Charlie Gard Case Captures Vast and Unmet Needs of People with Mitochondrial Disease, Groups Say

The case of Charlie Gard — a baby in the U.K. with a terminal mitochondrial disease who ended up in a legal feud over continuing life support — illustrates the need for more research and awareness of mitochondrial diseases, three non-profit organizations working with such diseases wrote in a letter provided to Mitochondrial Disease News.

The call for action, which was also sent out to major U.S. newspapers, was authored by MitoAction, the Foundation for Mitochondrial Medicine, and the United Mitochondrial Disease Foundation (UMDF) and underscores that, while each specific case of mitochondrial disease is rare, mitochondrial diseases as a group are, indeed, common.

“Charlie’s genetic mutation of mitochondrial deletion may be rare, but mitochondrial disease is not — approximately 1 in 2,500-5,000, adults, teens and children are affected, making mitochondrial disease more common than childhood cancers,” the letter reads. Its stated intention is to expand the conversation concerning Charlie Gard to a broader discussion of the need for more research.

A baby’s plight

Charlie Gard, 11 months old, was born with genetic mutations in a gene called RRM2B. This gene produces an enzyme, which, in turn, makes a building block needed to synthesize DNA in his cells’ mitochondria — the powerhouses that fuel all tissues with energy.

Since Charlie lacks this component, his mitochondria are unable to make DNA, causing what is known as encephalomyopathic mitochondrial DNA depletion syndrome (MDDS). Encephalomyopathic means that the lack of mitochondrial DNA has caused both brain damage and muscle weakness.

As brain and muscle are the two tissues that require the most energy, they are often affected in cases where mitochondria fail to produce enough energy. Charlie’s doctors, however, say that other organs are also affected by the disease.

In Charlie’s case, the damage is extensive. He is no longer able to move, keep his eyes open, or breathe for himself. He also has extensive brain damage, according to his physicians at the Great Ormond Street Hospital (GOSH), where he is being given care.

In April, GOSH physicians agreed there was nothing more they could do for Charlie, and recommended that life support — the ventilator, which helps Charlie to breathe — be removed, allowing him to “die with dignity.” As the boy’s parents objected, GOSH asked the High Court for an opinion — a standard procedure in cases where doctors and families do not agree on future care.

The parents — Connie Yates and Chris Gard of London — wanted doctors to try an experimental treatment in an attempt to save Charlie’s life. The treatment is commonly called nucleoside therapy, and GOSH physicians had earlier considered the treatment for Charlie, according to an article by BBC News.

But while legal procedures to obtain an ethics permit for the experimental therapy were ongoing, the child deteriorated to the degree that physicians no longer thought such an effort would be of benefit. Brain damage, which doctors say is now at a cellular level, was reported to have particularly influenced this decision. The damage is both severe and irreversible, the doctors said.

On April 11, after processing the case for more than a month, Justice Nicholas Francis of the High Court ruled that Charlie’s life support could be switched off. A long and still-tangled legal battle began.

Charlie’s parents turned to the Court of Appeal, asking that the verdict be reconsidered. But on May 25, the appeal was dismissed. Days later, the Supreme Court agreed to consider the case; then, in a June 8 ruling, its justices sided with earlier decisions that Charlie be allowed to die with dignity.

The couple’s lawyers next submitted the case to the European Court of Human Rights. But after a week of consideration, the European Court judges stated they would not intervene in the case, as they considered that further treatment would “continue to cause Charlie significant harm.”

Meanwhile, Pope Francis, soon followed by President Donald Trump, offered to treat the child in hospitals at the Vatican or in the U.S. with the experimental treatment Charlie’s parents are advocating for.

The couple has raised funds of more than £1.3 million (about $1.7 million) to afford the treatment, and public support for the case is mounting, with several websites, including a Facebook page, set up to spread awareness.

The Pope considered offering the child a Vatican passport to allow the treatment, according to The Sun. Meanwhile, two U.S. congressmen have raised the prospect of making Charlie an American citizen to enable treatment.

But U.K. legal rulings prevent the child from being moved, according to a BBC article, which also stated that GOSH denied the parent’s final wish to take Charlie home to die. GOSH confirmed that decisions by various legal institutions prevented Charlie from leaving the hospital in a July 7 statement.

“Great Ormond Street Hospital is bound by the ruling of the High Court which expressly forbids us from transferring Charlie for nucleoside therapy anywhere. This ruling has been upheld by the Court of Appeal, the Supreme Court and the European Court of Human Rights,” the statement reads.

It also notes that independent medical experts agree that attempting nucleoside therapy is “unjustified … futile and would prolong” Charlie’s suffering. “This is not an issue about money or resources, but absolutely about what is right for Charlie,” the GOSH officials wrote.

