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University of Cincinnati Academic Health Center
Publish Date: 06/12/03
Media Contact: AHC Public Relations, (513) 558-4553
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UC Medical Center Begins Research Collaboration on Creatine Transporter Deficiency

In a joint effort between the UC Medical Center and Cincinnati Children's Hospital Medical Center, researchers have discovered a defect on the X-chromosome housing the creatine transporter gene.  This defect, named creatine transporter deficiency, is expressed in humans through severe speech and language impairment, short attention span, low IQ, and the inability to follow commands.

The researchers at UC and Cincinnati Children's have formed a collaboration with the Massachusetts and California-based biotech company, The Avicena Group, Inc., to translate the discovery of creatine transporter deficiency into a method of treatment.  "We have been investigating the role of the creatine kinase system in central nervous system disorders for many years," said Rima Kaddurah-Daouk, PhD, co-founder of The Avicena Group, Inc.  "We believe that energy impairment compromises neuronal survival and cognitive functions."

Research indicates that this disease, resulting in cases of mental retardation, can be diagnosed early and treated.  "We need to determine how many people have this disease and detect it early," said Joseph Clark, PhD, associate professor, UC Department of Neurology.  "If we successfully develop a good treatment, the earlier the treatment starts the better."

Ton DeGrauw, MD, PhD, professor, Pediatrics-Division of Neurology, UC, Cincinnati Children's, and Kim M. Cecil, PhD, research assistant professor, Pediatrics-Department of Radiology, UC, Cincinnati Children's, first detected the creatine transporter defect in a six-year-old boy three years ago.  "The disorder is currently identified using either a proton magnetic resonance spectroscopy obtained with a magnetic resonance imaging (MRI) examination, or by DNA analysis," said Dr. Cecil.

While creatine transporter deficiency affects both males and females, the severity of the disease is increased in males because the defect is located on the X-chromosome, of which males have only one. 

"So far we have recognized five families with this disorder in Cincinnati alone," said Dr. DeGrauw.  "The disorder is not well known yet, but I believe that it is quite common.  Together with our collaborator, geneticist Gajja S. Salomons, PhD, in Amsterdam, the Netherlands, we now have diagnosed more than 30 families with creatine transporter deficiency." 

Creatine plays a central role in energy metabolism and is synthesized in the liver, kidney and pancreas.  In healthy patients, it is transported via the blood stream to the muscles, heart and brain with high and fluctuating energy demands by the molecule creatine transporter.  Creatine, although naturally synthesized in the human body, can be ingested in the form of supplements and is commonly used by athletes to provide a ready reserve of energy.  Research has shown that patients with low levels of creatine in their brain, with no defect on the gene for creatine transporter, may benefit from creatine supplements.  This is not the case however, with creatine transporter deficiency patients.  Supplements of creatine increase the levels of creatine found in serum and urine, but not in the brain.  The defect on the gene for the creatine transporter inhibits creatine from traveling to the brain. 

In February 2003 the UC Medical Center and Cincinnati Children's began a clinical study to determine if creatine supplementation can increase brain creatine concentration and improve cognitive function among patients with creatine transporter deficiency.  The goal of the treatment is to restore as much as possible of the normal creatine concentration in the central nervous system.  Patients with creatine in their brains, determined by proton magnetic resonance spectroscopy, will be treated with high quality, ultra-pure creatine supplements provided by The Avicena Group, Inc. in increasing dosages for several six-week periods.  Magnetic resonance spectroscopy will be repeated at the end of each six-week period.  If the test shows a significant increase in creatine concentration, the study will be ended and the subjects will be offered to continue the treatment at their current dose of creatine with clinical follow-up in the neurology clinic.

"Our clinical research focuses on regulating cellular energy," said Dr. Belinda Tsao-Nivaggioli, chief operating officer at The Avicena Group, Inc.  "Neurology is a major area of development for us, and we are delighted to be working with UC and Cincinnati Children's to identify an effective treatment to overcome this genetic disorder."

The collaboration with The Avicena Group, Inc. further emphasizes UC and Cincinnati Children's efforts to translate basic research into commercial products that benefit the public.  "Patent protection is currently being sought for the technology, and The Avicena Group, Inc. subsequently licensed the intellectual property under a joint agreement with UC and Children's Hospital Research Foundation (CHRF)," said Richard Kordal, PhD, director, Intellectual Property Office, UC.  "The license agreement is complemented by a collaborative sponsored research agreement program designed to investigate the
extent to which this defect is involved in cognitive impairment in males, and to identify diagnostic and treatment methods and therapeutics."

Joe Fondacaro, PhD, director of Intellectual Property and Venture Development at CHRF said, "The research project and subsequent license agreement with The Avicena Group, Inc. demonstrates that not only can our two research institutions work together collaboratively, but also cooperate and partner together with industry.  We are very pleased to be part of these relationships."

Information online:,,

Associated faculty:
Kim M. Cecil, PhD, research assistant professor, Pediatrics-Department of Radiology, UC, Cincinnati Children's; Joseph Clark, PhD, associate professor, Department of Neurology, UC; Ton DeGrauw, MD, PhD, professor, Pediatrics-Division of Neurology, UC, Cincinnati Children's.

Intellectual Property:
Richard Kordal, PhD, director, Intellectual Property Office, UC; Joseph Fondacaro, PhD, director, Office of Intellectual Property and Venture Development, Cincinnati Children's.
Scientific Journal References:
Cecil, K. M., T. J. DeGrauw, G. S. Salomons, C. Jakobs, J. C. Egelhoff, and J. F. Clark. Magnetic resonance spectroscopy in a 9-day-old heterozygous female child with creatine transporter deficiency. J Comput Assist Tomogr 27: 44-7, 2003.

Cecil, K. M., G. S. Salomons, W. S. Ball, Jr., B. Wong, G. Chuck, N. M. Verhoeven, C. Jakobs, and T. J. DeGrauw. Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect? Ann Neurol 49: 401-4., 2001.

DeGrauw, T., K. Cecil, A. Byars, G. Salomons, W. Ball, and C. Jakobs. The clinical syndrome of creatine transporter deficiency. Molecular and Cellular Biochemistry 244: 45-48, 2003.

DeGrauw, T. J., G. S. Salomons, K. M. Cecil, G. Chuck, A. Newmeyer, M. B. Schapiro, and C. Jakobs. Congenital creatine transporter deficiency. Neuropediatrics 33: 232-8, 2002.

Salomons, G. S., S. J. van Dooren, N. M. Verhoeven, K. M. Cecil, W. S. Ball, T. J. DeGrauw, and C. Jakobs. X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet 68: 1497-500, 2001.

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