Corporate Banner
Satellite Banner
Technology
Networks
Scientific Communities
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Genetic Disorder Causing Strokes, Vascular Inflammation in Children Discovered

Published: Thursday, February 20, 2014
Last Updated: Thursday, February 20, 2014
Bookmark and Share
NIH researchers have identified gene variants that cause a rare syndrome of sporadic fevers, skin rashes and recurring strokes, beginning early in childhood.

The team’s discovery coincides with findings by an Israeli research group that identified an overlapping set of variants of the same gene in patients with a similar type of blood vessel inflammation.

The NIH group first encountered a patient with the syndrome approximately 10 years ago. The patient, then 3 years old, experienced fevers, skin rash and strokes that left her severely disabled. Because there was no history of a similar illness in the family, the NIH group did not at first suspect a genetic cause, and treated the patient with immunosuppressive medication. However, when the NIH team evaluated a second patient with similar symptoms two years ago — a child who had experienced recurrent fevers and six strokes by her sixth birthday — they began to suspect a common genetic cause and embarked on a medical odyssey that has led not only to a diagnosis, but to fundamental new insights into blood vessel disease.

In their study, which appears in the Feb. 19, 2014, advance online edition of the New England Journal of Medicine, the researchers describe how next-generation genome sequencing, only recently available, facilitated a molecular diagnosis for patients in their study. The researchers found that harmful variants in the CECR1 gene impede production of a protein vital to the integrity of healthy blood vessel walls.

“This discovery is another example of genome sequencing playing a central role in revealing the genomic basis for an important rare disease,” said Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI), where the lead members of the research team are based. “Such studies illustrate how genomics is paving the way to improved human health.”

The researchers showed that faulty variants in their patients’ DNA that encode the CECR1 gene cause a loss of function of the gene’s ability to produce of an enzyme called adenosine deaminase 2 (ADA2). Without it, abnormalities and inflammation in blood vessel walls result. The researchers call the new syndrome, deficiency of ADA2, or DADA2. The enzyme ADA2 is chemically similar to the enzyme ADA1, whose deficiency results in severe combined immunodeficiency disease.

NHGRI Scientific Director Daniel Kastner, M.D., Ph.D., led the team of collaborators from NIH and beyond in mounting the study of nine patients. “It has been incredibly fantastic to see this kind of progress being made within the last decade,” he said. “Our study raises the possibility that the ADA2 pathway may contribute to susceptibility to stroke in the more general population.”

For children, as with adults, stroke can affect physical, cognitive and emotional functioning. Some outcomes, such as blindness and deafness, can be lasting; others, such as the ability to walk, can be relearned.

“While no other incidence of this condition occurred in the families who came to our clinic, the early age of onset suggested to us that the patients were born with a genetic condition,” Dr. Kastner said. “We used a whole-exome screen to locate genetic variants in each of the patients.”

Whole-exome sequencing determines the order of DNA bases for the 1 percent of the human genome that codes for proteins. Qing Zhou, Ph,D., a post-doctoral fellow in Dr. Kastner’s lab, methodically analyzed two of the patients’ exomes as well as exomes of their parents. Among hundreds of variants that distinguished each patient from their parents, they located two variants that are novel or rare in the CECR1 gene, which encodes ADA2. These variants were passed from both parents to the affected child. The whole-exome sequence of a third patient identified another harmful variant of CECR1 in addition to a small genomic deletion that shuts down the second copy of the gene. They needed only a sequence reading of that single gene to confirm that three other patients were affected by harmful variants in this gene. Three of the eight detrimental variants that eliminate the protein ADA2 were shared among the first six patients.

The team subsequently sequenced the CECR1 gene in three additional patients from Turkey who had some of the symptoms of the new syndrome. They found that a homozygous pair — a double dose of a different variant — from the one detected in the first six patients causes a disease called polyarteritis nodosa (PAN). PAN is a form of vasculitis, an inflammation of medium and small arteries that leads to pain, rashes, numbness, weakness and vital organ damage. PAN can cause kidney failure, heart attack and stroke.