Meanwhile, the parents circulated a petition, now signed by 490,000 people, calling on GOSH to allow the baby to travel. “We don’t want him in the ground, we want him riding a bike,” they argued, according to The Sun.

As researchers from two international hospitals contacted GOSH with more information about nucleoside therapy, the hospital again turned to the High Court. Doctors said the information had not changed their opinion regarding turning life support off for Charlie, but they agreed to a High Court reconsideration of the therapy in this case.

In a hearing on Monday, July 10, the parents were given two days to provide new evidence to the High Court supporting nucleoside therapy at a U.S. hospital. But according to The Guardian, Justice Francis — who ruled in GOSH’s favor in the court’s initial April hearing — said the evidence needed to be “drastic” for him to reconsider.

The case, meanwhile, is increasingly bitter and fraught — with Charlie’s parents accusing the hospital of lying. Charlie’s mother claimed that GOSH’s measurements of the boy’s head — which can signify a working brain if enlarging, which they reportedly are not — were wrong, and the court ordered an independent measurement.

The hearing was continuing today, July 13, although the parents reportedly left the hearing after a dispute with the judge.

The High Court is expected to issue a final decision by day’s close.

Nucleoside therapy

What exactly is the therapy that Charlie Gard’s parents are fighting for him to receive?

Nucleosides are components of DNA. Charlie has a faulty gene that prevents the production of a nucleoside — rendering DNA synthesis inside his mitochondria insufficient and causing his mitochondrial DNA depletion syndrome.

Without DNA, the mitochondria — the only cell structures that hold their own DNA — are not able to produce energy, leading to organ failure.

The treatment, which is given orally, supplements the lack of building block or blocks by delivering them to mitochondria in an appropriate form. The nucleoside is given in a form that prevents it from being degraded in the gut. Earlier studies in similar conditions showed that such nucleosides do enter mitochondria, even within the brain, in experimental animals.

The treatment has been used on a number of children, but none with the same type of mitochondrial depletion syndrome as Charlie.

The syndrome can be caused by mutations in several genes that help mitochondria produce DNA, and depending on the type of mutation, the treatment needs to deliver the right type of missing nucleoside — or DNA building block.

But the form that Charlie has, caused by mutations in the RRM2B gene, was only recognized in 2007. Nucleoside therapy has not been tested for this particular defect in a child, not even in mice.

So why do physicians differ as to whether the treatment may help Charlie?

GOSH physicians say that his brain damage will not be reversed by the treatment — which is, experts agree, in no way a cure.

But other doctors, including a group in Italy who sent a letter to GOSH, think that experimental evidence from similar conditions supports the idea that the treatment might help Charlie.

At Thursday’s hearing in the High Court, the lawyer for Charlie’s parents cited statements from experts, including one in the U.S. who said there is a 10 percent chance of “meaningful improvement” in muscle strength and brain function, The Guardian reported.

Yates interrupted the court to ask of the judge:“10%. You would if it was your son, wouldn’t you?”

Another expert claimed a 90 percent chance of the treatment entering the brain, and a 56 percent chance of it allowing muscle recovery, while yet another put the likelihood of brain penetration at 100 percent and the chance of increasing DNA in mitochondria at 60 percent.

How children who received this experimental treatment have fared has not been a large part of the debate so far, but the U.S. parents of one such child are supporting Charlie’s case.

Their son was born with a type of mitochondrial depletion syndrome caused by a mutation in the TK2 gene and, according to a Sun article, since the treatment is steadily improving — now being able to stand, smile, and communicate in a basic way.

A plea for more research, better treatments

But the highly varying views of medical professionals illustrate that there is, really, very little known about the treatment in Charlie’s case — beyond educated guesses.

The letter from the three non-profit organizations seeks to steer the debate about Charlie Gard and his potential treatment in a more productive direction. It places the spotlight on the vast need for more research into mitochondrial conditions, as well as more awareness of the disease in the public sphere.

Since mitochondrial disease can be caused by numerous genetic or molecular factors, patients display a wide variety of symptoms. This makes treatments “frustratingly basic,” its writers argue, “consisting mostly of supportive care that focuses on symptom management and the prevention of complications.”

Cellular powerhouses are not only implicated in “pure” mitochondrial diseases, but also likely play a role in the development of conditions as disparate as autism, Parkinson’s and Alzheimer’s, as well as some cancers.

“Research centered on the mitochondria has the potential to be the Holy Grail of medicine,” the letter states.

Whatever its outcome, Charlie Gard’s case illustrates the lack of knowledge and awareness that are essential for treatment-oriented research to move forward. The varying symptoms of mitochondrial disease also require researchers, pharmaceutical companies, and physicians to work together across specialties, its writers state.

Nonprofits are already forming partnerships to “maximize” this work, they say, but so much more is needed.

“Treatments cannot come quickly enough to help Charlie and the many other adults and children across the globe struggling every day with mitochondrial disease,” the letter concludes.