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DiseaseID HGD49
Genetic Disorder Alexander disease
Gene Name GFAP gene
Description

Alexander disease is one of a group of neurological conditions known as the leukodystrophies, disorders that are the result of abnormalities in myelin, the “white matter” that protects nerve fibers in the brain. Alexander disease is a progressive and usually fatal disease. The destruction of white matter is accompanied by the formation of Rosenthal fibers, which are abnormal clumps of protein that accumulate in non-neuronal cells of the brain called astrocytes. Rosenthal fibers are sometimes found in other disorders, but not in the same amount or area of the brain that are featured in Alexander disease. The infantile form is the most common type of Alexander disease. It has an onset during the first two years of life. Usually there are both 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 is less common and has an onset between the ages of two and thirteen. These children may have excessive vomiting, difficulty swallowing and speaking, poor coordination, and loss of motor control. Adult-onset forms of Alexander disease are rare, but have been reported. The symptoms sometimes mimic those of Parkinson’s disease or multiple sclerosis. The disease occurs in both males and females, and there are no ethnic, racial, geographic, or cultural/economic differences in its distribution.

Symptoms

Symptoms may include: mental and physical retardation, dementia, enlargement of the brain and head, spasticity (stiffness of arms and/or legs), and seizures.

Causes Most cases of Alexander disease are genetic, caused by a dominant mutation (change) in the glial fibrillary acidic protein (GFAP) gene on chromosome 17. Usually this mutation occurs randomly in an individual without a family history of the disease. There are reports of rare familial cases with affected siblings. Therefore, unaffected parents of a child with ALX are at a low risk to have another affected child. Individuals with ALX who live long enough to reproduce have a 50% chance for an affected child. Since GFAP mutations have not been found in all cases of ALX, there may rarely be other genetic or non-genetic explanations for this disease. The glial fibrillary acidic protein gene encodes a protein by the same name. GFAP helps to provide structural stability to the astrocytes, which are supporting cells in the brain similar to blood vessels. GFAP is found in Rosenthal fibers. Reports have suggested that GFAP gene mutations result in a toxic gain of function of the protein (GFAP) that leads to a minimal or absent production of myelin. As of 2003, the precise mechanisms by which GFAP mutations cause ALX were unresolved.
Diagnosis A diagnosis of Alexander disease is usually based on radiologic findings and/or genetic test results in an individual who has symptoms suggestive of this condition. Radiologic studies that may aid in diagnosis include magnetic resonance imaging (MRI), a computerized tomography (CT) scan, or a head ultrasound. For example, an MRI of an individual with the infantile form typically reveals white matter loss that involves the frontal lobes of the brain, abnormalities of the basal ganglia and thalamus, and possibly, enlargement of the ventricles. Genetic testing is accomplished by looking for known or detectable mutations in the GFAP gene. In up to 94% of cases of ALX, a GFAP mutation is found. Prenatal diagnosis for couples with an affected child can be performed when the mutation responsible for ALX is known. The DNA of a fetus can be tested using cells obtained from chorionic villus sampling (CVS) or amniocentesis. Prior to the discovery of the gene responsible for the disease, diagnosis of ALX was made by demonstration of Rosenthal fibers in a biopsy or autopsy sample from the brain. Though genetic testing has largely replaced these histologic studies, a brain biopsy or autopsy may be indicated in select cases if the diagnosis cannot be made through other means.
Treatment There is no cure for Alexander disease. Treatment, which is symptomatic and supportive, primarily consists of attention to general care and nutritional needs, antibiotic therapy for infections, and management of associated complications such as anti-epileptic drug therapy for seizures. Surgical interventions, including placement of a feeding tube and/or shunting for hydrocephalus, may also be required. Orthopedic surgery for scoliosis has been reported in a case of Alexander disease.
     

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