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Inborn Errors of Metabolism
The inborn errors of metabolism is a large nationally-based effort, focusing on urea-cycle enzymes (Mendel Tuchman, MD, Mark L. Batshaw, MD, Uta Lichter-Konecki, MD, Andrea Gropman, MD). A national network of clinics, clinical trials and basic research has been designed and implemented with both NIH and philanthropic funding. Dr. Tuchman, in addition, has two R01 grant on ornithine transcarbamylase (OTC) deficiency and a second to study the molecular biology of N-acetylglutamate synthetase (NAGS) deficiency. Junior faculty in this program include Uta Lichter-Konecki MD, PhD (neurogenetics of amino acid disorders), Andrea Gropman, MD (neuroimaging of urea cycle disorders), Hiroki Morizono, PhD (biochemistry of OTC and NAGS deficiency), Ljubica Caldovic, PhD (biochemistry of OTC and NAGS deficiency) and Dashuang Shi, PhD (crystallography of NAGS deficiency) who was awarded a new K01 grant from the NIH.
Ornithine transcarbamylase deficiency
Much of the work has been directed at understanding how defects in ornithine transcarbamylase, a metabolic enzyme of the urea cycle, lead to elevated ammonia levels in the body that become neurotoxic. Hyperammonemia is a serious condition that can lead to mental retardation, coma and death. Ornithine transcarbamylase deficiency accounts for nearly half of all inheritable defects of the urea cycle, all of which can cause hyperammonemia.
N-acetylglutamate synthase deficiency
Our team recently discovered and cloned the last gene of the vertebrate urea cycle, N-acetylglutamate synthase (NAGS). Using this information, we were able to conclusively diagnose several patients that had NAGS deficiency. NAGS catalyzes the formation of a molecule called N-acetylglutamate that behaves like a key for the activation of the urea cycle pathway. In a collaboration with the Center for Clinical Research and Experimental Therapeutics facilities at Children’s, we have been able to show that a small, structurally similar compound, called carbamylglutamate, can substitute in patients with NAGS deficiency to restore essentially normal urea cycle function.
Related Links
The American Society of Human Genetics
www.ashg.org
Organization for professionals specializing in human genetics. Publishes The American Journal of Human Genetic s and other resources.
Cornelia de Lange Syndrome Foundation, Inc.
http://www.cdlsoutreach.org
Supports parents and children affected by de Lange syndrome, encourages research and disseminates information to increase public awareness through a newsletter and informational pamphlet.
5p-Society
www.fivepminus.org
Family support and information group for caretakers, grandparents, and guardians of individuals with 5p- (cri-du-chat) syndrome. Publishes a newsletter and sponsors an annual meeting.
GeneTestsoGeneClinics
www.geneclinics.org; www.genetests.org
Free medical genetics information resource developed for physicians, other healthcare providers, researchers, and the public. Provides GeneReviews, peer-reviewed articles describing the application of genetic testing to the diagnosis, management and genetic counseling of patients; international directories for genetic testing laboratories and genetic and prenatal diagnosis clinics; and various educational materials.
Genetic Alliance, Inc.
www.geneticalliance.org
International organization of families, health professionals, and genetic organizations dedicated to enhancing the lives of individuals living with genetic conditions through the provision of education, policy and information services. Helpline staff are available to address questions about genetics and to connect callers with support groups and informational resources.
Genetics Society of America
www.faseb.org/genetics/gsa/gsamenu.htm
Professional organization that aims to bring together genetic investigators and provide a forum for sharing research findings. Cooperates in the organization of an international congress held every five years under the auspices of the International Genetics Federation. Publishes the journal GENETICS and other resources.
Little People of America, Inc.
www.lpaonline.org
Nationwide organization dedicated to helping people of short stature. Provides fellowship, moral support, and information to "little people" or individuals with dwarfism. The toll-free helpline provides information on organizations, products and services and doctors in the caller's area.
National Gaucher Foundation
www.gaucherdisease.org
Publishes quarterly newsletter, operates support groups and chapters, provides referrals to organizations for appropriate services, and funds research on Gaucher disease.
The National Neurofibromatosis Foundation, Inc.
www.nf.org
Supplies information to lay people and professionals and offers genetic counseling and support groups throughout the United States.
National Organization for Rare Disorders (NORD)
www.rarediseases.org
Nonprofit group of voluntary health organizations serving people with rare disorders and disabilities. Dedicated to the identification, treatment and cure of rare disorders through education, advocacy, research, and service.
National Tay-Sachs and Allied Diseases Association
www.NTSAD.org
Promotes genetic screening programs nationally; has updated listing of Tay-Sachs disease prevention centers in a number of countries; provides educational literature to general public and professionals; and coordinates a peer group support for parents.
National Urea Cycle Disorders Foundation
www.nucdf.org
Provides information and support for families. Supports and stimulates medical research and increased awareness by the public and the legislators of issues related to urea cycle disorders.
Online Mendelian Inheritance in Man (OMIM)
www.ncbi.nlm.nih.gov/Omim
Web site database of human genes and genetic disorders with textual information, pictures and reference information.
Osteogenesis Imperfecta Foundation, Inc.
www.oif.org
Supports research on osteogenesis imperfecta and provides information to those with this disorder, their families and other interested people.
Prader-Willi Syndrome Association
www.pwsausa.org
National organization that serves as a clearinghouse for information on Prader-Willi syndrome; shares information with parents, professionals and other interested people.
Sickle Cell Disease Association of America, Inc.
www.sicklecelldisease.org
Provides education, screening, genetic counseling, technical assistance, tutorial services, vocational rehabilitation, and research support in the United States and Canada.
Support Organization for Trisomy 18, 13, and Related Disorders (SOFT)
www.trisomy.org
Chapters in most states provide support and family packages with a newsletter and appropriate literature underscoring the common problems for children with trisomy 13 or trisomy 18. Holds yearly conference for families and professionals.
Tourette Syndrome Association
www.tsa-usa.org/
Offers information, referral, advocacy, education, research, and self-help groups to those affected by Tourette syndrome.
Treacher Collins Foundation
www.treachercollinsfnd.org
Resource and referral for families, individuals and professionals who are interested in developing and sharing knowledge and experience about Treacher Collins syndrome and related disorders. Publishes newsletter and makes print and videotape resources available by loan.
Tuberous Sclerosis Alliance
www.tsalliance.org
Offers public information about manifestations of the disease to newly diagnosed individuals, their families and interested professionals. Referrals are made to support groups located in most states. Funds research through membership fees and donations.
Urea Cycle Disorders Consortium
http://rarediseasesnetwork.epi.usf.edu/ucdc/index.htm
A group of healthcare professionals and researchers dedicated to improving the lives of patients with urea cycle disorders. The Consortium has established centers of clinical and scientific excellence across the United States to work with patients and physicians to provide information and care with the latest information and technology. The UCDC strives to provide current and useful information on urea cycle disorders to healthcare professionals and families. The Consortium is also dedicated to research in clinical and scientific issues in urea cycle disorders. To better understand the nature of these diseases, the Consortium has established a National Registry for patients, and is conducting long-term studies on the outcome of patients with urea cycle disorders.
Medline
www.ncbi.nlm.nih.gov
Contact Information:
Cynthia J. Tifft, MD, PhD
Children’s Research Institute
Center for Clinical Research and Experimental Therapeutics
Children's National Medical Center
111 Michigan Avenue, NW
Washington, DC 20010
202-476-2187
ctifft@cnmc.org
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Watch Dr. Mark Batshaw explain his research findings on urea cycle disorders