Pasadena, Calif.--Children born with a rare genetic disorder that can lead to debilitating and irreversible brain injury may find protection with the aid of brain imaging and a modified diet.
Caltech researchers joined scientists at Penn State College of Medicine to study the signs of glutaric aciduria type I (GA-I), a disorder arising from a gene defect that blocks a child's ability to break down the amino acids lysine and tryptophan. Lysine in the blood stream goes straight to the brain, where acids concentrate and damage the mitochondria, the brain's energy producers. The team made two significant discoveries: all the mice fed a tailored diet survived the disorder symptom-free, and signs of impending brain injury could be detected with brain imaging techniques.
The findings are available online this week in the latest issue of Journal of Clinical Investigation.
A rare disorder in the general population, GA-I affects around 1 in 35,000 children in the United States. However, 1 in 400 Amish children are born with GA-I-sometimes called "Amish cerebral palsy"-because in their small communities, chances are higher that two carriers of the recessive gene will marry. Not all children with the disorder will develop symptoms, but when a GA-I-affected child gets an inflammation from a mainstream illness like the flu, they can suffer a stroke. Despite current treatments, GA-I can lead to severe brain damage, painful crippling, or death in 25 to 30 percent of children who have it.
Jelena Lazovic, a postdoctoral scholar in biology, specializes in imaging brain injuries. She had spent the six months prior to her 2004 arrival at Caltech working in a clinic specializing in genetic disorders like GA-I. So when Penn State biologists Keith Chang and William Zinnanti--her husband and the study's lead author--asked her to lend her expertise to studying the disease in mice, she was happy to get on board.
Lazovic and Russell Jacobs, a researcher at Caltech's Biological Imaging Resource Center, began with magnetic resonance imaging (MRI) of mice that Zinnanti fed with a high-lysine diet, in order to pinpoint the regions of the brain affected by GA-I. Zinnanti used a "knockout" mouse model that lacked the functional gene that is disrupted in children with the disease. He discovered that increasing the level of lysine in the mouse diet could trigger a brain injury that was strikingly similar to those caused by GA-I in human patients.
The disease affects a region of the brain called the striatum in a manner similar to Huntington's disease. "We first thought we need to image the mice to see what areas of the brain will get damaged when we give them a lysine diet," says Lazovic. Other approaches to the problem are invasive, she says, but "imaging seemed to be the most convenient; it's in vivo and the findings can translate to humans." At the imaging center, Lazovic and Jacobs put the mice in an MRI machine first to get a brain image, and then to run proton nuclear magnetic resonance spectroscopy. The peaks of the spectroscopic reading reveal different compounds, called metabolites, which aid in growth and development. "Each peak is like a fingerprint with its own frequency," says Lazovic, and the area under a peak shows how much of the metabolite is present. The team found that one of the brain's more important metabolites, a neural transmitter called glutamate, is actually reduced just before brain injury occurs
One aspect of the disease that puzzled the scientists was the appearance of symptoms primarily in children younger than age three. Zinnanti found the same age-dependent brain-damage susceptibility in his mice. The scientists think that young mice are more susceptible to GA-I because their immature brains metabolize and accumulate more lysine than an adult brain does. The young mice were also seen to develop hypoglycemia just as patients with GA-I do.
Using a dietary intervention strategy, Zinnanti and colleagues showed that a combination of homoarginine, which limits lysine accumulation in the brain, and glucose, which prevents hypoglycemia and reduces lysine breakdown in the brain, can prevent brain injury in 100 percent of susceptible young mice. Lazovic's and Jacobs's spectroscopic analyses may also provide a means to monitor children with GA-I for impending brain injury, something that has previously been impossible. Children who test positive for the genetic deficiency at birth could be monitored on a monthly basis.
"We had no pointers as to what was happening with these kids," says Lazovic. "Now we think we have a method where you can do spectroscopy on the children, and you can measure decreased glutamates, and you can tell that energy production in the brain is suppressed." The technique may also help with other genetic disorders that inhibit amino-acid metabolism, like maple syrup urine disease (so called because of the sweet smell it gives infants' urine), propionic acidemia, and methylmalonic academia. Each of these affects children at about the same rate as GA-I, and is more prevalent in tight-knit communities.
"This disease is certainly a major concern in the Amish community, so it's something they know to be on the lookout for," Zinnanti says. "But it also affects children around the world, and it's ten times worse when you're not expecting it and don't know what to look for. We hope our work begins to offer tools for these patients and their caregivers to diagnose and treat this disorder before it causes irreversible damage."
Other authors of the paper are Cathy Housman, Kathryn LaNoue, Ian Simpson, James Connor, and Keith Cheng of Penn State; James O'Callaghan of the Centers for Disease Control and Prevention; and Michael Woontner and Stephen Goodman of the University of Colorado at Denver.
