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Severe Congenital Disorder Treated Successfully in Mouse Model

Using a mouse model, Heidelberg University Hospital researchers have for the first time successfully treated a severe congenital disorder in which sugar metabolism is disturbed. The team headed by Professor Christian Körner, group leader at the Center for Child and Adolescent Medicine, demonstrated that if female mice are given mannose with their drinking water prior to mating and during pregnancy, their offspring will develop normally even if they carry the genetic mutation for the congenital disorder. The team’s outstanding work will contribute to better understanding of the molecular processes of this metabolic disease, along with the key stages in embryonic development, and may offer a therapeutic approach for the first time. The Heidelberg-based researchers also collaborated with colleagues working with Professor Hermann-Josef Gröne of the German Cancer Research Center (DKFZ)’s Division of Cellular and Molecular Pathology in Heidelberg. Their results were published online on December 11, 2011 in Nature Medicine in advance of their publication in the print edition of that journal. So far, 1,000 children worldwide are affected by congenital disorders of glycosylation (CDG), which are classified as rare diseases. Affecting around 800 children, type CDG-Ia is most frequent. The number of unreported cases is high, however. Children with CDG are severely physically and mentally disabled, with approximately 20 percent dying before the age of two. To date, no therapy has been available to treat the disorder. CDG-Ia is caused by mutations in the genetic information for the enzyme phosphomannomutase 2 which is involved in important glycosylation processes: mannose-1-phosphate is not produced in sufficient quantities. As a result, glycosylation malfunctions, meaning that sugar chains that normally aid in the form, stability, and function of the glycoproteins are not completely attached to the body’s proteins or in some cases, are not attached at all. The lack of oligosaccharide chains leads to impairment of neurological, growth, and organ development. The disorder only manifests if the baby inherits a mutated gene from both the mother and the father. The parents, who each carry one mutated and one “healthy” copy of the gene, do not exhibit any symptoms. The mouse model developed by Professor Körner and his team is characterized by mutations in the phosphomannomutase 2 gene and demonstrates reduced enzyme activity, comparable to CDG-Ia in man. In their current study, the scientists exploited the ability of mannose to cross the placental barrier. This means that if the pregnant mouse takes up mannose, it also reaches the embryos in the uterus. “One week prior to mating, we began giving the female mice mannose with their drinking water,” explained biochemist Professor Körner. The additional mannose supply up to birth increased the mannose levels in the embryos’ blood. “The mice were born without defects and also after they were born, developed without any symptoms of the disorder, even if they no longer took up any mannose,” Professor Körner added. The successful studies performed by the Heidelberg University Hospital researchers clearly show the key role played by the supply of proteins with sugar chains during embryonic development. “Clinical studies in the U.S. and Germany have already been performed in which children with CDG-Ia were given mannose after they were born, either orally or by intravenous infusion. Unfortunately, these attempts have not been successful,” explained Dr. Christian Thiel, head of the laboratory. “This means that the critical point at which it is possible to influence development must be during development in the uterus.” For women with a risk of CDG-Ia, administering mannose during pregnancy may serve as a new therapeutic approach. Heidelberg University Hospital’s Center for Child and Adolescent Medicine (Managing Director: Professor Georg F. Hoffmann) is one of the world’s top centers for research, diagnosis, and treatment of congenital metabolic disorders. In April 2011, the Center for Rare Diseases, which includes congenital metabolic disorders, was founded at Heidelberg University Hospital in order to further advance research and patient care. [Press release] [Nature Medicine abstract]