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 Prof. 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 Prof. Hermann-Josef Gröne of the German Cancer Research Center (DKFZ)’s Division of Cellular and Molecular Pathology in Heidelberg. Their results have now been published online in the internationally respected journal Nature Medicine in advance of their publication in the print edition.
Rare disease: Approx. 1,000 children affected
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 approx. 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 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.
Mice take up mannose in drinking water
The mouse model developed by Prof. 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 Prof. 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,” 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.
New therapeutic approach
“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: Prof. 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.Literature:
Dr. Annette Tuffs | idw
New technique for in-cell distance determination
19.03.2019 | Universität Konstanz
Dalian Coherent Light Source reveals hydroxyl super rotors from water photochemistry
19.03.2019 | Chinese Academy of Sciences Headquarters
The Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) in Arizona released its first image of the surface magnetic field of another star. In a paper in the European journal Astronomy & Astrophysics, the PEPSI team presents a Zeeman- Doppler-Image of the surface of the magnetically active star II Pegasi.
A special technique allows astronomers to resolve the surfaces of faraway stars. Those are otherwise only seen as point sources, even in the largest telescopes...
Researchers at Chalmers University of Technology and the University of Gothenburg, Sweden, have proposed a way to create a completely new source of radiation. Ultra-intense light pulses consist of the motion of a single wave and can be described as a tsunami of light. The strong wave can be used to study interactions between matter and light in a unique way. Their research is now published in the scientific journal Physical Review Letters.
"This source of radiation lets us look at reality through a new angle - it is like twisting a mirror and discovering something completely different," says...
New research group at the University of Jena combines theory and experiment to demonstrate for the first time certain physical processes in a quantum vacuum
For most people, a vacuum is an empty space. Quantum physics, on the other hand, assumes that even in this lowest-energy state, particles and antiparticles...
Physicists in the EPic Lab at University of Sussex make crucial development in global race to develop a portable atomic clock
Scientists in the Emergent Photonics Lab (EPic Lab) at the University of Sussex have made a breakthrough to a crucial element of an atomic clock - devices...
Every year earthquakes worldwide claim hundreds or even thousands of lives. Forewarning allows people to head for safety and a matter of seconds could spell...
11.03.2019 | Event News
01.03.2019 | Event News
28.02.2019 | Event News
19.03.2019 | Physics and Astronomy
19.03.2019 | Life Sciences
19.03.2019 | Physics and Astronomy