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http://quest.mda.

org/article/mitochondrial-disease-research-talk-michio-hirano
MNGIE: Mitochondrial disease that starts in nuclear DNA
In 1988, Hirano was in a neurology training program (residency) at Columbia University.
He remembers the day that year when he and other neurology residents were introduced to two new patients, a
brother and sister, both in their 40s and neither weighing more than 90 pounds a result of abnormalities of the
gastrointestinal tract. They both had peripheral nerve abnormalities, droopy eyelids and unusual features in their
muscle biopsy samples that suggested malfunctioning mitochondria.
Their disorder seemed like a mitochondrial defect that had been described the previous year calledMNGIE
syndrome (for mitochondrial neurogastrointestinal encephalomyopathy, denoting abnormalities in the nervous
system, gastrointestinal tract, brain and muscles).
But something didnt fit. Disorders resulting from mutations in mitochondrial DNA are inherited through the maternal
line. (Mitochondria from the egg, but not the sperm, contribute to a developing embryo at conception.) Mothers who
transmit mitochondrial disorders often have symptoms of these disorders themselves, although they rarely recognize
them as such.
But neither parent of the siblings with suspected MNGIE syndrome had symptoms, suggesting that the disease might
be inherited in an autosomal recessive pattern, in which both parents are carriers and children who inherit a mutation
from each parent develop the disorder. Autosomal recessive disorders originate in nuclear DNA, not mitochondrial
DNA.
MNGIE, it appeared, might be a type of disorder that in 1988 had not yet been recognized a disease in which
mitochondrial malfunction is due to a mutation in a gene in the nucleus of the cell.
Hirano and a small group of colleagues sought out families with MNGIE. We identified a family in Brooklyn in which
four of the eight children were affected, he recalls. And then through that family and three others, we were able to
map the gene to chromosome 22 [in the nucleus] in 1998.
It was one of the first mitochondrial diseases to be linked to a nuclear chromosome. (A nuclear gene mutation
for Leigh syndrome, identified in 1995, was the first.)

Thymidine phosphorylase deficiency causes MNGIE


In 1999, in a study funded in part by MDA, Hirano and two colleagues pinpointed mutations in the gene for
the thymidine phosphorylase enzyme as the root cause of MNGIE.
A postdoctoral fellow from Japan found the gene, Hirano says, graciously giving credit for the discovery to Ichizo
Nishino, who was working in his Columbia University lab at the time.
Thymidine phosphorylase is present in most types of cells, where it breaks down thymidine and deoxyuridine.
Without this essential enzyme, these two substances build up to toxic levels, poisoning mitochondria.
To make matters worse, thymidine phosphorylase deficiency also results in a shortage of the building blocks of
mitochondrial DNA, resulting in mitochondrial DNA deletions (missing pieces of genetic material).

Patients with MNGIE have less than 10 percent of normal thymidine phosphorylase activity, Hirano says. The
disease usually starts in the late teens, progresses for about two decades and results in death at an average age of
38.

Platelet transfusions: A temporary MNGIE fix


We knew the thymidine phosphorylase enzyme was abundant in platelets [a type of blood cell], Hirano says. They
also knew that platelet transfusions had been used for years to treat other conditions, such as platelet depletion
caused by cancer drugs. Why not, Hirano thought, see what platelet transfusions could do for MNGIE patients?
We gave platelets to two patients, Hirano says, and it restored enzyme activity transiently, for two to three days
after each infusion.
The small study, which had MDA support, gave the scientists the needed proof of principle that infused platelets
could take in thymidine and deoxyuridine from the bloodstream and break them down into harmless byproducts. But
clearly a longer-lasting treatment was necessary. Hirano and his colleagues decided to try transplanting stem cells to
see if they could provide the needed thymidine phosphorylase for a much longer period of time.

Stem cells offer longer-lasting relief


In 2005, Hirano infused stem cells from umbilical cord blood into a young man with MNGIE, hoping they would
engraft into his bone marrow and continuously give rise to circulating blood cells, supplying a longer-lasting treatment
than infused platelets could provide. Unfortunately, however, the donated cells failed to engraft.
The second individual was a young woman with MNGIE whose brother donated bone marrow stem cells, which, once
again, the researchers hoped would incorporate into the bone marrow and supply long-term thymidine
phosphorylase.
She was 5-feet-2 inches tall and weighed 55 pounds, Hirano says of the first woman to receive stem cells for
MNGIE. We did the transplant in October 2005, and a month later, 60 percent of the blood cells in her peripheral
[circulating] blood were from the donor. A year later, it was 100 percent, and the thymidine phoshorylase activity was
good.
Slowly, the young woman began to show improvement. She got stronger, was able to stop her intravenous feedings
and resume eating. She gained five or 10 pounds and even returned to work, Hirano says, smiling.
Six-and-a-half years later, shes doing OK, he says proudly She comes to see us every May. She can run and jump
now. So far, she has not needed any further infusions of stem cells.

Hoping to improve stem cell procedure


Since those first two stem cell transplants, 24 more people have undergone the procedure at Columbia University
10 remain alive, which is encouraging, considering that MNGIE is a fatal disease.
All had biochemical improvement, and some showed clinical improvements, Hirano says. Weve since held two
international meetings at which we developed a protocol that we hope will maximize the safety and efficacy of bone
marrow stem cell transplants in MNGIE, Hirano says. Were planning to conduct a study soon to test the new
protocol.
(See a video from the Mayo Clinic called How a Stem Cell Transplant Works.)

