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Genetic and Clinical Heterogeneity in eIF2B-Related Disorder

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine

Raphael Schiffmann, MD

Developmental and Metabolic Neurology Branch, National Institute of Neurologic Disorders and Stroke (NINDS)/National Institutes of Health (NIH), Bethesda, Maryland

J. Rafael Gorospe, MD, PhD

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine

Erynn S. Gordon, MS

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine

Michelle Mintz, PhD

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine

Eric P. Hoffman, PhD

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine

Gulay Alper, MD

Division of Child Neurology, Children's Hospital of Pittsburgh, Pennsylvania

David R. Lynch, MD

Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia

Bhim S. Singhal, MBBS

Department of Neurology, Bombay Hospital Institute of Medical Sciences, Mumbai, India

Cary Harding, MD

Oregon Health Sciences University, Portland

Hernan Amartino, MD

Fundación para el Estudio de Enfermedades Neurometabolicas, Buenos Aires, Argentina

Candida M. Brown, MD

Children's Hospital Oakland, Division of Neurology, California

Alicia Chan, MD

Medical Genetics Clinic, University of Alberta, Edmonton, Canada

Deborah Renaud, MD

Mayo Clinic, Department of Neurology, Rochester, Minnesota

Michael Geraghty, MD

Children's Hospital of Ontario, Genetics Clinic, Ottawa, Canada

Lloyd Jensen, MD

University of Washington School of Medicine, Department of Pediatrics, Seattle

Nesrin Senbil, MD

Department of Radiology (NK), Washington, DC, Dr. Sami Ulus Children's Hospital, Department of Child Neurology, Ankara, Turkey

Nadja Kadom, MD

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine

Javad Nazarian, PhD

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine

Yuanjian Feng, MS

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine

Zuyi Wang, PhD

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine

Thomas Hartka, MS

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine

Hiroki Morizono, PhD

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine

Adeline Vanderver, MD

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine, avanderv{at}cnmc.org

Eukaryotic initiation factor 2B (eIF2B)-related disorders are heritable white matter disorders with a variable clinical phenotype (including vanishing white matter disease and ovarioleukodystrophy) and an equally heterogeneous genotype. We report 9 novel mutations in the EIF2B genes in our subject population, increasing the number of known mutations to more than 120. Using homology modeling, we have analyzed the impact of novel mutations on the 5 subunits of the eIF2B protein. Although recurrent mutations have been found at CpG dinucleotides in the EIF2B genes, the high incidence of private or low frequency mutations increases the challenge of providing rapid genetic confirmation of this disorder, and limits the application of EIF2B screening in cases of undiagnosed leukodystrophy.

Key Words: eIF2B • leukodystrophy • vanishing white matter disease • leukoencephalopathy

Journal of Child Neurology, Vol. 23, No. 2, 205-215 (2008)
DOI: 10.1177/0883073807308705


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