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Mitochondrial disease strikes at the cellular level, hitting children hardest

By Scott LaFee
June 26, 2008
UNION-TRIBUNE STAFF WRITER

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At 8 months old, Mikey Tighe suffered an unexplained seizure but recovered. Over the next two years, the Spring Valley boy got every kind of test imaginable, said his mother, Grace. Everything came back negative. Then, just before his third birthday in 2005, Mikey went into severe respiratory distress, unable to breathe. Again, he recovered, but no cause was found. Less than a year later, he had a second mysterious respiratory attack only worse. Doctors were flummoxed. His symptoms fit no obvious disease or diagnosis. This time, Mikey didn't recover quickly. He slipped into a coma that lasted 2! months. When he woke up, he said 'Mom,' recalled Grace. It was the last thing he said. Now almost 5, Mikey uses a wheelchair, with limited control of his body. His head lolls. His left arm flails, while

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EARNIE GRAFTON / Union-Tribune Four-year-old Mikey Tighe of Spring Valley, who suffers from mitochondrial disease, slipped into a coma when he was 3. "When he woke up, he said 'Mom,' " recalled his mother, Grace. "It was the last thing he said."

For more information:

Mitochondrial and Metabolic Disease Center UCSD Medical Center 200 West Arbor Drive San Diego, CA 92103 (619) 543-7800 biochemgen.ucsd.edu/mmdc/ United Mitochondrial Disease Foundation 8085 Saltsburg Road, Suite 201 Pittsburgh, PA 15239 (888) 317-8633 umdf.org
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his right arm moves hardly at all. He attends school a specialeducation preschool program at Lindbergh Schweitzer Elementary but spends most nights at Rady Children's Hospital in Kearny Mesa. Mikey was eventually diagnosed with Leigh's syndrome, one of a diverse group of disorders that fall under the broad classification of mitochondrial disease (MD). It's an inherited condition, the result of a defect or mutation in Mikey's mitochondria the tiny organelles found in every nucleated cell in the human body. Mitochondria are best known as cellular power plants, responsible for converting sugars into usable energy. As such, they are critical not only to the basic functioning of each cell, but also to the body's overall metabolism.

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EARNIE GRAFTON / Union-Tribune In spite of mitochondrial disease, Julia Haith (right) of Chula Vista engages in many normal activities for a 13-year-old: homework, reading, talking on the phone, said her mother, Carmella.

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Mikey's condition is relatively rare. One estimate puts the incidence rate for Leigh's syndrome at 1 in every 77,000 births. Mitochondrial disease in general is more common. It's estimated that the minimal risk of a U.S. child developing a form of mitochondrial disease before age 10 is 1 in 4,000. But mitochondrial disease may be far more widespread than that. For one thing, it is not strictly a childhood disease. Half of all cases first appear in adulthood. Indeed, experts suspect dysfunctional mitochondria may be linked to a wide range of well-known diseases, from diabetes, heart disease, stroke and multiple sclerosis to Alzheimer's disease, lupus and rheumatoid arthritis. You might even say that aging is the ultimate mitochondrial disease, said Dr. Robert Naviaux, an associate professor of medicine and pediatrics at the University of California San Diego. No one, of course, has figured out how to cure aging. No one has figured out mitochondrial disease, either. Doctors can effectively treat some symptoms of some conditions some of the time, but the broader,

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underlying affliction remains incurable. It is progressive, degenerative and frequently fatal. That particularly describes Leigh's syndrome, according to the National Institute of Neurological Disorders and Stroke (NINDS). Leigh's has a mortality rate of 50 percent per year after diagnosis. It often strikes hardest at the youngest. The worst cases die within a few years of diagnosis. Those with partial deficiencies have a better prognosis and may live to be 6 or 7 years of age, NINDS reports. Some have survived to their mid-teenage years. Grace Tighe, who wants to become a nurse, has heard these numbers. But she's Mikey's mother and so remains full of hope and optimism. To tell you the truth, I'm still in denial, she said. The fact is, Mikey's still here. I'm going to do this one day at a time and just hope to see Mikey the next morning.