Treating other mitochondrial disorders


MNGIE is an unusual mitochondrial disease, because the missing thymidine phosphorylase protein can be supplied
by blood cells. In this situation, the blood cells act like miniature dialysis machines, cleansing the blood of substances
that would otherwise build up and become toxic to mitochondria.
But for most mitochondrial disorders (as well as many other genetic conditions), supplying a protein via blood cells
wont help.
To treat most mitochondrial muscle diseases (mitochondrial myopathies) or mitochondrial muscle and brain diseases
(mitochondrial encephalomyopathies), a therapeutic gene or protein would have to be delivered to muscle or nerve
cells.

One way to get a cell to make a protein it hasnt been producing is via gene therapy, an approximately 30-year-old
science in which new DNA is inserted into cells.
That strategy is being investigated for many genetic diseases in which the defect is in nuclear DNA,
including Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy. And, putting a functional
gene into the cell nucleus is a viable strategy in mitochondrial diseases that are caused by mutations in nuclear DNA,
such as MNGIE, some forms of Leigh syndrome and some forms of progressive external ophthalmoplegia (PEO).
But for some mitochondreal disorders, getting a gene into the nucleus is only part of the challenge. Further steps
must be taken in disorders where the defect is in mitochondrial DNA, such as Kearns-Sayre syndrome
(KSS), maternally inherited Leigh syndrome (MILS), mitochondrial encephalomyopathy, lactic acidosis and
strokelike episodes (MELAS), myoclonus epilepsy with ragged red fibers (MERRF), neuropathy, ataxia and
retinitis pigmentosa (NARP), Pearson syndrome and some forms of PEO.

Correcting mitochondrial gene defects


So far, no one has figured out how to get DNA into human mitochondria, Hirano says. But in 2002, researchers at
Columbia and elsewhere, with partial support from MDA, showed they could use current nuclear gene therapy
methods to correct a mitochondrial gene defect.
Knowing that a mutation in a mitochondrial gene called ATPase 6 causes two devastating mitochondrial disorders
MILS and NARP these investigators reasoned that they might be able to convert a functioning mitochondrial
gene into a nuclear gene that would produce a protein that could be delivered to mitochondria.
The genetic code in mitochondrial genes is slightly different from that of nuclear genes, so the researchers first had to
do the mitochondrial-to-nuclear code conversion. Then, they had to attach an additional code to notify the cell to
insert the protein into the mitochondria.
They succeeded in doing both, finding that human cells with a mutation in the mitochondrial gene for ATPase 6 were
restored to health by the therapy.
The cells were in a laboratory dish not in animals or people but the strategy is sound and could be further
developed and applied to other disorders of mitochondrial DNA, Hirano says.
Thus, it may not be necessary to put DNA into mitochondria if mitochondrial genes can be modified and inserted into
the nucleus and generate proteins that can be imported into the mitochondria.

Registry is first step toward better treatments


For now, Hirano says, most people with mitochondrial diseases cant be treated with genes or proteins that correct
fundamental defects in energy production. However, there are a number of supportive therapies from cardiac
pacemakers and even cardiac transplants, to seizure-controlling medications, to surgeries to lift droopy eyelids, to
nutritional supplements like coenzyme Q10 that help some people.
But Hirano knows that isnt really enough, and therefore, hes joined with his colleagues in mitochondrial disease
research to create the North American Mitochondrial Disease Consortium (NAMDC). A member of the Rare Diseases
Clinical Research Network sponsored by U.S. National Institutes of Health, the networks ultimate goal is to conduct
clinical trials in mitochondrial disease.
But crucial first steps are establishment of a patient registry database, in which information about these disorders will
be recorded; and the collection of tissue and blood samples from people with mitochondrial diseases for research
purposes.
The registry, which protects personal data from unauthorized access, allows people with mitochondrial disorders to
be notified about clinical trials for which they may be eligible and provides periodic updates about research in the
field.
To learn more about the NAMDC and the privacy-protected registry, visit the Rare Diseases Clinical Research
Network NAMDC registry.
We need more data, Hirano says. We want to revolutionize how we approach these diseases.

RESEARCH THEME: Mitochondrial and Other Neuromuscular Diseases Using molecular genetic techniques, my
laboratory focuses on identifying the causative mutations in neurogenetic diseases and on elucidating how the mutations
disrupt normal cellular functions. For more than ten years, I have been studying a rare inherited mitochondrial disease called
mitochondrial neurogastrointestinal encephalomyopathy or MNGIE, a fatal degenerative disease characterized by impaired
eye movements, severe gastrointestinal symptoms leading to weight loss, and degeneration of motor and sensory nerves.
We identified causative mutations in the gene encoding thymidine phosphorylase in MNGIE patients. In this disease, loss of
thymidine phosphorylase activity leads to toxic accumulations of molecules that lead to damage in mitochondrial DNA. We
are testing potential therapies for this disease. We also identified causative mutations for Danon disease and deficiency of
coenzyme Q10. We are currently looking for mutations that cause specific types of muscular dystrophy. I am collaborating
with Drs. Hiroshi Mitsumoto, Paul Gordon, and Ali Naini who are looking for a genetic modifier that seems to make women
more likely to develop amyotrophic lateral sclerosis in a family with an unusual mutation in superoxide dismutase 1 (SOD1).
BACKGROUND AND EDUCATION : Michio Hirano is an Associate Professor of Neurology and Co-Director of the Columbia
Muscular Dystrophy Association clinic (Dr. Hiroshi Mitsumoto, Director). He received his M.D. from the Albert Einstein
College of Medicine and did his internship at the affiliated Bronx Municipal Medical Center. He did his Neurology Residency
at Columbia-Presbyterian Medical Center and was a Chief Resident in his last year. He did a neuromuscular research
fellowship under Drs. Salvatore DiMauro and Eric Schon at the H. Houston Merritt Clinical Research Center at ColumbiaPresbyterian Medical Center where he became an Assistant Professor of Neurology in 1992.

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