infantile alexander s disease
Alexander disease likely results from a dominant gain of function. Drawing upon the homology of many of the Alexander disease mutations to those found in other intermediate filament diseases, it is suggested that the gain of function is due to a partial block of filament assembly that leads to accumulation of an intermediate that participates in toxic interactions. ScienceDirect - Experimental Cell Research : GFAP and its role in Alexander disease
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In six patients , the diagnosis of infantile Alexander disease was suspected on the basis of typical clinical presentation characterized by onset at age <6 mo, delay or deterioration of psychomotor development, and the presence of seizures and progressive megalencephaly.
All mutations were located in the rod domain of GFAP, and there is a correlation between clinical severity and the affected amino acid. These results confirm that GFAP mutations are a reliable molecular marker for the diagnosis of infantile Alexander disease, and they also form a basis for the recommendation of GFAP analysis for prenatal diagnosis to detect potential cases of germinal mosaicism.
GFAP mutations are a reliable marker for infantile Alexander disease diagnosed according to neuropathological or MRI defined criteria.
Figure 1 A and B, Typical T 2 -weighted MRI images of brains of patients with infantile Alexander disease.
Although GFAP gene mutations appear to be the predominant cause of infantile Alexander disease, it is possible that other genes may contribute, particularly in patients with the most-severe or mildest forms of the disease . In other human genetic diseases involving intermediate filaments, mutations have been found in both the intermediate filament protein and associated proteins.
We evaluated the GFAP gene for mutations in 15 patients with sporadic infantile disease. Although they had heterogeneous clinical presentations, all 15 patients had MRI abnormalities suggestive of Alexander disease, and 4 had neuropathologically proved Alexander disease .
It is not clear, however, that the disorders described in older children and adults are all the same disorder and should be called Alexanders disease.
ALEXANDERS DISEASE For Updated Info you should check with the ULF this is the info that was available to us Alexanders disease belongs to a group of progressive neurological disorders in which the destruction of white matter in the brain is accompanied by the formation of fibrous, eosinophilic deposits known as Rosenthal fibers.
The demyelinated areas do not correspond to the distribution of the Rosenthal fibers. Children who develop Alexanders in infancy generally do not survive past the age of 5 or 6 years.
The majority of cases of Alexanders are sporadic; that is, without a known family history of the disorder.
In the two studies, the eight patients who had the R239C mutation had a less-severe clinical course than that of the two patients with the R239H mutation, and none of the eight patients has died before the age of 4 years . Heterozygous, de novo mutations in the glial fibrillary acidic protein gene have recently been reported in 12 patients affected by neuropathologically proved Alexander disease.
Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease.
Messing A, Goldman JE, Johnson AB, Brenner M Alexander disease: new insights from genetics.
Histologically, Alexander disease is characterized by the presence in astrocytes of cytoplasmic inclusions, termed “Rosenthal fibers. ” These inclusions, which contain the intermediate filament protein GFAP in association with small heat-shock proteins, are found predominately in astrocytes located in subependymal, subpial, and periventricular areas.
Online Mendelian Inheritance in Man , http://www.ncbi.nlm.nih.gov/Omim .
Figure 2 A, Identification of novel mutations in the GFAP gene in four patients with Alexander disease.
We searched for GFAP mutations in a series of patients who had heterogeneous clinical symptoms but were candidates for Alexander disease on the basis of suggestive neuroimaging abnormalities.
Most of the neuropathologically proved cases of Alexander disease are sporadic, but rare familial cases have been reported .
Reichard EA, Ball WS Jr, Bove KE Alexander disease: a case report and review of the literature.
Springer S, Erlewein R, Naegele T, Becker I, Auer D, Grodd W, Krageloh-Mann I Alexander disease: classification revisited and isolation of a neonatal form.
Seil FJ, Schochet SS Jr, Earle KM Alexander’s disease in an adult: report of a case.
Herndon RM, Rubinstein LJ, Freeman JM, Mathieson G Light and electron microscopic observations on Rosenthal fibers in Alexander’s disease and in multiple sclerosis.
For these three patients, the disease course was particularly severe, with onset by age 4 mo, feeding and respiratory difficulties at age 12 24 mo, recurrent seizures, and death at age 15 65 mo.
In patient 12, head circumference was normal, but the course of the disease was severe.
Pridmore CL, Baraitser M, Harding B, Boyd SG, Kendall B, Brett EM Alexander’s disease: clues to diagnosis.
Borrett D, Becker LE Alexander’s disease, a disease of astrocytes.
Fuchs E, Cleveland DW A structural scaffolding of intermediate filaments in health and disease.
The disease is also usually associated with myelin loss in a rostrocaudal gradient.
Alexander WS Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant.