Outside in
If a cure for mitochondrial disease is eventually to be found, it will be up to doctors and researchers like Naviaux and Dr. Richard Haas, co-directors of the UCSD Mitochondrial and Metabolic Disease Center, one of only 30 or so such specialized centers in the world. Haas, who is a professor of neuroscience and pediatrics at UCSD, is Mikey's doctor. Years ago, he became interested in mitochondrial disease after examining a patient with Leigh's syndrome. Haas had never seen anything quite like it, though he had seen every symptom before. There must be 50 different EARNIE GRAFTON / Union-Tribune ways that mitochondrial Mikey Tighe looked at a book with his mother, Grace, disease can present itself, and father, Michael, at Rady Children's Hospital, where the boy spends most nights. Haas said, That's one of the biggest problems, because it can look like so many things. An official diagnosis of mitochondrial disease requires that three or more organ systems are deemed to be failing or that a recognizable disease is present but displays atypical symptoms. Making a diagnosis almost invariably involves extensive testing, including a brain MRI and muscle biopsy. One reason mitochondrial disease may be so hard to define is that mitochondria are so fundamentally involved in life and living. Scientists believe mitochondria originated eons ago as free-living bacteria that were absorbed and incorporated into eukaryotes (cells with nuclei) as complex life developed on Earth. The relationship is endosymbiotic. The cell provides refuge and sustenance; the mitochondria provide the means to convert food into a form of energy (called adenosine triphosphate) that the cell can use. But
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mitochondria, says Naviaux, have evolved into much more than mere fuel factories. The human body consists of more than 250 kinds of nucleated cells. Each cell type contains mitochondria tailored to its particular needs. Mitochondria in a neuron (a brain cell) are different from mitochondria in an astroglial cell that's right next to it, Naviaux said. High-energy cells have lots of mitochondria. Photoreceptor cells in the eye, for example, have thousands. Mitochondria make up 80 percent of the cell's volume. Heart muscle cells are 40 percent mitochondria by volume.

On the other hand, a platelet or white blood cell contains only two to six mitochondria. And a red blood cell, which has no nucleus, has no mitochondria, though mitochondria are critical to its construction.

EARNIE GRAFTON / Union-Tribune Carmella Haith said there are plans for her daughter Julia to begin physical therapy to strengthen her muscles.

Packed inside the nucleus of every human cell is roughly 6 et of DNA a full set of inherited genetic blueprints for that individual. Mitochondria contain DNA too, the only other cellular structure that can make that claim. Because of its distinct origins, mitochondrial DNA (known as mtDNA) is different from nuclear DNA. It is transmitted only through the female. Remarkably, very few of the genes in mtDNA encode for its signature energy-making function. Most genes a whopping 95 percent appear to be involved in other, less well-defined duties. They tell the cell how to build, use, break down and recycle proteins the workhorses of life. It is this broad, jack-of-all-trades talent that makes mitochondria so intrinsically valuable to life and health. When mitochondria do their job, our bodies work well. When they don't, thanks to a harmful mutation or a gene-copying error, bad things happen.

Julia's story
In 1999, at the age of 4, Julia Haith of Chula Vista was diagnosed with diabetes. But that was just the beginning of her problems. When she was in the second grade, her eyes began to droop. She lost energy and strength. She fell a lot. There were times when Julia would go into a kind of semi-coma sleep, said her mother, Carmella. She would sleep for three to five days. It was like her brain wasn't being fed and would just shut down for a while. Every time Julia awoke from one of these semi-coma sleeps, her condition would be worse. When she was 11, she went to sleep one day and woke up unable to walk anymore. As in Mikey's case, doctors struggled to figure out what was going on. It was very frustrating, said Carmella. I didn't know what to expect next,
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and the doctors couldn't tell me. Julia, too, was eventually diagnosed with a form of mitochondrial disease. Two years ago, she had a pacemaker implanted in her weakening heart. Carmella says her daughter is now doing reasonably well, attending sixth grade at the local public school for two hours a day and doing many of the things that 13-year-old girls do: homework, reading, watching TV, talking on the phone. I also like to crack my knuckles, Julia said. Treatment is strictly therapeutic. It consists of five insulin shots each day for her diabetes, six kinds of oral medication and a daily intravenous infusion of magnesium. Carmella said there are plans to begin physical therapy to strengthen Julia's muscles. Nutrient therapy is a common form of treatment for MD, the idea being that high doses of key vitamins, antioxidants and coenzymes may encourage improved mitochondrial function. It generally works, said Haas, but rarely produces dramatic improvement. More promising but also more distant and still unproven are approaches like somatic gene therapy, said Dr. Salvatore DiMauro, a mitochondrial specialist at The Neurological Institute of New York and Columbia University. There are glimmers of hope. Specifically, DiMauro said, researchers are investigating the possibility of correcting and recoding a mutant mtDNA gene, essentially converting it into a normal nuclear gene. The work, however, remains at the in vitro, or test tube, stage. Meanwhile, DiMauro said English scientists have developed reagents substances used to create a chemical reaction that may reduce the percentages of mutant mitochondria in an mtDNA genome. But profound hurdles remain. The track record for gene therapy is mixed; most efforts thus far have fallen short of expectations or failed altogether. Similarly, any effort to convert a large enough percentage of mutant mitochondria to elicit a recognizable therapeutic effect is likely to be extremely difficult. And there's no telling yet if the therapy will also cause harm.

