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.)
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.
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.
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.