“We now know that this mutation exists in the Middle East and in Pakistani populations and that it is not that uncommon,” said Ivona Aksentijevich, M.D., senior author and staff scientist in NHGRI's Inflammatory Diseases Section. The Israeli researchers, whose study is published concurrently in the journal, found the same mutation in CECR1 as those NIH patients with PAN. The patients in the Israeli study are from families that emigrated to Israel from the country of Georgia. “This is the first time a single gene has been discovered that is involved in causing a system-wide form of vasculitis.” Dr. Aksentijevich said.

The researchers found data from a study of adult patients showing that those who carry only one mutation in this gene may have a predisposition to develop adult onset stroke. They also induced ADA2 deficiency in a zebrafish animal model. They found that zebrafish embryos that produce less ADA2 than normal embryos have cerebral bleeds, similar to those seen in some of the children with ADA2 deficiency. The primary role for ADA2 protein is as a growth factor. Data from the zebrafish model suggest that this growth factor plays a role in blood vessel development.

Members of the research team led by Manfred Boehm, M.D., senior investigator at the National Heart, Lung, and Blood Institute, established the link between ADA2 deficiency and inflammatory blood vessel disease in the patients. Dan Yang, M.D., Ph.D., a staff scientist in Dr. Boehm’s lab, discovered that ADA2 deficiency causes a faulty function in a subset of white blood cells called monocytes/macrophages. The faulty monocyte/macrophages attack the patients’ own blood vessels, resulting in a vicious circle of vessel damage and inflammation that leads to stroke and other blood vessel-related problems.

The discovery of the molecular basis of DADA2 has treatment implications. As an alternative to high doses of steroids, which produce profound side effects, the study suggests that treatment may include specialized drugs that inhibit inflammatory proteins produced during the syndrome. Also, since ADA2 is made in the bone marrow and circulates in the blood stream, the team is evaluating a way to replace ADA2 that is missing in the bloodstreams of those affected by DADA2. The researchers obtained approval from the Food and Drug Administration to test the safety and efficacy of using freshly frozen plasma to restore ADA2 functionality for treated patients. Alternatively, an artificial form of the protein would help, but is not currently in development. Bone marrow transplantation or genetic manipulation of bone marrow could also have a role in the treatment of these patients.

“This genome sequencing study expands what has previously been known about vascular biology, and it is truly gratifying to be among two labs using next-generation genome sequencing technology to arrive at complementary conclusions about the functionality of the same gene,” said Dr. Kastner. “The role of ADA2 in such serious human disease is important and suggests that ADA2 variants may contribute to other more common illnesses.”

The collaboration that brought the discovery of this new syndrome to light included researchers from NHGRI and five additional NIH institutes, including the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Cancer Institute; and the National Institute of Diabetes and Digestive and Kidney Diseases, as well as the NIH Clinical Center.

NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. 


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,500+ scientific posters on ePosters
  • More Than 3,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

