Alexander disease is a very rare autosomal dominant leukodystrophy, which are neurological conditions caused by anomalies in the myelin which protects nerve fibers in the brain. The most common type is the infantile form that usually begins during the first two years of life. Symptoms include mental and physical developmental delays, followed by the loss of developmental milestones, an abnormal increase in head size and seizures. The juvenile form of Alexander disease has an onset between the ages of 2 and 13 years. These children may have excessive vomiting, difficulty swallowing and speaking, poor coordination, and loss of motor control. Adult-onset forms of Alexander disease are less common. The symptoms sometimes mimic those of Parkinson's disease or multiple sclerosis, or may present primarily as a psychiatric disorder.
According to the National Institute of Neurological Disorders and Stroke, the destruction of white matter is accompanied by the formation of Rosenthal fibers—abnormal clumps of protein that accumulate in astrocytes in the brain.
The disease was first documented in 1949 by W. Stewart Alexander, who treated a 15 month-old infant presenting with megalencephaly, hydrocephaly, seizures, and developmental delays. Between 1949 and 1964, 15 more cases with similar symptoms were observed, leading to suggestions that the cases were the same disease and that the disease be named after Alexander.
The disease occurs in both males and females, and no ethnic, racial, geographic or cultural/economic differences are seen in its distribution. Alexander disease is a progressive and often fatal disease.
Presentation
Symptoms observed include delays in development of some physical, psychological and behavioral skills; progressive enlargement of the head (macrocephaly), seizures, spasticity, and in some cases also hydrocephalus, idiopathic intracranial hypertension, and dementia. Symptoms vary greatly between patients.
Classification
Traditionally, Alexander disease has been classified by age at onset and is divided into infantile, juvenile, and adult forms. In line with this method of classification, some researchers have proposed adding an additional neonatal division for cases where the disease began before birth. These divisions have the following characteristics:
{| class="wikitable"
!Form
!Age at Onset
!Symptoms/Pathology
|-
|Neonatal
|< 1 month failure to thrive
|-
|Juvenile
|2–12 years bulbar symptoms that maps to chromosome 17q21. It is inherited in an autosomal dominant manner, such that the child of a parent with the disease has a 50% chance of inheriting the condition, if the parent is heterozygotic. However, most cases arise de novo as the result of sporadic mutations.
Pathology
thumb|Rosenthal fibers characteristic of Alexander disease
Alexander disease causes the gradual loss of bodily functions and the ability to talk. It also causes an overload of long-chain fatty acids in the brain, which destroy the myelin sheath. The cause of Alexander disease is a gain-of-function mutation in the gene encoding GFAP. The mutation causes protein aggregates called Rosenthal fibers to form in astrocytes' cytoplasm, but the exact method of this formation mechanism is not well understood. but occur in specific diseases, like some forms of cancer, Alzheimer's, Parkinson's, Huntington's, and ALS. It is even possible to detect adult-onset Alexander disease with MRI. A rough diagnosis may also be made through revealing of clinical symptoms, including enlarged head size, along with radiological studies, and negative tests for other leukodystrophies. A bone marrow transplant has been attempted on a child, but it made no improvement.
Prognosis
The prognosis is generally poor. Individuals with the infantile form usually die before the age of seven. The average duration of the infantile form is usually about three years. Duration of the juvenile form is about six years.