Tag Archive for: developmental delay

caspase molecule

Caspases may link brain cell degeneration and cardiac surgery

caspase molecule

The review summarizes both the known physiological roles of caspases as well as some of the well-characterized neurotoxic effects of anesthetics in pre-clinical models.

A review article in the journal Cell Press: Trends in Neuroscience outlines the wide variety of cellular signaling roles for caspase proteins — a type of cellular enzyme best known for its documented role in the natural process of cell death (apoptosis). The authors, including Nemanja Saric, Ph.D., Kazue Hashimoto-Torii, Ph.D., and Nobuyuki Ishibashi, M.D., all from Children’s National Research Institute, pay particular attention to what the scientific literature shows about caspases’ non-apoptotic roles in the neurons specifically. They also highlight research showing how, when activated during a cardiac surgery with anesthesia and cardiopulmonary bypass, these enzymes may contribute to the degeneration of brain cells seen in young children who undergo heart surgery for critical congenital heart defects (CHDs).

Why it matters

The review summarizes both the known physiological roles of caspases as well as some of the well-characterized neurotoxic effects of anesthetics in pre-clinical models.

The authors propose that these non-apoptotic activities of caspases may be behind some of the adverse effects on the developing brain related to cardiac surgery and anesthesia. Those adverse effects are known to increase risk of behavioral impairments in children with congenital heart disease who underwent cardiac surgery with both anesthesia and cardiopulmonary bypass at a very young age.

This work is the first to propose a possible link between developmental anesthesia neurotoxicity and caspase-dependent cellular responses.

The patient benefit

Better understanding of the time and dose-dependent effects of general anesthetics on the developing brain, particularly in children who have genetic predispositions to conditions such as CHDs, will help researchers understand their role (if any) in behavioral problems often encountered by these patients after surgery.

If found to be a contributing factor, perhaps new therapies to mitigate this caspase activity might be explored to alleviate some of these adverse effects on the developing brain.

What’s next?

The authors hope to stimulate more in-depth research into caspase signaling events, particularly related to how these signaling events change when an anesthetic is introduced. Deeper understanding of how anesthetics impact caspase activation in the developing brain will allow for better assessments of the risk for children who need major surgery early in life.

Children’s National leads the way

Children’s National Hospital leads studies funded by the U.S. Department of Defense to better understand how these other roles of caspases, which until now have not been well-documented, may contribute to brain cell degeneration when activated by prolonged anesthesia and cardiopulmonary bypass during cardiac surgery for congenital heart disease.

DNA

International collaboration discovers new cause for dwarfism

DNA

An international collaboration resulted in the identification of a new cause of dwarfism: mutations in a gene known as DNMT3A.

Beyond diabetes, short stature is the most common reason for children in the U.S. to visit an endocrinologist. For the vast majority of children with short stature, the cause remains unknown – even though many of these conditions stem from an as-yet unidentified genetic cause, says Andrew Dauber, M.D., M.M.Sc., division chief of Endocrinology at Children’s National Health System.

“Parents are concerned about why their child isn’t growing and if there are other complications or health problems they’ll need to watch out for,” he says. “Without a diagnosis, it’s very hard to answer those questions.”

Dauber’s research focuses on using cutting-edge genetic techniques to unravel the minute differences in DNA that limit growth. This research recently led him and his colleagues to identify a new cause of dwarfism: mutations in a gene known as DNMT3A. The discovery, which the team published in the January 2019 Nature Genetics, didn’t happen in isolation – it required a rich collaboration of labs spread across the world in Scotland, Spain, France and New Zealand, in addition to Dauber’s lab in the U.S.

The journey that brought Dauber into this group effort got its start with a young patient in Spain. The boy, then four years old, was at less than 0.1 percentile on the growth curve for height with a very small head circumference and severe developmental delays. This condition, known as microcephalic dwarfism, is incredibly rare and could stem from one of several different genetic causes. But his doctors didn’t know the reason for this child’s specific syndrome.

To better understand this condition, Dauber used a technique known as whole exome sequencing, a method that sequences all the protein-coding regions in an individual’s entire genome. He found a mutation in DNMT3A – a change known as a de novo missense mutation, meaning that the mutation happened in a single letter of the boy’s genetic code in a way that hadn’t been inherited from his parents. But although this mutation was clear, its meaning wasn’t. The only clue that Dauber had as to DNMT3A’s function was that he’d read about overgrowth syndromes in which the function of this gene is lost, leading to large individuals with large heads, the exact opposite of this patient’s condition.

To gather more information, Dauber reached out to Andrew Jackson, Ph.D., a researcher who studies human genes for growth at the University of Edinburgh in Scotland. Coincidentally, Jackson had already started studying this gene after two patients with a shared mutation in a neighboring letter in the genetic code – who also had short stature and other related problems – were referred to him.

