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From the Research Center for Genetic Medicine (Drs. Gorospe and Hoffman), Children’s National Medical Center, Washington DC; Kennedy Kreiger Institute (Drs. Naidu and Raymond), Baltimore, MD; Departments of Pathology and Neuroscience (Dr. Johnson), Albert Einstein College of Medicine, Bronx, NY; Department of Neurology and Pediatrics (Dr. Puri), University of Louisville, KY; Department of Neurology (Dr. Jenkins), Children’s Hospital Oakland, CA; Department of Pediatrics (Dr. Pedersen), Neurology Service, Tripler Army Medical Center, Honolulu, HI; Division of Neurology (Dr. Lewis), Department of Pediatrics, Duke University Medical Center, Durham, NC; T.C. Thompson Children’s Hospital, Chattanooga, TN (Dr. Knowles); Pediatric Neurology Associates (Dr. Fernandez), Tampa, FL; Neurological Institute (Dr. De Vivo), New York, NY; Department of Child Neurology (Dr. van der Knaap), Free University Hospital, Amsterdam, the Netherlands; Department of Pathobiological Sciences (Dr. Messing), Waisman Center and School of Veterinary Medicine, University of Wisconsin, Madison; Departments of Neurobiology (Dr. Brenner), and Physical Medicine and Rehabilitation, University of Alabama, Birmingham.
Address correspondence and reprint requests to Dr. Eric Hoffman, Research Center for Genetic Medicine, Children’s National Medical Center, 111 Michigan Ave NW, Washington, DC 20010; e-mail: ehoffman{at}cnmcresearch.org
Background and Objective: Alexander disease is a slowly progressive CNS disorder that most commonly occurs in children. Until recently, the diagnosis could only be established by the histologic finding of Rosenthal fibers in brain specimens. Mutations in the glial fibrillary acidic protein (GFAP) gene have now been shown in a number of biopsy- or autopsy-proven patients with Alexander disease. A prospective study on patients suspected to have Alexander disease was conducted to determine the extent to which clinical and MRI criteria could accurately diagnose affected individuals, using GFAP gene sequencing as the confirmatory assay.
Methods: Patients who showed MRI white matter abnormalities consistent with Alexander disease, unremarkable family history, normal karyotype, and normal metabolic screening were included in this study. Genomic DNA from patients was screened for mutations in the entire coding region, including the exon-intron boundaries, of the GFAP gene.
Results: Twelve of 13 patients (
90%) were found to have mutations in GFAP. Seven of those 12 patients presented in infancy with seizures and megalencephaly. Five were juvenile-onset patients with more variable symptoms. Two patients in the latter group were asymptomatic or minimally affected at the time of their initial MRI scan. The mutations were distributed throughout the gene, and all involved sporadic single amino acid heterozygous changes that changed the charge of the mutant protein. Four of the nine changes were novel mutations.
Conclusions: In symptomatic and asymptomatic patients with a predominantly frontal leukoencephalopathy by MRI, GFAP gene mutation analysis should be included in the initial diagnostic evaluation process for Alexander disease.
This article has been cited by other articles:
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A. Dinopoulos, J.R. Gorospe, J.C. Egelhoff, K.M. Cecil, P. Nicolaidou, P. Morehart, and T. DeGrauw Discrepancy Between Neuroimaging Findings and Clinical Phenotype in Alexander Disease AJNR Am. J. Neuroradiol., November 1, 2006; 27(10): 2088 - 2092. [Abstract] [Full Text] [PDF]
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W. D. Graf and H. B. Sarnat Intermediate filament proteinopathies: From cytoskeletons to genes to functional nosology Neurology, May 28, 2002; 58(10): 1451 - 1453. [Full Text] [PDF]
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