took place in the church’s parking lot. Attendees were able to pick up school supplies and books from CHLA’s Literally Healing program, have their vital signs checked through health screenings, participate in art and music therapy, and learn first-aid training.
This year’s fair was held on Oct. 22, 2022, and included many of the same stations, plus CHLA therapy dogs and an expanded vaccination clinic that offered COVID-19 boosters and the flu shot.
“In Watts, people are used to hearing about supply chain issues, so they might not be getting a flu shot or will have to wait,” says Guerrero. “The fact that this was available to them, along with the latest COVID booster, the feedback I heard was that they felt cared for and paid attention to.”
Guerrero, Rev. Scott, Dr. Baird and the CHLA team who helped organize the fair hope it will become an annual event and aim to have a lasting partnership that will have a greater presence and impact in the community. Some future goals include having CHLA doctors, nurses and other health care professionals who also grew up in under-resourced communities come out to share their paths into the health care field, or having HR personnel host a resume-writing workshop.
Health, however, will remain at the center of it all.
“A ZIP code should not determine the life expectancy nor the diseases that we get,” says Guerrero. “It breaks my heart that what should be simple things—medical care, access to fruits and vegetables—can be complex for some. It all starts with being healthy. If you’re not, you can’t get a job, you can’t provide for your family. It’s all connected.”
Though there are plenty of medical institutions in Los Angeles County, when it came to partnering with one, Rev. Scott ultimately knew it would be Children’s Hospital Los Angeles. He has always had a heart for pediatric medical institutions, and during his early years as a minister in Northern California, he would visit local children’s hospitals.
“I was just amazed, impressed and inspired by the level of care there,” he recalls. “Sick children were being loved on by everyone from doctors and nurses to janitors and phlebotomists as if these children belonged to them.”
Beyond the urgent, lifesaving medical care that children’s hospitals provide, it’s the dedication to health at the earliest stages of life that Rev. Scott believes can shape a community.
“In communities like Watts that are so overtaken with other health disparities, socioeconomic issues and crime, children are often forgotten about. But if you don’t invest in the health and well-being of children early, then you don’t have healthy and productive adults later,” he says.
“By working with Children’s Hospital Los Angeles,” adds Rev. Scott, “I hope we are planting the seeds that can ultimately germinate into something much bigger. It’s a relationship that is deepening, and there is so much that can come from this.”
Source: Children’s Hospital Los Angeles
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