ARTICLE IN BRIEF
The outcome of the Charlie Gard case, in which his parents fought (unsuccessfully) for an experimental treatment for their baby with a mitochondrial DNA depletion syndrome, elicits discussion among pediatric neurologists about how they deal with families of children with these nearly always fatal, progressively neurodegenerative disorders.
On July 24, the legal battle over the treatment of terminally ill British baby Charlie Gard, who suffered from an inherited mitochondrial disease, came to an end when Charlie's parents withdrew their request to the British courts to allow them to transport him to the United States for an experimental treatment.
Mitochondrial disorders overall are not particularly rare; the estimated birth prevalence of inherited mitochondrial disorders is greater than one in 5,000 births, making them more common than other inherited myopathies, like Duchenne muscular dystrophy or myotonic dystrophies.
But mitochondrial DNA depletion syndromes (MDDS), a group of autosomal recessive disorders that involve a lack of functioning DNA in mitochondria and result in impaired energy production in affected tissues and organs, are extremely rare. The most “common” of these syndromes, TK2 (thymidine kinase 2)-related MDS, had been reported in approximately 50 known individuals, according to a 2013 scientific review in the journal Neurotherapeutics.
Charlie's condition, an encephalomyopathic form of MDDS that involves the ribonucleoside-diphosphate reductase subunit M2 B (RRM2B) mutation, was exceptionally rare. Prior to his case, only about 15 infants had been reported to have the RRM2B-mutation form of MDDS. The fact that he survived as long as he did — Charlie was a week short of his first birthday when he passed away on July 28 — was also exceptional: In a 2008 review of seven infants with RRM2B-related MDDS, all died before they reached 4 months of age.
“Mitochondria, of course, are the power plants of the cell, and each mitochondrion has about five to 10 copies of mitochondrial DNA,” explained Bruce H. Cohen, MD, FAAN, director of the NeuroDevelopmental Sciences Center at Akron Children's Hospital and a specialist in metabolic and mitochondrial diseases. “Through an array of well-balanced control mechanisms, they maintain the proper amount of that DNA. But when these mutations occur, the copy numbers of mitochondrial DNA decline, so they can't make enough mitochondrial proteins and the mitochondria just don't function.”
“This particular mutation affects the brain, liver, heart and muscles,” Dr. Cohen said. “Although the press primarily talks about the brain and the muscles, these children typically die of heart and liver failure. You may have a rescue therapy that could save the brain, heart, liver and eyes, and pull a person back from an irreversible state of decline. But when you go past a certain point, symptoms develop that can no longer be reversed.”
While Charlie Gard's story was unusual in that it garnered international press attention, including input from the Pope and the US President, the painful, complex decisions faced by Charlie's parents — and the medical team at London's Great Ormond Street Hospital that treated him — are a regular occurrence in Dr. Cohen's program, and in others focused on mitochondrial diseases.
HOW TEAMS WORK WITH FAMILIES
How do these expert teams work with families when, as in Charlie's case, there is disagreement over how and whether to pursue further treatment?
“I think for me personally, I feel that miracles do occur, and that parents actually do know best in most circumstances,” said Dr. Cohen. “I've had plenty of parents say to me, enough is enough, let's keep our child comfortable, I'm not going to put them through any more. We get them into palliative care programs and hospice programs quickly, and we focus on quality of life and keeping the child free of anxiety and free of pain. Other, equally loving families say, that's not what I'm about. I want my child alive, and I'll go to the ends of the earth to do that. So we push forward.”
He described the case of one young woman he had cared for since childhood whose stable mitochondrial disease had suddenly gone into extreme lactic acidosis. “In two days, she went from baseline to the ICU. I had an experimental mitochondrial therapy I could offer her, and we were in the process of getting her on therapy when she died.”
In this patient's case, although she was a young adult, the parents still made the decision to pursue the therapy as her condition rendered her unable to consent. “It's what they wanted and what they felt she would want, so we pushed forward,” said Dr. Cohen. “You could look back as a skeptic and say we put her through undue pain and suffering. But it's what we as a team felt was the right thing to do in that situation.”
The team-based, patient-centered approach is particularly important in managing patients with mitochondrial disease. “We have to take a team approach with the family, and not put our own personal feelings about when enough is enough onto them,” Dr. Cohen said. “Some physicians aren't up for that. If you're dogmatic about your feelings about this sort of thing, this isn't the type of medicine for you.”
Aneal Khan, MD, is a medical geneticist specializing in inborn errors of metabolism at the University of Calgary and the Alberta Children's Hospital; in early 2017, he led the team that provided the world's first genetic therapy for Fabry disease. He agrees with Dr. Cohen.