NIH Study Shows No Benefit of Omega-3 Supplements for Cognitive Decline
Research was published in the Journal of the American Medical Association.
Thursday, August 27, 2015
NIH Launches Human RSV Study
Study aims to understand infection in healthy adults to aid development of RSV medicines, vaccines.
Thursday, August 27, 2015
In Uveitis, Bacteria in Gut May Instruct Immune Cells to Attack the Eye
NIH scientists propose novel mechanism to explain autoimmune uveitis.
Wednesday, August 19, 2015
Novel Mechanism to Explain Autoimmune Uveitis Proposed
A new study on mice suggests that bacteria in the gut may provide a kind of training ground for immune cells to attack the eye.
Wednesday, August 19, 2015
Large Percentage of Youth with HIV May Lack Immunity to Measles, Mumps, Rubella
NIH study finds those vaccinated before starting modern HIV therapy may be at risk.
Tuesday, August 18, 2015
Cellular Factors that Shape the 3D Landscape of the Genome Identified
Researchers have identified 50 cellular factors required for the proper 3D positioning of genes by using novel large-scale imaging technology.
Tuesday, August 18, 2015
Nuclear Process in the Brain That May Affect Disease Uncovered
Scientists have shown that the passage of molecules through the nucleus of a star-shaped brain cell, called an astrocyte, may play a critical role in health and disease.
Tuesday, August 18, 2015
Scientists Uncover Nuclear Process in the Brain that May Affect Disease
NIH-funded study highlights the possible role of glial brain cells in neurological disorders.
Tuesday, August 18, 2015
Newly Discovered Cells Restore Liver Damage in Mice Without Cancer Risk
The liver is unique among organs in its ability to regenerate after being damaged. Exactly how it repairs itself remained a mystery until recently, when researchers supported by the NIH discovered a type of cell in mice essential to the process
Monday, August 17, 2015
Study Finds Cutting Dietary Fat Reduces Body Fat More than Cutting Carbs
In a recent study, restricting dietary fat led to body fat loss at a rate 68 percent higher than cutting the same number of carbohydrate calories when adults with obesity ate strictly controlled diets.
Friday, August 14, 2015
Inappropriate Medical Food Use in Managing Patients with a Type of Metabolic Disorder
Researchers have proposed that there is a need for more rigorous clinical study of dietary management practices for patients with IEMs, including any associated long-term side effects, which may in turn result in the need to reformulate some medical foods.
Friday, August 14, 2015
PINK1 Protein Crucial for Removing Broken-Down Energy Reactors
NIH study suggests potential new pathway to target for treating ALS and other diseases.
Thursday, August 13, 2015
Tell-tale Biomarker Detects Early Breast Cancer in NIH-funded Study
The study published online in the issue of Nature Communications.
Thursday, August 13, 2015
Neurons’ Broken Machinery Piles Up in ALS
NIH scientists identify a transport defect in a model of familial ALS.
Thursday, August 13, 2015
Dr. Peter Kilmarx Appointed Deputy Director of Fogarty International Center
An expert in infectious disease research and HIV/AIDS prevention.
Wednesday, August 12, 2015
Scientific News
The Changing Tides of the In Vitro Diagnostics Market
With the increasing focus in personalized medicine, diagnostics plays a crucial role in patient monitoring.
LaVision BioTec Reports on the Neuro Research on the Human Brain After Trauma
Company reports on the work of Dr Ali Ertürk from the Institute for Stroke and Dementia Research at LMU Munich.
NIH Study Shows No Benefit of Omega-3 Supplements for Cognitive Decline
Research was published in the Journal of the American Medical Association.
Less May Be More in Slowing Cholera Epidemics
Mathematical model shows more cases may be prevented and more lives saved when using one dose of cholera vaccine instead of recommended two doses.
Investigating the Vape
Expert independent review concludes that e-cigarettes have potential to help smokers quit.
NIH Launches Human RSV Study
Study aims to understand infection in healthy adults to aid development of RSV medicines, vaccines.
Researchers Discover Synthesis of a New Nanomaterial
Interdisciplinary team creates biocomposite for first time using physiological conditions.
Poor Survival Rates in Leukemia Linked to Persistent Genetic Mutations
For patients with an often-deadly form of leukemia, new research suggests that lingering cancer-related mutations – detected after initial treatment with chemotherapy – are associated with an increased risk of relapse and poor survival.
Flu Remedies Help Combat E. coli Bacteria
Physiologists from the University of Zurich have now discovered why the intestinal bacterium Escherichia coli (E. coli) multiplies heavily and has an inflammatory effect.
Marijuana Genome Unraveled
A study by Canadian researchers is providing a clearer picture of the evolutionary history and genetic organization of cannabis, a step that could have agricultural, medical and legal implications for this valuable crop.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!