Biopsy Diagnosis of Familial Alexander’s Disease

Abstract

A 26-year-old woman presented with headaches, incordination and a cerebellar mass (1982). The CT scan revealed dilated ventricles and a hypodense space-occupying lesion adjacent to the fourth ventricle. Neuronal loss, gliosis and masses of Rosenthal fibers were seen in biopsy. There was no evidence of neoplasm. A second biopsy 2 years later was similar to the original specimen. A diagnosis of Alexander’s disease was suggested. Later that year the patient’s 11-year-old brother manifested a clinical picture intially diagnosed as brainstem glioma, but whose biopsy was characteristic of Alexander’s disease. There has been a gradual deterioration of these siblings over the past 6 years (1986–1991). No evidence of neoplasm has appeared.

Archetypal and New Families With Alexander Disease and Novel Mutations in <emph type="ital">GFAP</emph>

“…We now report that GFAP mutations, albeit novel ones, account for the patients described by Seil et al 2 and Duckett et al 3 , as well as previously unreported members of their respective families. Analyses of these families also expands the spectrum of phenotypic variability associated with GFAP mutations, even within families, and indicate that some patients not only stabilize but sustain long periods of clinical improvement.…”

“…Two of these siblings were previously reported by Duckett et al 3 to document the existence of “familial” Alexander disease. A pedigree for this family is shown in Figure 1A, with birth order disguised to protect confidentiality.…”

“…Most mutations arise de novo, though in some instances patients live to reproductive age and transmit the mutation to subsequent generations. Germline mosaisicm, which might be the explanation for the family described by Duckett et al 3 , has yet to be documented for any families where Alexander disease occurred in multiple siblings. The penetrance of Alexander disease approaches 100%, the few exceptions being patients who may have only been pre-symptomatic at the time of study.…”

“…Subsequently other patients with intermediate ages of onset were identified. In 1992, Duckett et al 3 described an unusual family with two affected children, one juvenile onset and the other adult onset, both of whom received biopsy confirmation of their diagnoses.…”

Alexander-disease mutation ofGFAPcauses filament disorganization and decreased solubility of GFAP

“…Since then, many more cases have been described in patients of various ages (Borrett and Becker, 1985;Duckett et al, 1992;French et al, 1976;Reichard et al, 1996;Sawaishi et al, 1999) (see http://www.waisman.wisc.edu/alexander/index.html for a literature summary). Clinically, Alexander disease is a fatal leukoencephalopathy that leads to the dysmyelination or demyelination of the central nervous system.…”