Anemia in the pediatric patient

Why Rare Genetic Diseases Are Not So Rare In India

Thousands of years of endogamy may have shaped genetic disease risk in India. Scientists are now trying to identify those risks in communities

In a crowded lab at the Centre for Cellular and Molecular Biology (CCMB), Kumarasamy Thangaraj points to a machine rotating test tubes that contain tissue from an animal model. The process is one step in a months-long study of a genetic mutation recently discovered in a small South Indian community. The variant, when carried by both parents, can lead to a fatal disease in the child.The mutation likely emerged in an ancestor's genes thousands of years ago, says Thangaraj. And, because they kept marrying within their group, the variant persisted.

Scientists Use DNA From Three People To Protect Babies From Rare Disease

Mitochondria are commonly known as the "powerhouse of the cell" and produce energy required for major parts of the body to function. However, small mutations in mitochondrial DNA can affect tissues with high-energy demands such as the heart, muscle, and brain, causing devastating disease and, in some cases, death.

Mitochondrial DNA is inherited from the mother, and although males can be affected, they do not transmit the disease, researchers said. About 1 in 5,000 babies are born worldwide each year with mutations that can cause the disease, researchers said.

Now, scientists have detailed how an IVF technique called pronuclear transfer has been used to combine the DNA of three people to reduce the risk of mitochondrial disease being passed down the generations, in accompanying studies published in the New England Journal of Medicine on Wednesday.

The technique uses 99.9 percent of the DNA from a man and woman, with another 0.1 percent from a second woman's donor egg. It works by transplanting the nuclear genome of an egg from the mother with the condition — which contains genes essential for individual characteristics like hair color and height — to an egg donated by an unaffected woman that has had its nuclear genome removed, researchers said.

The resulting embryo inherits nuclear DNA from its two parents, but the mitochondrial DNA comes from the donated egg, researchers said. The treatment was offered to certain women at very high risk of passing on serious mitochondrial disease, in accordance with UK regulations that assess each application for the procedure on a case-by-case basis.

The eight infants — who range in age from newborn to over 2 years old — were assessed to be healthy, meeting developmental milestones and reported levels of mitochondrial disease-causing mutations that were undetectable or at levels unlikely to cause disease, the Newcastle University statement said. Three of the babies had levels of disease-causing mitochondrial DNA mutations of up to 20 percent, which is still below the 80 percent threshold for clinical disease, it added.

Doug Turnbull, a neurologist at Newcastle University who co-wrote the study, said it was the first to document a "cohort" of children who had received the treatment. He said it is the result of an extremely cautious approach by scientists and regulators that has been more than two decades in the making.

"People have used very similar techniques, but nobody's quite used this particular technique," he told The Washington Post in a phone interview Thursday. "It's just absolutely critical when you're doing a new technique to be cautious and to make sure … it's as safe and efficient as possible."

The procedure has also raised concern from some, including religious groups, about its ethics and the fear that it could open the door to further genetic modification.

Peter Thompson, chief executive of the Human Fertilization and Embryology Authority, which regulates the process in Britain, said that only people with a "very high risk" of passing on a serious mitochondrial disease are eligible for the treatment and that every application is assessed individually. As of July 1, 35 patients have been granted approval by UK authorities to proceed with the treatment since it was first licensed in 2017.

"These robust but flexible regulatory processes allow the technique to be used safely for the purposes that Parliament agreed in 2015," Thompson said in a statement in response to Wednesday's news.

Scientists have cautiously welcomed the findings, while stressing the importance of long-term monitoring and raising the prospect of whether the procedure offers advantages over embryo screening for genetic disease. Others have raised the issue of cost in the long-term project that is supported by Britain's National Health Service and medical charity the Wellcome Trust, among other groups.

Mary Herbert, who is professor of reproductive biology at Newcastle University and lead author of the research paper, said "the findings give grounds for optimism" but further research is needed to "bridge the gap" between reducing risk of mitochondrial disease and preventing it.

