Congenital Creatine Transporter Deficiency Identified as Cause of Mental Retardation
Creatine transporter deficiency, first identified in 2000 by researchers at Cincinnati Children's, may be a more common X-linked genetic disorder than originally presumed. The affected males have mental retardation with severe expressive language impairment.
Neurologist Ton deGrauw, MD, PhD, and spectroscopist Kim M. Cecil, PhD, of Cincinnati Children's, unexpectedly discovered creatine transporter deficiency in a 6-year-old patient with developmental delay, but no specific diagnosis, being followed for epilepsy. Because the boy's head appeared to be growing too fast, he underwent MRI with magnetic resonance spectroscopy. The researchers found a severe abnormality: no creatine was present in the boy's brain. Essential for energy storage and transfer, creatine is transported to the brain via the blood by the creatine transporter.
"We didn't know immediately that this was a new disease, because a few patients had been reported with creatine synthesis disorder – the child couldn't make creatine due to an inborn error of metabolism. However, when we measured creatine levels in the boy's blood, they were in the high normal range. This boy could make creatine, but it wasn't getting to the brain due to transport problems. This was a new finding," explains Dr. deGrauw.
To find the gene responsible for creatine transport and further investigate the workings of the gene, the researchers collaborated with a molecular biologist in Amsterdam. They established that the creatine transporter gene was located on the X chromosome and its malfunction was due to mutations. With this information, they identified creatine transporter deficiency.
New Insights from Family History
The patient's family history revealed new insights. A maternal brother had severe mental retardation, and the boy's mother and maternal grandmother had a history of severe learning disability. "Because this deficiency is X-linked, the boys and men who have it can't transport creatine into the brain at all. However, women with the deficiency have one abnormal and one normal X chromosome, so they appear to be able to get half of the needed level of creatine into their brain cells," Dr. deGrauw explains.
The researchers have defined two main questions. How does mental retardation result from a lack of creatine in the brain? How many children actually have creatine transporter deficiency? Research continues to find answers.
After the first patient was diagnosed, Dr. Cecil was able to perform MR spectroscopy on additional children with developmental and speech delays who were already undergoing MRI. MR spectroscopy adds approximately three minutes to a routine MRI of the brain. "Spectroscopy is performed to answer a specific question," she explains. "That's how we found six families in Cincinnati with creatine disorders. Among them, eight people have creatine synthesis disorder and five have creatine transporter deficiency."
Speech, Language Are Affected
Current patients at Cincinnati Children's with creatine disorders range from 2 to 22 years old. "The younger kids have reasonably normal development, but the older ones with mental retardation are slow in many areas. Our first patient didn't speak at all. Since then, we've found that speech delay is the only common defect among those with creatine synthesis disorder and creatine transporter deficiency," Dr. deGrauw says. In addition, among the seven carriers identified, five have learning disabilities.
Researchers unsuccessfully treated three male patients with high doses of creatine in an effort to increase creatine levels in the brain. However, preliminary results show that a 14-year-old girl with learning disabilities, a carrier of the X-linked creatine transporter deficiency, may be responding to high-dose creatine treatment. "In males, we think the transport deficiency and the blood-brain barrier keep creatine out of the brain. But we're hopeful that women can be treated more successfully," Dr. deGrauw says.
In addition to using spectroscopy for diagnosis, researchers also are testing whether creatine levels can be screened first in urine samples, with spectroscopy used to confirm the findings.
Working with Greenwood Genetic Center in South Carolina, which has identified four persons with X-linked mutations, Drs. deGrauw and Cecil believe the prevalence of X-linked creatine transporter deficiency is high among males with mental retardation. "Mental retardation is more common in boys, and 40 percent of boys with mental retardation have disorders that are not yet diagnosed," Dr. deGrauw says. "Fragile X syndrome is the most common disorder, causing mental retardation in 3 percent of cases. Our research shows that 2 percent of all X-linked cases in boys may result from creatine transporter deficiency."
Dr. deGrauw is professor of pediatrics and neurology in the Division of Neurology at Cincinnati Children's. Dr. Cecil is assistant professor of pediatrics and radiology in the Department of Radiology. Their paper was published in Neuropediatrics (33[5]: 232-8, 2002 October) and was supported by a grant from the National Institutes of Health.
