Wednesday, November 15, 2017

Grappling with hope and futility in mitochondrial disease

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…

“This particular mutation affects the brain, liver, heart and muscles,” Dr. [Bruce] 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.”…

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.”…

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.”…

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….

“As humans, sometimes we run into situations where it may seem difficult to move forward together and people get their backs arched,” said Dr. [AnealKhan. “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.

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