Turnbull said the team is also looking to improve medical techniques and follow up with the children involved for as long as possible to track their health outcomes. He said researchers are offering health assessments for five years, but it "would be lovely to be able to follow them up much longer."

Joanna Poulton, a professor in mitochondrial genetics at the University of Oxford, who was not involved in the research, said "time will tell" whether the treatment results in "dramatic clinical advance."

The births come amid a wider boom in genomic sequencing and IVF start-ups that have sparked a wider debate about the ethics and science behind embryo screening and genetic preselection.

In the United States, those undertaking IVF typically test for rare genetic disorders stemming from a single gene mutation, such as cystic fibrosis, or chromosomal abnormalities such as Down syndrome. The use of donor mitochondria, however, is not permitted under US regulations. In Britain, the creation of babies using DNA from three people was first made legal in 2015, hailed for its ability to prevent serious disease being passed on.

Raising Awareness About Rare Diseases - Fairfaxtimes.com

Khartik Uppalapati is a student at Oakton High School. He is also the founder of RareGen, a non-profit that advocates for people with rare genetic diseases. His work has won him a Princeton Prize in Race Relations.  

The work he is doing and the prize are personal for Uppalapati. At the height of the COVID-19 pandemic, when he was  12, he was diagnosed with lymphedema, a rare liver disease, and arteriovenous malformations of the hip. Getting diagnosed, finding consistent medical care, and connecting with others to talk to about it was hard.  

"At first, it was a very difficult experience because there weren't that many support groups or resources, especially during the world's largest global health event in recent times. So, out of that experience, I started networking with other people who had rare diseases in their youth, particularly teens," said Uppalapati.  "We all noticed that we have these really severe conditions. COVID makes our  symptoms even worse, and we feel really isolated."  

He talks about how these diseases often suppress a person's immune system. A condition that makes it easier for immunocompromised individuals to catch COVID or other common diseases and can extend recovery time.  

The pandemic also made it difficult for people with rare diseases to receive in-person patient care. Face-to-face care was often replaced by telehealth, which is less accurate and effective. Specialist referrals were also harder to come by.  

Uppalapati attended the Summit of the Future at the United Nations last summer in New York.

Khartik Uppalapati

His struggle pushed Uppalapati to start RareGen, the world's largest solely youth-led coalition of rare disease patients. He believes that focusing on youth leadership is essential. He noticed an age gap between the people who developed rare diseases, who are often diagnosed under age 25, and the professors and doctors who create policy.  

"We were really shocked at this disparity. We wanted to be the ones bridging this gap and then providing a spot for people with rare diseases who are in their youth, who are actually experiencing the symptoms, to advocate for themselves and speak out on what they're experiencing," said Uppalapati. 

RareGen began to examine the intersection of rare diseases and variables like race, gender, and climate policy. The goal was to develop a more comprehensive view of what needs to be addressed within the rare disease community.  

"There are problems that exist within the medical system for both rare diseases and race, where patients aren't prioritized. The mechanisms by which that happens are very similar. Oftentimes, the doctors just don't have the resources to  deal with the problem," said Uppalapati  

He explained that, in addition to pressures from medical debt, these families don't have the same financial resources as other demographics. This means they can't afford even small aspects of patient care, which he said are vital.  

The Princeton Prize in Race Relations committee recognized RareGen's research on the intersection of race and rare diseases. Each year, Princeton awards a set number of regionally based prizes. This year, 25 winners were selected from 4,000 entries. Uppalapati received $1,500 to use for RareGen research and advocacy. He was invited to speak at a Princeton symposium next week.  

Uppalapati no longer feels isolated. He said working to spread information about rare diseases has given him purpose.  

"Over time, I've been able to manage my symptoms, but then also grow into the advocacy part of rare diseases, and realizing that I'm not alone. I'm not the only person who has a rare disease," said Uppalapati. He explained that more people, even those without rare diseases, are becoming involved in rare disease advocacy. Uppalapati said this is because rare diseases are a health issue that people generally agree needs attention, unlike more divisive topics.

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