Alexander disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo M.D.

Synonyms and keywords: Dysmyelogenic leukodystrophy, Dysmyelogenic leukodystrophy-megalobare, Fibrinoid degeneration of astrocytes, Fibrinoid leukodystrophy, Hyaline panneuropathy, Leukodystrophy with Rosenthal fibers, Megalencephaly with hyaline inclusion, Megalencephaly with hyaline panneuropathy

Overview

Alexander disease is a slowly progressing and fatal neurodegenerative disease. It is a very rare disorder which results from a genetic mutation and mostly affects infants and children, causing developmental delay and changes in physical characteristics.

Historical Perspective

• Alexander disease was first described in 1949 by the New Zealand pathologist William Alexander in London, England under his paper "Progressive Fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant", where he reported a case of a 16-month old child who died after presenting a history of increasing macrocephaly and developmental delay.
• By the decade of 1960´s, the presence of Rosenthal fibers accompanied by progressive neurologic imapairment was recognized as a hallmark of patients with Alexander disease.
• In 2001, Brenner et. al discovered that mutations in GFAP encoding for glial fibrillary acidic protein, could be the causant of most of the cases of Alexander disease.

Pathophysiology

Alexander disease is inherited in an autosomal dominant pattern.

The cause of Alexander disease is a mutation in the gene encoding glial fibrillary acidic protein.

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.

Genetics

Alexander disease is a genetic disorder affecting the central nervous system (midbrain and cerebellum). It 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.

Epidemiology and Demographics

This is a very rare with no more than 300 cases reported. 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.

Natural History, Complications and 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.

Diagnosis

History and Symptoms

• Delays in development of some physical, psychological and behavioral skills
• Progressive enlargement of the head (macrocephaly)
• Seizures
• Spasticity
• Hydrocephalus
• Dementia
• Clumsy movements.

CT Findings

• Decreased density of white matter
• Frontal lobe predominance
• +/- Dilated lateral ventricles

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.

See also

• The Myelin Project
• The Stennis Foundation
• Glial fibrillary acidic protein

External links

• alexander at NIH/UW GeneTests
• The Stennis Foundation - Registered charity committed to raising awareness and funds for Leukodystrophies research
• The Stennis Foundation's MySpace site