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
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
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 ...