Acacia MacDonald is a lot like any healthy 2-year-old. She is growing. She enjoys playing with her toys. And she loves it when her dad reads to her at bedtime.
Researchers are excited that Acacia acts her age because she has a syndrome that normally causes mental retardation.
Acacia is participating in groundbreaking research at the Health Science Center. She is part of an intensive basic science and clinical project focusing on children with a genetic disorder called "18q minus" syndrome.
Children with the syndrome exhibit poor growth and developmental delays. About 96 percent of them are mentally retarded to varying degrees.
Although researchers are reluctant to say that retardation can be reversed in these children, they are finding encouraging signs in Acacia's preliminary treatment.
The scientists are investigating the possibility that daily therapy with a naturally occurring substance called growth hormone may improve the children's mental abilities and their ability to grow physically. Many of the children in the study have low natural levels of growth hormone. Acacia is the first of three children to be evaluated after at least one year of the therapy. Another child also showed marked improvement but the third showed little progress. "Acacia's progress is encouraging, but it is too early and too few children are involved to reach any conclusion about specific growth hormone effects on neurodevelopment," said Charles T. Gay, MD, assistant professor of pediatrics and the project's neurologist.
A total of 12 children are now on growth hormone therapy, and in various stages of evaluation.
"At 12 months of age when we first saw her, Acacia had attained a developmental age of only about 5 months," said Nora M. Thompson, PhD, clinical assistant professor of psychiatry and a project investigator. "She was placed on growth hormone treatment. When we saw her a second time at age 31 months, her score had improved in four categories and her general cognitive development was at 32 months.
"Her cognitive skills have advanced significantly, as have her language skills, and her fine and gross motor skills have also shown tremendous progress. These are remarkable improvements — and we hope to see similar benefit in other children," Dr. Thompson said.
Acacia's syndrome is a genetic disorder traced to human chromosome 18, specifically to its "q" region. Acacia was born with a "deletion," a place in her genetic blueprint where something is missing.
"The 18q minus syndrome is one of the most common chromosomal deletion syndromes," said Celia I. Kaye, MD, PhD, professor of pediatrics and clinical coordinator of the research project. "Studying it is quite a challenge, since each child is missing a unique set of genes and the physical characteristics of each case vary widely."
To grow normally, a person must have the correct number of genes and these must be "expressed," or start to work, at the correct time in life. The normal human genetic endowment, or human genome, consists of two pairs of 23 chromosomes in each cell. Children inherit one set of chromosomes from their mother and another from their father.
Most of the 18q minus deletions result from a genetic error occurring during the formation of the egg, and are not carried by the mother or father, said the project's principal investigator, Robin J. Leach, PhD, associate professor of cellular and structural biology and of pediatrics.
"The human genome contains an estimated 100,000 genes, but of course, we're focusing on a much smaller area. Chromosome 18 contains about 1,250 genes, and the 'q' region commonly missing in these children represents as many as 500 genes," Dr. Leach said.
"We are examining the clinical features of the syndrome in each child and then determining which genes are deleted in each individual. We believe that the clinical features will directly correlate with the extent of the genetic deletions," she said.
A model of scientific teamwork, the 18q minus project involves 20 investigators from seven Health Science Center departments. It is privately funded. Geneticists are poring over the DNA (genetic material) of children and parents, a pediatric endocrinologist is charting the children's short stature and poor growth, neurologists are producing computer-generated pictures of the children's brains for study, a biostatistician is designing ways to analyze data, and an early childhood development specialist is evaluating the children's intelligence and adaptive skills. The team has examined 40 children so far.
Why are the researchers using growth hormone to improve cognitive skills? From their preliminary studies, they have evidence that growth hormone helps with a vital process of brain maturation called "myelination."
Signals from the brain originate in neurons, or nerve cells, in gray matter. These signals then travel along axons -- the brain's "wiring" -- in white matter. As a child grows, the brain white matter produces sheaths of a substance called myelin. Myelin wraps around axons and enhances the speed and efficiency of signals traveling along the axons.
"For the most efficient transfer of information, myelin is needed. Without it, transfer is diminished," Dr. Gay said.
While patients with multiple sclerosis and other neurological diseases experience a degenerative loss of myelin, children born with 18q minus syndrome show an incomplete development of myelin. The researchers believe this may partially account for the children's developmental delays.
"A substance called myelin-basic protein (MBP) is essential for normal brain myelination," Dr. Gay said. "The gene that encodes this protein happens to be at the very end of the 18q region, so it's expected that children with 18q deletions would be missing the MBP gene. We have found this to be true."
Using magnetic resonance imaging at the Health Science Center's Research Imaging Center. Dr. Gay has scanned the brains of 20 children with 18q minus syndrome and 11 healthy children. Researchers detected delayed myelination in all of the 18q minus children having only one copy of the MBP gene. The healthy children showed normal myelination.
"Everyone has two copies of chromosome 18, so the DNA from each child in the study contains the normal 18 and the deleted 18," said Jannine Cody, a doctoral candidate in genetics at the Health Science Center whose daughter, 10-year-old Elizabeth, was born with the syndrome. "We use special techniques to analyze what's missing from each of the patients."
"Some people think the break point is the key — that the exact location of a deletion is the predictor for the expression of the disease," Dr. Kaye said. "We would argue that the size of a deletion correlates with the severity of the disease. We believe that once all the genes in the region are known, this correlation will be found to exist.
"Of course, we still have a long way to go in our understanding of how genes interact with one another, but part of the power of a project like this is that it contributes to basic understanding. Therapies can be better designed for specific conditions when we understand genes fully at the basic level," she said.
Mouse models are useful tools for understanding human diseases, and two mouse studies are under way as part of the 18q minus project. The first, headed by Cody's husband, John Cody, PhD, a biochemist with the Air Force, will evaluate the effects of growth hormone deficiency on myelination.
The second project, headed by Peter O'Connell, PhD, associate professor of pathology and of cellular and structural biology at the Health Science Center, is creating mouse models to mimic what is happening in the human disorder. "We're making a series of mice with different sized deletions — a series of graded deletions on chromosome 18. This will give us a model that will help us understand genetic disorders caused by chromosomal deletions," Dr. O'Connell said.
The implications are important. About one in every 180 children born in the United States has a chromosomal abnormality. The 18q minus syndrome itself affects one in every 40,000 newborns.
Acacia's parents, Brian and Suchada MacDonald, who live outside Seattle, are excited about the research. They have contributed to the project and their gift has been matched by Brian's employer, Microsoft Corp.
The Codys are excited, too. Their daughter, Elizabeth, also is on growth hormone. It was the Codys, with their child's neurologist, Sid Atkinson, MD, who first proposed the growth hormone/myelination study about five years ago.
"The seeds of love planted by these two concerned parents grew into a large project that will help other parents in similar straits," Dr. Atkinson said. "As many people will tell you, Jannine has put her whole life into this. It started with her determination to understand her daughter's condition and continued when she entered Dr. Leach's laboratory to further her studies. The project literally leaped from a geneticist's lab to a pediatrician's examining room to a neurologist's imaging chamber. Now these dedicated people are working together for a cause that is close to the hearts of many."
Contact information: Chromosome 18 Registry and Research Society, a San Antonio-based registry of parents, physicians and researchers.
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