Delays in development of some physical, psychical and behavioral skills, progressive enlargement of the head (macrocephaly), seizures, spasticity, in some cases also hydrocephalus, dementia, clumsy movements.

Pathology

This genetically based condition, affecting the central nervous system (mid brain and cerebellum)is caused by mutations in the gene for glial fibrillary acidic protein (GFAP) that maps to chromosome 17q21. It is inherited in an autosomal dominant manner. Alexander disease belongs to leukodystrophies, a group of diseases which affect growth or development of the myelin sheath. The destruction of white matter in the brain is accompanied by the formation of fibrous, eosinophilic deposits known as Rosenthal fibers.

CT shows:

decreased density of white matter
frontal lobe predominance
+/- dilated lateral ventricles

Etiology

Unknown.

Occurrence and prevalence

Very rare, occurs mostly in males. The infantile form (80% of all cases) starts usually at the age of six months or within the first two years. The average duration of the infantile form of the illness is usually about 3 years. Onset of the juvenile form (14% of all cases) presents usually between four to ten years of age. Duration of this form is in most cases about 8 years. In younger patients, seizures, megalencephaly, developmental delay, and spasticity are usually present. Neonatal onset is also reported. Onset in adults is least frequent. In older patients, bulbar or pseudobulbar symptoms and spasticity predominate. Symptoms of the adult form may also resemble multiple sclerosis. There are no more than 300 cases reported.

Treatment

There is neither cure nor standard treatment for Alexander disease. All treatment is symptomatic and supportive, for example antibiotics for intercurrent infection and anticonvulsants for seizure control are usually used.

Prognosis

The prognosis is generally poor. With early onset, death usually occurs within 10 years after the onset of symptoms. Usually, the later the disease occurs, the slower its course is.

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Gene Defect for Alexander Disease
From Applied Genetics News, 1/1/01

Scientists led by University of Wisconsin-Madison researcher Able Messing have pinpointed the gene responsible for a rare and devastating childhood brain disorder called Alexander disease, solving a 50-year-old mystery regarding its cause. Their work is reported in the January 3 issue of Nature Genetics.

Musing's team discovered the gene after a genetic analysis of 13 cases of the disease. Because of the rarity of the disease, it took nearly two years to assemble enough cases from international sources to complete the study.

Alexander disease is in a family of disorders called leukodystrophies, in which abnormalities arise in the myelin sheath. It often strikes infants before their first year of age and causes catastrophic damage throughout the nervous system. Most children do not survive past age six.

Serendipity was on the side of the researchers in discovering the mutation. Messing and collaborator Michael Brenner of the University of Alabama-Birmingham developed a transgenic mouse that unexpectedly exhibited the hallmark traits of Alexander disease, which narrowed the field for finding the responsible gene.

Mutations in a gene called GFAP (glial fibrillary acidic protein) are associated with nearly all cases of Alexander disease. Messing says the mutation triggers production of an abnormal protein, which causes a build-up of fibers that damage the nervous system.

"Finding this gene would have been a shot in the dark without that initial discovery," says Messing. "GFAP is a very well-known and widely studied protein among neuroscientists because it's the identifying feature of astrocytes."

Astrocytes maintain the function of neurons and their myelin sheaths. GFAP proteins increase when spinal or brain injuries occur.

Other disorders that involve the 'protein aggregation' that damages nerve function include Alzheimer's and Parkinson's disease. Messing says that it is not yet clear whether these aggregations are a by-product or a cause of the disease, or whether the process can be short-circuited with treatment.

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