CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia

Cause Of Leukemia In Trisomy 21 - ScienceDaily

People with a third copy of chromosome 21, known as trisomy 21, are at high risk of developing Acute Myeloid Leukaemia (AML), an aggressive form of blood cancer. Scientists led by the Department of Paediatrics at University Hospital Frankfurt have now identified the cause: although the additional chromosome 21 leads to increased gene dosage of many genes, it is above all the perturbation of the RUNX1 gene -- a gene that regulates many other genes -- that seems to be responsible for AML pathogenesis. Targeting the perturbed regulator could pave the way for new therapies.

Leukaemia (blood cancer) is a group of malignant and aggressive diseases of the blood-forming cells in the bone marrow. Very intensive chemotherapy and in some cases a bone marrow transplant are the only cure. Like all cancers, leukaemia is caused by changes in the DNA, the heredity material present in human cells in the form of 46 chromosomes. In many forms of leukaemia, large parts of these chromosomes are altered. People with Down syndrome, who have three copies of chromosome 21 (trisomy 21) are highly vulnerable: the risk of developing aggressive Acute Myeloid Leukaemia (AML) in the first four years of their life is more than 100 times greater for children with Down syndrome. Down syndrome is the most common congenital genetic disorder, affecting about one in 700 newborn babies.

RUNX1 transcription factor is responsible

The research group led by Professor Jan-Henning Klusmann, Director of the Department of Paediatric and Adolescent Medicine at University Hospital Frankfurt, has now discovered how the additional chromosome 21 can promote AML. With the help of genetic scissors (CRISPR-Cas9), they examined each of the 218 genes on chromosome 21 for its carcinogenic effect. It emerged that the RUNX1 gene is responsible for the chromosome's specific carcinogenic properties. In further analyses, the researchers were able to corroborate that only one particular variant -- or isoform -- of the gene promotes the development of leukaemia. Klusmann explains: "Other RUNX1 isoforms were even able to prevent the cells from degenerating. This explains why RUNX1 has so far not stood out -- in several decades of extensive cancer research."

The RUNX1 gene encodes a "transcription factor" -- a protein responsible for regulating the activity of other genes. RUNX1 regulates many processes, including embryonic development and early and late haematopoiesis, or blood formation. Disruption of this important regulator is therefore a key event in the development of AML. "Thanks to our research results, we now have a better understanding of what happens in leukemogenesis," explains Klusmann, an expert in paediatric cancer. "The study underlines how important it is to examine all gene variants in carcinogenesis. In many cases, certain mutations in cancer cells alter how these variants form," he says.

Development of more sophisticated therapeutic approaches

These insights are important for a better understanding of the complex mechanisms of carcinogenesis, as Klusmann explains: "In this way, we have laid the groundwork for developing more sophisticated therapeutic approaches. Through our biochemical analyses, we now know exactly how the gene variant alters the blood cells. From there, we were able to use specific substances that block the disease mechanism." The intention now is to further explore the effect of these substances for use in medical care. Klusmann: "On the basis of our expertise, we now want to develop therapies to correct this malfunction. Applying them in clinical practice will certainly take a few more years, but hopefully they will lead in the future to sparing our young patients from intensive chemotherapy."

Coordinated Health Teams May Help Improve Outcomes For Children With ...

A coordinated, multidisciplinary health care team to address the specific physical, psychological and developmental needs of children with Trisomy 21, or Down syndrome, and congenital heart disease may help children with these conditions lead longer and more productive lives, according to a new scientific statement from the American Heart Association.

The scientific statement, "Trisomy 21 and Congenital Heart Disease: Impact on Health and Functional Outcomes from Birth Through Adolescence," published today in the Journal of the American Heart Association, an open-access, peer-reviewed journal of the Association.

Statement highlights include:

Trisomy 21, also known as Down syndrome, is a genetic condition that occurs when a person has an extra copy of chromosome 21. According to the American Heart Association's 2018 scientific statement on the genetic basis for congenital heart disease, Down syndrome is the most common chromosome abnormality, with approximately 5,300 infants born with Down syndrome in the U.S. Each year. About 35-50% of children with Down syndrome are also affected by congenital heart disease.

Around 70% of congenital heart disease conditions in children with Down syndrome present as some type of atrial septal defect or ventricular septal defect of the heart, often referred to as "a hole in the heart."

Pulmonary hypertension and single ventricle heart disease are two known cardiovascular conditions that may reduce life expectancy in individuals with Down syndrome.

Conditions affecting other body systems, including respiratory, endocrine, gastrointestinal, hematological, neurological and sensory systems, may interact with cardiovascular health concerns and lead to adverse effects for children with congenital heart disease and Down syndrome.

Improvements in diagnostic, medical and surgical interventions for cardiovascular disease over the past several decades have resulted in greatly improved survival for infants and children with congenital heart disease including those with Down syndrome. Current research on survival in children with congenital heart disease indicates that more than 97% of children with congenital heart disease can be expected to reach adulthood, highlighting the need for multidisciplinary care throughout their lifetime.

Neurodevelopmental and functional challenges may affect quality of life for children with Down syndrome and congenital heart disease. About 75% of children with these conditions experience feeding and swallowing problems as infants, increasing the risk of malnutrition and failure to thrive, which would affect physical and neurologic development. They also often face lifelong respiratory problems and hypothyroidism (an underactive thyroid; the thyroid produces important hormones that help regulate many functions in the body).