“The first principle we use in working with these families is that it is not our child. It is the family and their child. While we as the physicians, social workers, and nurses are all involved in looking after the child, no one is going to face the impact of the decision the way that the family does.”
For rare mitochondrial disorders like Charlie's, experimental therapies may be a patient's only possibility of access to treatment. That was what his parents had hoped for in applying to bring Charlie to the United States, where Michio Hirano, MD, FAAN, chief of the division of neuromuscular disorders at Columbia University Medical Center, had originally offered to treat the baby using an experimental nucleoside bypass therapy that had had some success in a boy with a related, though different, mitochondrial depletion disorder.
After examining Charlie personally in the UK, and reviewing his scans, Dr. Hirano determined that his condition had deteriorated to the point that he was unlikely to benefit from the treatment. (Dr. Hirano did not respond to a request from Neurology Today for an interview.)
“Depending on the child's condition, there may be reasonable evidence that there might be an impact from an experimental therapy,” said Dr. Khan. “But one does need to consider what the child will need to go through and what the parents' hopes and fears are in pursuing that course of action. Many experimental therapies can involve painful procedures, and a high degree of uncertainty, and things that might work in the lab don't necessarily work in people. That all needs to be taken into consideration, but we try to make a decision with the family together. That usually leads to an outcome with less conflict.”
This discussion occurs in an extremely fraught environment, as families of children with mitochondrial disorders are usually processing multiple losses in an impossibly short period of time.
“They are facing the loss of the kind of life they've planned and imagined for their child, as well as the loss of the child,” said Melissa Walker, MD, PhD, director of the Massachusetts General Hospital Pediatric Mitochondrial Disorders Clinic. “So I try to give them as much time as possible and review information about the diagnosis in different ways, preferably during multiple outpatient or inpatient visits. It is difficult to imagine that any person would be able to know the ‘right’ questions to ask, let alone process the answers in moments of anguish.
“With this in mind, I start with the assumption that nothing is known about the biology of the disease before our conversation and do my best to provide accurate material that can be easily read. I also try to put families in contact with the appropriate support/advocacy groups, social work, as well as the wonderful palliative care team my institution is fortunate to have, when appropriate. I always make sure a follow up is planned in either setting before ending the visit and reach out to the family shortly after the first discussion.”
Dr. Khan said that it is also important to address the issue of what constitutes a truly meaningful improvement. “An experimental therapy may offer a person with a muscle disease the ability to twitch their hand, but never move it intentionally — is that a meaningful improvement? Or if a drug improves levels of a certain substance in the blood, but the brain doesn't function any better — is that meaningful? As a parent, you might want to continue to try things, hoping that they will work. But if you have a situation where on a brain scan there's hardly any brain left, and it's been replaced by fluid, no therapy can turn that around. We have to look at the stage of the disease and what results are available from the experimental treatment, and whether there's any meaningful improvement that can take place, and put all that into context.”
Most of the time, these situations are difficult and painful, but do not result in the kind of open conflict that played out in the media over Charlie Gard. But the experts consulted by Neurology Today acknowledged that they have faced situations in which the care team and the family found themselves in opposition.
“As humans, sometimes we run into situations where it may seem difficult to move forward together and people get their backs arched,” said Dr. Khan. “That can result in people challenging any number of things that come forward and wanting things done their way. That can happen on both sides. And as caregivers, we must understand that this is not something that you provide through a lecture or a small series of meetings; it's something you have to come to appreciate through lots of dialogue, lots of questions, showing the parents results of tests and scans, and explaining what is possible and what is not possible. In my experience, eventually those conflicts were resolved, but not in the time frame of somebody's shift, or even a week or two weeks or a month in the hospital.”
On the question of futility of treatment, Dr. Cohen pointed out that “tilting at windmills” is what he and his colleagues got into the mitochondrial disease field to do. “We're taking diseases like the one Charlie has — including a current trial in Leigh syndrome, which is often fatal before the age of 10 — and giving new drugs to try to change the course of the disease. I wouldn't be able to be in this field if I accepted that these fatal diseases were always going to be fatal,” he said.
“I'm 61 years old, and pretty much anyone older than 40 was taught that diseases like spinal muscular atrophy and Duchenne and mitochondrial diseases were incurable. It was just a matter of time. And now we have therapies that are effective. So we do need to put down our old notions about what incurable really means. We are now entering the most exciting phase of medicine ever, as we have the technology to start tackling these diseases. It's not the time to give up and say I'm just going to go with the flow.”