Dauber and his colleagues sent the results from their genetic analysis back across the Atlantic to Jackson’s Edinburgh lab, and the doctors from Spain sent more information to Jackson’s lab, including the patient’s clinical information, blood samples and skin biopsy samples. Then the whole team of collaborators from around the globe set to work to discover the processes influencing short stature in each of these three patients.

Their results showed that these mutations appear to cause a gain of function in DNMT3A. This gene codes for a type of enzyme known as a methyltransferase, which places methyl groups on other genes and on the protein spools called histones that DNA wraps around. Each of these functions changes how cells read the instructions encoded in DNA. While the mutations that cause the overgrowth syndromes appear to allow stem cells to keep dividing long past when they should taper off and differentiate into different cell types – both normal processes in development – the gain of function that appears to be happening in these three patients prompts the opposite situation: Stem cells that should be dividing for a long time during development stop dividing and differentiate earlier, leading to smaller individuals with far fewer cells overall.

The researchers confirmed their findings by inserting one of the gain-of-function human DNMT3A mutations into a mouse, leading to short animals with small heads.

Eventually, says Dauber, these findings could help lead to new treatments for this and other types of dwarfism that act on these genetic pathways and steer them toward normal growth. These and other scientific discoveries hinge on the type of international collaboration that he and his colleagues engaged in here, he adds – particularly for the types of rare genetic syndromes that affect the patients that he and his colleagues study. With only a handful of individuals carrying mutations in certain genes, it’s increasingly necessary to combine the power of many labs to better understand the effects of these differences and how doctors might eventually intervene.

“The expertise for all aspects of any single research project is rarely centered in one institution, one city, or even one country,” Dauber says. “Often, you really need to reach out to people with different areas of expertise around the world to make these types of new discoveries that can have pivotal impacts on human health.”

Marva Moxey Mims

Making the case for a comprehensive national registry for pediatric CKD

Marva Moxey Mims

“It’s of utmost importance that we develop more sensitive ways to identify children who are at heightened risk for developing CKD.,” says Marva Moxey-Mims, M.D. “A growing body of evidence suggests that this includes children treated in pediatric intensive care units who sustained acute kidney injury, infants born preterm and low birth weight, and obese children.”

Even though chronic kidney disease (CKD) is a global epidemic that imperils cardiovascular health, impairs quality of life and heightens mortality, very little is known about how CKD uniquely impacts children and how kids may be spared from its more devastating effects.

That makes a study published in the November 2018 issue of the American Journal of Kidney Diseases all the more notable because it represents the largest population-based study of CKD prevalence in a nationally representative cohort of adolescents aged 12 to 18, Sun-Young Ahn, M.D., and Marva Moxey-Mims, M.D., of Children’s National Health System, write in a companion editorial published online Oct. 18, 2018.

In their invited commentary, “Chronic kidney disease in children: the importance of a national epidemiological study,” Drs. Ahn and Moxey-Mims point out that pediatric CKD can contribute to growth failure, developmental and neurocognitive defects and impaired cardiovascular health.

“Children who require renal-replacement therapy suffer mortality rates that are 30 times higher than children who don’t have end-stage renal disease,” adds Dr. Moxey-Mims, chief of the Division of Nephrology at Children’s National. “It’s of utmost importance that we develop more sensitive ways to identify children who are at heightened risk for developing CKD. A growing body of evidence suggests that this includes children treated in pediatric intensive care units who sustained acute kidney injury, infants born preterm and low birth weight, and obese children.”

At its early stages, pediatric CKD usually has few symptoms, and clinicians around the world lack validated biomarkers to spot the disease early, before it may become irreversible.

While national mass urine screening programs in Japan, Taiwan and Korea have demonstrated success in early detection of CKD, which enabled successful interventions, such an approach is not cost-effective for the U.S., Drs. Ahn and Moxey-Mims write.

According to the Centers for Disease Control and Prevention, 1 in 10 U.S. infants in 2016 was born preterm, prior to 37 weeks gestation. Because of that trend, the commentators advocate for “a concerted national effort” to track preterm and low birth weight newborns. (These infants are presumed to have lower nephron endowment, which increases their risk for developing end-stage kidney disease.)

“We need a comprehensive, national registry just for pediatric CKD, a database that represents the entire U.S. population that we could query to glean new insights about what improves kids’ lifespan and quality of life. With a large database of anonymized pediatric patient records we could, for example, assess the effectiveness of specific therapeutic interventions, such as angiotensin-converting enzyme inhibitors, in improving care and slowing CKD progression in kids,” Dr. Moxey-Mims adds.