eIF2B-Related Disorders: Antenatal Onset and Involvement of Multiple Organs

• Published in: American journal of human genetics Vol. 73; no. 5; pp. 1199 - 1207
• Main Authors: van der Knaap, Marjo S., van Berkel, Carola G.M., Herms, Jochen, van Coster, Rudy, Baethmann, Martina, Naidu, Sakkubai, Boltshauser, Eugen, Willemsen, Michèl A.A.P., Plecko, Barbara, Hoffmann, Georg F., Proud, Christopher G., Scheper, Gert C., Pronk, Jan C.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.11.2003; University of Chicago Press; The American Society of Human Genetics
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - mortality; Abnormalities, Multiple - pathology; Abnormalities, Multiple - physiopathology; Age of Onset; Amino Acid Sequence; Animals; Biological and medical sciences; Brain - abnormalities; Brain - metabolism; Brain - pathology; Brain Diseases - complications; Brain Diseases - genetics; Brain Diseases - pathology; Brain Diseases - physiopathology; DNA Mutational Analysis; Eukaryotic Initiation Factor-2B - chemistry; Eukaryotic Initiation Factor-2B - genetics; Eukaryotic Initiation Factor-2B - metabolism; Female; General aspects. Genetic counseling; Genotype; Humans; Infant; Infant, Newborn; Male; Medical genetics; Medical sciences; Mutation - genetics; Organ Specificity; Phenotype; Human; Genetics; Multiple
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/379524

Leukoencephalopathy with vanishing white matter, also called “childhood ataxia with central nervous system hypomyelination,” is the first human disease related to mutations in any of the five genes encoding subunits of eukaryotic initiation factor eIF2B or any translation factor at all. eIF2B is essential in all cells of the body for protein synthesis and the regulation of this protein synthesis under different stress conditions. It is surprising that mutations in the eIF2B genes have been reported to lead to abnormalities of the white matter of the brain only, although it has been shown recently that ovarian failure may accompany the leukoencephalopathy. Another surprising observation is that the onset of the disease varies from early childhood to adulthood, with the exception of Cree leukoencephalopathy, a disease related to a particular mutation in one of the eIF2B genes, which invariably has its onset within the first year of life. We analyzed the eIF2B genes of nine patients with an antenatal- or early-infantile–onset encephalopathy and an early demise and found mutations in eight of the patients. In addition to signs of a serious encephalopathy, we found oligohydramnios, intrauterine growth retardation, cataracts, pancreatitis, hepatosplenomegaly, hypoplasia of the kidneys, and ovarian dysgenesis. Until now, no evidence had been found for a genotype-phenotype correlation, but the consistently severe phenotype in affected siblings among our patients and in Cree encephalopathy patients suggests an influence of the genotype on the phenotype.