Diseases with Astrocyte Abnormalities
Marvin A. Fishman
Alexander disease is a degenerative disorder of the nervous system caused by a mutation in the gene encoding glial fibrillary acidic protein (GFAP). The disease usually presents in infancy, but later-onset forms have been described.
Pathology and Pathogenesis
GFAP is the main intermediate filament protein in astrocytes. Mutations appear to exert a dominant toxic gain of function. The vast majority of mutations are found in exons 1, 4, 6, and 8. They involve changes in a single nucleotide. The altered protein presumably affects the interaction between astrocytes and oligodendrocytes. The histologic correlate is a finding of Rosenthal fibers in the brains of affected children. The fibers are the result of a conglutination of altered glial filaments, which form eosinophilic hyalin spheres in the cytoplasm of astrocytes. The spheres are particularly prevalent beneath the pia mater and around blood vessels. Several stress proteins plus glial fibrillary protein have been identified as major constituents of Rosenthal fibers. Hypomyelination or demyelination occurs, but it is thought to be a secondary event and not to represent a feature of the primary pathogenesis of the disease. Abnormally enlarged mitochondria have been noted, but whether this finding is indicative of an abnormality of mitochondria metabolism is unclear.
The common feature of all the variants of Alexander disease is the presence of refractile eosinophilic bodies in relation to astrocytes. These bodies are most abundant in the subpial, subependymal, and perivascular areas, but they may be found throughout the nervous system in both the white and gray matter and may be seen in the spinal cord. The eosinophilic bodies are found in large, hypertrophied astrocytes, which have a perpendicular orientation to the surface of the brain in the subpial area and form a radial array around blood vessels. In the juvenile form of the disease, the brainstem may be involved predominantly, and the medulla has been noted to be hypertrophied. Electron microscopy demonstrates filaments of granular osmophilic material that form the Rosenthal fibers in the astrocytes. Alpha B-crystallin, a stress protein, is a major protein component of Rosenthal fibers, but its gene structure is normal. A variable loss of myelin occurs in patients with Alexander disease and results in a soft and retracted appearance of the white matter. In infantile cases, the myelin loss may be marked and present in a diffuse pattern. In patients with the juvenile- and adult-onset forms of the disease, demyelination is more limited and patchy. Rosenthal fibers are not specific for Alexander disease and have been noted in patients with a variety of disorders, including syringomyelia, astrocytic glioma, optic nerve glioma, multiple sclerosis, central pontine myelinolysis, disseminated cerebral gliomatosis, and neurofibromatosis.
Clinical Manifestations and Complications
Three variants of Alexander disease have been described and are distinguished by their age of onset: infantile, juvenile, and adult. Recently, a neonatal form of the disease that begins within the first month of life has been suggested. These variants are grouped together under the term Alexander disease because they result in similar pathologic changes in various portions of the central nervous system (CNS), and mutations in the GFAP gene have been found in the first three forms.
The infantile form affects children between birth and 2 years of age, but the average age of onset of the illness is at 6 months. The course usually is 2 to 3 years, but the duration of the disease varies from months to more than 5 years. Psychomotor retardation, megalencephaly (with or without hydrocephalus), spasticity, and seizures are prominent features. The head may not be large at birth, but it increases progressively in size during infancy. Increased intracranial pressure (ICP) may be present, even without hydrocephalus. When hydrocephalus is present, it often is the result of a partial obstruction of the aqueduct by proliferating astrocytes in the ependymal lining. Clinical examination does not disclose any abnormality of peripheral nervous system function.
The juvenile-onset form of the disease is much less common than is the infantile form. This type is seen in patients between 7 and 14 years of age. Its course is longer, varying between 1 and more than 10 years (average, 8 years). The intellect remains intact, unlike in the infantile form. Findings are related to dysfunction of the brainstem and include ptosis, nystagmus, facial diplegia, difficulty in swallowing, nasal speech, and tongue atrophy. Other features include generalized spasticity, weakness, and ataxia.
The adult-onset type of Alexander disease is rarest and occurs in young adults. The clinical syndrome resembles that of multiple sclerosis and includes blurred vision, spasticity, nystagmus, dysarthria, and dysphagia.
The neonatal form has onset within the first month of life and is characterized by refractory seizures, hydrocephalus, and severe motor and mental retardation. The course is rapidly progressive, leading to severe disability or death within the first 2 years of life.
Diagnosis and Therapy
Molecular genetic testing of the gene encoding GFAP is available. The diagnosis also can be confirmed by the detection of astrocytic bodies on examination of brain tissue. The syndrome occurs in a sporadic fashion, and familial cases rarely are noted.
The diagnosis can be suspected on the basis of characteristic findings on magnetic resonance imaging (MRI). Abnormality of the white matter, predominantly involving the frontal regions, can be seen, as can abnormalities in the periventricular regions. Abnormal signals also are noted in the basal ganglia and thalamus. Abnormalities in the brainstem may be present. Contrast enhancement may occur in the involved areas. The imaging findings may suggest the diagnosis even when the clinical picture is nonspecific.