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Download CETT CDG handout for clinicians AKT 4-30-10 17-39-08
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Predicting prognosis Assisting researchers in understanding the molecular basis of disease in the pursuit for improved treatments and cures Assessing the possibility of therapy for some forms of CDG Providing the opportunity for carrier testing in at-risk family members of those with a known mutation Interpreting Test Results • Positive result: A biochemical finding and mutations have been identified that are of particular diagnostic and clinical significance Negative result: No abnormal biochemical pattern or mutation has been identified. A negative result does not exclude the presence of a glycosylation defect or a mutation that cannot be identified by the current panel and technology. If variants of unknown significance with or without abnormal biochemical findings are detected, follow-up testing of parents and other available family members is generally recommended to aid in determining the segregation pattern of the identified variant(s). Sample requirements Ship overnight to: Emory Genetics Laboratory 2165 North Decatur Road Decatur, GA 30033 404-778-8500 Please contact the lab for current pricing and CPT information. Resources/References • • • • GeneReviews: http://www.ncbi.nlm.nih.gov/bookshe lf/br.fcgi?book=gene&part=cdg National Organization for Rare Diseases (NORD): www.rarediseases.org Euroglycanet: www.euroglycanet.org/uz/CDG The CDG Family Network: www.cdgs.com Biochemical and Molecular Testing For Congenital Disorders of Glycosylation (CDG) Contact Information Emory Genetic Lab Customer Service 1-800-366-1502 (toll free) or 404-778-8499 Ijmkje Cuperus, MS, Genetic Counselor 1-800-366-1502 (toll free) or 404-778-8550 J. Daniel Sharer, PhD, FACMG, Emory Genetics Biochemical Laboratory 1-800-366-1502 (toll free) or 404-778-8500 Transferrin Analysis: 3-5 ml blood in a red top (serum) or green top (plasma) tube. Centrifuge to separate serum or plasma. Ship frozen. Michael J. Gambello, MD, PhD Associate Professor of Human Genetics and Pediatrics 1-800-366-1502 (toll free) or 404-778-8500 DNA Analysis: 3-5 ml whole blood in a purple top (EDTA) tube. Ship at room temperature within 5 days of collection. Emory Genetics Laboratory (EGL) is a comprehensive clinical genetics testing laboratory specializing in molecular cytogenetics, rare disease testing, and newborn screening confirmatory testing. CDG Ia Ib Ic Id Ie If Ig Ih Ii Ij Ik IL Im In Gene PMM2 MPI ALG6 ALG3 DPM1 MPDU1 ALG12 ALG8 ALG2 DPAGT1 ALG1 ALG9 DOLK RFT1 CDG Gene IIa MGAT2 IIb GCS1 IIc SLC35C1 IId B4GALT1 IIe COG7 IIf SLC35A1 IIg COG1 IIh COG8 GNE-Related TUSC3-Related ATP6V0A2-Related Congenital Disorders of Glycosylation Congenital disorders of glycosylation (CDGs), formerly called carbohydrate deficient glycoprotein syndromes, are a group of genetic disorders caused by alterations in protein and lipid glycosylation. Glycosylation is a process whereby sugars (glycans) are linked together in a specific pattern and are attached to proteins and lipids. The sugar complexes are used as signals for the proper cellular localization of the proteins and lipids. These sugar-protein and sugar-lipid complexes are called glycoproteins and glycolipids, and they are needed for normal function and growth of all tissues and organs in the human body. abnormal sugar chain: disorders of Nglycosylation, disorders of Oglycosylation, multiple glycosylation disorders, and glycolipid disorders. Disorders of N-glycosylation are the most common, and can be divided into type I and type II (CDG I, CDG II) based on the location in the glycosylation pathway in which the defect occurs. Different subtypes in each group are defined by the specific gene involved and are designated by a small letter code (Ia, Ib, Ic, etc.). Type I CDGs are caused by defects in genes coding for enzymes that create the sugar chain precursors or that attach them to proteins and lipids. Type II CDGs are caused by defects in genes coding for enzymes that modify the sugar chains after they are added to the protein or lipid. Currently, more than 30 variants of CDG have been described. CDG type Ia is the most common form of CDG, having been reported in more than 700 individuals. Symptoms The process of glycosylation is very complex, involving at least 100 separate enzymes used to create and modify the sugar chains and add them to thousands of different proteins and lipids. Incorrect glycosylation, and therefore mislocalization of proteins and lipids, is the underlying basis of the different clinical features seen in individuals with CDG. Classification CDGs can be classified into four major groups depending on the nature of the The symptoms and severity of CDGs vary significantly between people. Clinical manifestations can range from severe developmental delay, failure to thrive, seizures, and hypotonia with multiple organ system involvement, to hypoglycemia and protein-losing enteropathy with normal development. The specific symptoms a person displays will depend upon the tissues affected by the mislocalization of glycoproteins and glycolipids. Most commonly, CDG disorders begin in infancy and are associated with minor dysmorphic features (e.g., inverted nipples, sub-cutaneous fat pads, strabismus, cerebellar atrophy and hypoplasia). Some of the symptoms may become more or less prominent at later ages. Failure to thrive is often a good indicator for a CDG diagnosis. Treatment Current treatment for CDG patients is supportive therapy and treatment of symptoms and sequelae. There is not a specific medicine available to treat CDG, except for patients with CDG-Ib (who can take mannose) and some patients with CDG-IIc (who can take fucose). Testing for CDG Most CDG patients can be diagnosed by biochemical analysis of transferrin isoforms and glycan structural analysis to determine the glycosylation status of proteins in serum. Once CDG is diagnosed biochemically, genetic testing is required to determine the type and subtype of CDG. Because of the wide variety and overlap of symptoms seen in affected individuals, it is very difficult to identify which CDG gene may be responsible for the symptoms in any given patient. While single gene testing is available, our panel allows for simultaneous testing of multiple CDG genes which provides a significant diagnostic advantage over single gene sequencing. Because DNA analysis is available for some but not all forms of CDG, biochemical analysis is an integral component of CDG testing. If you have questions about what testing would be best for your patient, please contact the lab. Additional benefits of testing include: Providing information for recurrence risk, prenatal diagnosis, and family planning Helping physicians to determine appropriate follow-up testing and develop a health maintenance plan