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A degenerative disorder of the nervous system caused by leukodystrophy. Affects mostly males and usually begins at approximately 6 months of age. Symptoms include mental and physical retardation, enlargement of the brain and head, spasticity (arms and legs), and seizures.

Demyelinogenic Leukodystrophy; Dysmyelinogenic Leukodystrophy; Fibrinoid Leukodystrophy; Fibrinoid Degeneration of Astrocytes; Megalencephaly with Hyaline Panneuropathy; Macrocephaly with Feeble Mindedness and Encephalopathy with Peculiar Deposits.

First described in 1949 by William Stuart Alexander, a British pathologist.

Unknown. Fewer than 100 cases have been reported. No racial preferences have been reported. Males are affected approximately 2.5 times more often than females.

Alexander syndrome is a transmissible astrocytic abnormality with varying expression. It is thought to be inherited in an autosomal dominant way, but de novo mutations have been described. The genetic defect has been mapped to 17q21 and 11q13, and more than 20 different mutations have been identified. These genes encode for glial fibrillary acidic protein (GFAP), which is the main intermediate filament protein synthesized in mature astrocytes. Most likely, GFAP in Alexander syndrome is defective and hinders the normal interaction between astrocytes and oligodendrocytes, finally resulting in dysmyelination and demyelination.

Cause unknown. Nonneoplastic white matter expansion with neuronal dysfunction and astrocyte proliferation associated with demyelination occur. An association of an astrocyte response to an exogenous stimulus (e.g., diphtheria-tetanus-pertussis vaccination) has been hypothesized. Histopathology shows widespread reactive gliosis and hyaline inclusions in astrocytes, so-called Rosenthal fibers (RFs). RFs consist mainly of big aggregations of α B-crystallin (a stress protein), heat shock protein, and glial fibrillary acidic protein. They are often found in subpial, periventricular, and perivascular brain areas. Their occurrence in brainstem and spinal cord is less frequent. The distribution of RFs is closely correlated with areas of demyelination and loss of oligodendroglia. Although extensive and progressive frontal white matter demyelination occurs, no inflammatory cells can be found. These areas may degenerate into brain lacunae. Signs of storage disease are absent.

Brain biopsy and histology demonstrate perivascular hyaline, eosinophilic, and argyrophilic RFs. Abnormal astrocytes with functional demyelination is the prominent feature. Brain imaging is useful only for the infantile form of Alexander syndrome. It shows progressive white matter reduction and cystic changes predominantly in the frontal lobes. No enzyme defect has been identified. Progressive megalencephaly (very large head) during the first year of life is a very common finding. The disease is associated with progressive spasticity and dementia. Molecular genetic testing is available to confirm the diagnosis of Alexander syndrome, so a brain biopsy is no longer mandatory. Prenatal diagnosis is possible.

Infantile type: This is the most common type of Alexander syndrome. Onset usually is between 6 and 24 months of age. Failure to thrive, vomiting, hyperreflexia, hydrocephalus secondary to aqueductal stenosis, megalencephaly with frontal bossing, psychomotor retardation and regression, and loss of intellect, followed by spasticity and intractable seizures, are seen. A few cases of hydrocephalus result ...

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