HomeResearchIntramural ResearchResearch Branches at NHGRIMedical Genetics Branch Krasnewich Lab

Donna Krasnewich, M.D., Ph.D. Associate Investigator Medical Genetics Branch Deputy Clinical Director National Human Genome Research Institute Head Medical Genetics Clinic M.D. Wayne State University School of Medicine, 1986 Ph.D. Wayne State University School of Medicine, 1986 (301) 402-8255 (301) 496-7157 dkras@mail.nih.gov Building 10-CRC, Room 3-2551 10 Center Dr, MSC 1205 Bethesda, MD 20892-1205 Selected Publications Refining the Genomics of Rare Sugar Metabolism Disorders

Dr. Krasnewich investigates metabolically and biochemically based developmental delay disorders, especially those involving defects in sugar metabolism. This work is performed within the Section on Human Biochemical Genetics, led by Dr. William Gahl. Sugars are important for brain development and the proper functioning of other organs in the body. A group of genetic defects in sugar metabolism are termed congenital disorders of glycosylation (CDG), which result from abnormal carbohydrate metabolism- specifically, the abnormal synthesis of N-linked oligosaccharides. About 400 cases of CDG are known worldwide, although given the variable clinical presentations of CDG, many individuals likely go undiagnosed. Affected children may appear normal at birth but begin showing signs of delayed development by the time they reach four to six months of age. As the disorder progresses, the children develop problems that range in severity from mild to debilitating. Children with milder forms of the condition may have only gastrointestinal symptoms and a failure to thrive; those at the other end of the spectrum may suffer severe central nervous system impairment and chronic complications, including liver disease, cardiac disease, and blood clotting problems.

The most common form of the 16 CDG genotypes identified so far, CDG type Ia, results from a deficiency in the enzyme phosphomannomutase. Less-common forms result from efective enzyme activities at other steps in the N-linked oligosaccharide synthetic pathway. CDG type Ib is the only treatable form of the disorder, but Dr. Krasnewich hopes research will lead to treatment strategies for other forms of CDG.

To study the underlying metabolic defects associated with CDG, Dr. Krasnewich is collaborating with investigators at the National Institute of Mental Health using glycobiologic and cell biologic experimental tools. They are examining the initial clinical presentation and course of CDG in patients to determine what the observed clinical spectrum of the disorder reveals about the role of glycobiology in human physiology. Understanding these enzyme defects will pave the way for candidate gene identification, mutation analysis, and, eventually, prenatal diagnosis in appropriate families. Dr. Krasnewich also is part of a team investigating other glycobiologic disorders, including those affecting sialic acid metabolism. NHGRI occupies a unique niche in the study of these disorders, because it is the only facility in the United States able to perform the necessary diagnostic tests.

When a person produces too little sialic acid, myopathy sets in- usually at 20 to 30 years of age- eventually causing affected individuals to become wheelchair bound. Dr. Krasnewich and her colleagues are working on potential therapies that involve administering compounds to increase the amount of sialic acid in muscles. Dr. Krasnewich also is interested in other sugar-based congenital myopathies that are just coming to light and the many she believes remain undiagnosed and unidentified. She hopes these studies will help advance the development of drugs that can be used to treat patients with these metabolic disorders.

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Last Reviewed: September 8, 2008