Vision and hearing impairments (sensory processing disorders) are also common among children with Down syndrome and may impact development of language and communication, as well as cognitive and social behavior skills.

Psychological conditions, including autism spectrum disorder, attention deficit/hyperactivity disorder, anxiety and depression, are also common in children with Down syndrome as well as children with congenital heart disease.

Social determinants of health may affect outcomes in children with Down syndrome and congenital heart disease because intellectual limitations and chronic health conditions often contribute to discrimination, bias, inequity, education and socioeconomic status.

Physical, occupational, speech and behavioral therapies are integral in health care plans for children with Down syndrome and congenital heart disease. Early speech intervention is important to improve communication and autonomy, while physical and occupational therapy are focused on strengthening gross and fine motor skills, increasing independence in activities of daily living, and supporting social skills and sensory integration.

A comprehensive "medical home" with primary and specialty care that includes a multidisciplinary team of professionals is advised to support care continuity, family-centered care and advocacy. Effective care coordination improves health care access and reduces delays in care, hospitalizations and health care costs. It can also result in enhanced care satisfaction and improvements in overall health outcomes.

With appropriate support and resources from the multidisciplinary care team, community, school and family, children with Down syndrome and congenital heart disease have opportunities to live fulfilling and productive lives with independence. It is important that the transition to adulthood includes assessment of their needs, skills and decision-making capacity.

Future research focused on reducing the burden of these conditions is needed to improve functional outcomes and quality of life for children with Down syndrome and congenital heart disease.

The statement was written on behalf of the American Heart Association's Pediatric Cardiovascular Nursing Committee of the Council on Cardiovascular and Stroke Nursing, the Council on Clinical Cardiology, the Council on Genomic and Precision Medicine, and the Council on Cardiovascular Radiology and Intervention. American Heart Association scientific statements promote greater awareness about cardiovascular diseases and help facilitate informed health care decisions. Scientific statements outline what is currently known about a topic and what areas need additional research. While scientific statements inform the development of guidelines, they do not make treatment recommendations.

Source:

Journal reference:

Peterson, J. K., et al. (2024). Trisomy 21 and Congenital Heart Disease: Impact on Health and Functional Outcomes From Birth Through Adolescence: A Scientific Statement From the American Heart Association. Journal of the American Heart Association. Doi.Org/10.1161/jaha.124.036214.

Mom Had Three Kids With Down Syndrome, Discovers She Has It Too (Exclusive)

A mom of three discovered that she shares more than just DNA with her three kids — she shares their specific genetic mutation, too.

TikTok creator Ashley Zambelli, 23, went viral after she discovered that not only would she be having a third baby with trisomy 21 — also known as Down syndrome — but she herself had tested positive for the mutation. In a series of videos posted to her TikTok account, the mom of three shared her shocked reaction.

In one video, Zambelli writes, "My geneticist SHOCKED I'm having a baby with trisomy 21 for the 3rd time."

Across her videos, Zambelli shares that she has three children, two of whom have tested positive for trisomy 21. Zambelli experienced a pregnancy loss with a third baby who also tested positive for the mutation. When her geneticist noticed that she was having so many babies with this specific genetic mutation, Zambelli was prompted to get tested herself.

"Finding out I was pregnant with another baby that has trisomy 21 was definitely a shock to all of us," Zambelli tells PEOPLE exclusively. "It's not unheard of to conceive one to two since Down syndrome is, as far as we know, usually caused by a random failed separation of chromosomes during mitosis. But to have more than one or two? That's when this might not be a 'random' mutation."

Zambelli is mom to three young girls, Lillian, Evelyn, and Katherine.

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"Our oldest daughter Lillian has trisomy 21 and we can't wait to see [her and her sibling] grow up together, including our second daughter, Evelyn, who does not have Down syndrome. We are also very excited to see the person Evelyn grows to become since there's just something special about having siblings with Down syndrome."

Asked what inspired her to get herself genetically tested, Zambelli explains that it was actually her OB/GYN that came up with the idea. "She is the one who informed me that it's pretty rare to conceive a child with Down syndrome three times and wrote me a referral to a geneticist to see if I had a chromosomal abnormality."

Once Zambelli was tested, it came back positive for mosaic Down syndrome, or trisomy 21 mosaicism/mosaic trisomy 21.

According to the Stanford Children's Hospital, this form of Down syndrome is diagnosed when there's a mixture of two types of cells. Some have the usual 46 chromosomes and some have 47, which are the ones with the extra chromosome 21 that defines trisomy 21. Although this can cause babies born with mosaic Down syndrome to have similar features to babies with Down syndrome, it is also possible to have few features.

"When I got the call [with the diagnosis], I was happy! I've always had some miscellaneous complications throughout my life that never made sense to doctors, but now they do," Zambelli tells PEOPLE.

Although her kids are too young to understand their diagnoses, her friends and family were happy and supportive of Zambelli. "My friends and family were very surprised with my diagnosis...Everyone was very happy for me and supportive."

In her TikTok videos, Zambelli strives to create an educational platform where she can spread awareness about the genetic mutation. "TikTok has been such an amazing community to be in for spreading awareness of Down syndrome and the three forms of it — trisomy 21, mosaic, and translocation," she says. "All I can do is present the facts, keep spreading awareness, and hope to see a change."

As for the hardest part of her journey? "Encountering some people within the Down syndrome community. There have been a few who do not take me seriously and make me feel as if I need to prove my condition to them," the mom revealed.

"The stigma around Down syndrome unfortunately exists in our own community. I'm hoping that will change soon for the better."

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