Small wonders
Mitochondria are incredibly tiny, ranging from 0.5 micrometer to 1 micrometer in size. (A micrometer is one-millionth of a meter. A hair is typically 25 to 100 micrometers wide.) Yet they represent one of medicine's bigger mysteries. They were discovered in the 1800s, but it was not until 1963 that scientists learned they contained DNA. Most doctors, said Naviaux, possess only a basic knowledge of mitochondria, stuff they learned in college and medical school. One result: In 1996, a patient would see 12 doctors on average before being referred to a mitochondrial disease expert. That has improved, said Naviaux. The average number of doctors seen now
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is less than half that. But funding for mitochondrial disease research remains minuscule. According to the United Mitochondrial Disease Foundation, the National Institutes of Health spends roughly $12 million each year on mitochondrial disease research out of an annual budget of $29 billion. Last year, only 2 percent of NIH grants even included the word mitochondria. That's appalling, say Naviaux, Haas and other researchers, who argue that a better, fuller understanding of mitochondrial function and dysfunction would likely help explain myriad ills, including some of humanity's most confounding conditions. A case in point: In 2000, at the age of 19 months, a seemingly healthy girl named Hannah Poling received her standard vaccinations against childhood diseases like measles, mumps and chicken pox. In the months that followed, Hannah suffered from fevers, diarrhea and appetite loss, and began screaming. By February 2001, she reportedly had lost some speech ability, no longer made eye contact and didn't sleep through the night. She was diagnosed with autism. Her father and mother a practicing neurologist and a registered nurse blamed the vaccination shots for causing the autism a widespread and persistent claim but one unsubstantiated by research. Indeed, in the same year that Hannah was diagnosed with autism, an independent review by the Institute of Medicine found no association between vaccines and autism. The American Academy of Pediatrics and the Centers for Disease Control say there is no cause-and-effect link. Nonetheless, Hannah's parents sued, filing a case in a federal court that handles vaccine claims. Late last year, in an unprecedented act, attorneys for the U.S. government conceded that Hannah's vaccines were probably linked to her autistic condition. But the ruling was not quite the legal and medical victory that anti-vaccine forces immediately claimed. Government lawyers and a jury concluded that Hannah had an underlying undiagnosed mitochondrial disease. The shots had simply worsened the disease. Fever a common but usually mild side effect in some vaccinated children had resulted in brain disease that appeared as symptoms of autism. Hannah also suffers from muscle weakness, motor-skills problems and gastrointestinal difficulties all documented symptoms of mitochondrial disease. Naviaux said if more was known about MD, cases like Hannah's might not happen. As a general policy, everybody should be immunized because the overall health benefits are simply too compelling and indisputable, he said. But in children with known histories of adverse immune reactions, the kind of thing you see in mitochondrial disease, decisions could and should be made on a case-by-case basis. Children are the primary interest of MD researchers because it's generally easier to identify genetic influences because they have had less exposure to environmental factors, such as pollutants, than adults have. But adults, too, would benefit from answers. Fifteen years ago, when she was 43, Rachel Hernandez of Chula Vista began having trouble swallowing. Her voice became hoarse. She started to feel weak. Worst of all, her eyelids began to droop. It was hard to see.

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Her doctors didn't know what was wrong and could provide no remedy, except to suggest eyelid surgery. She underwent that procedure. Twice. But the problems either didn't go away or eventually returned. After several years, Hernandez was finally diagnosed with a form of mitochondrial disease and prescribed a vitamin therapy, which has helped. But her eyes continue to cause trouble. She needs a third surgery. Unless I pull my eyelids up, everything is blurry. Mostly, I see a lot of eyelashes, she said. I don't really understand my disease. All I know is that it affects different parts of the body, that there's basically no cure right now, just ways to control it. Hernandez says she would like to control her disease long enough to see a cure, eyelids notwithstanding.

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