.: Treating every progeria patient in the world
.: A first glimpse at healthy cognitive development
Progeria, a disease that causes some aspects of premature aging, is so rare that only about 40 children in the world are known to have it. In a new clinical trial, Mark Kieran, MD, of Children's Hospital Boston's Division of Hematology/Oncology, has begun treating as many of these fragile children as are able to travel to Boston, with costs paid by the Progeria Research Foundation. The children will receive an experimental cancer drug called lonafarnib.
Children with progeria usually appear healthy at birth, but within months begin to show signs like hair loss and aged skin. Within a few years, they begin to develop osteoporosis and cardiovascular disease and die from heart attacks at an average age of 13, never growing taller than about 4 feet.
While at Children's, the patients are being cared for by a multidisciplinary team, including Monica Kleinman, MD, of the Division of Critical Care Medicine, who is also a founding member of the Progeria Research Foundation's Board of Directors, and David Miller, MD, PhD, of the Division of Genetics. Kieran was chosen to lead the trial because of his extensive experience with lonafarnib in children with malignant brain tumors.
Why use a cancer drug to treat progeria? Brain tumors and progeria turn out to have a similarity in their underlying biochemistry. In both diseases, lonafarnib prevents harmful proteins from attaching to the cell membrane, leaving them to float inside the cell where they may do less damage. In the case of progeria, lonafarnib blocks attachment of a protein called progerin. When tested in mice with progeria-like disease, lonafarnib and similar drugs prevented some signs of premature aging—the mice gained weight and had fewer bone fractures. Further mouse studies are exploring whether cardiovascular disease is reduced as well.
The trial starts with doses of lonafarnib known to be tolerated by children with cancer; doses will be increased if no serious side effects occur. Patients will be monitored every four months for weight gain, increased bone density and other signs of improvement. "The families are willing to try it because their children are dying," says Kieran. "The clock starts ticking the day they're diagnosed." One of these children, Megan Nighbor, 7 (above), travelled here from Wisconsin. "We're so excited treatment has begun," says her mother, Sandy. "We went into this trial with mixed emotions, but we know our beautiful Megan is in good hands. We hope to be making history."
Yes, there are gender differences in cognitive function, but they're more limited than previously thought. And yes, income does affect cognitive performance—but less than expected. And while cognitive skills steadily improve in middle childhood, they then seem to level off, putting into question the generally accepted idea of a burst of brain development in adolescence.
These are the first findings from the National Institutes of Health MRI Study of Normal Brain Development, a large, population-based study that began in 1999. The analysis, led by Deborah Waber, PhD, in Children's Hospital Boston's Department of Psychiatry, focused on cognition and behavior in 385 demographically diverse 6- to 18-year-olds enrolled at Children's and five other centers across the country. Children with medical or psychiatric disorders (or risk factors for them) were excluded, providing a glimpse of how a healthy brain develops.
In the study, published online May 18 by the Journal of the International Neuropsychological Society, boys performed better on tests of perceptual analysis, and girls on tests of processing speed, motor dexterity and, initially, verbal learning. Children from low-income homes scored lower on reading comprehension and calculation tests and had lower overall IQ scores. However, these healthy children matched their peers on basic cognitive tasks like memory and word reading, and their overall performance surpassed previously reported population averages.
Cognitive performance rose steadily in middle childhood, but on most tests leveled off around ages 10 to 12 and improved more slowly or not at all during adolescence. Waber cautions, however, that these findings average a whole age group's performance at one point in time. "We don't know whether everyone improves more slowly in adolescence, or whether some continue to improve while others don't," she notes. "As we follow these children over time, we'll have a better understanding."
Eventually, the children's test performance will be correlated with the results of brain imaging, measuring growth of different brain structures, formation of connections between them and even changes in brain chemistry.