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. [Aneal] 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.
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