Alexander disease (ALX) is a rare and often fatal nervous system disorder that primarily occurs in infants and children.
The main features of Alexander disease are progressive mental impairment and loss of motor control. Based on the age of onset and type of symptoms present, ALX has been classified into three forms: infantile, juvenile, and adult. Alexander disease is named for Dr. W. Stewart Alexander, an Australian pathologist who first described an infantile case in 1949. Since that time, 80% of cases described have also been the infantile form. About 14% of patients have the juvenile form, and adult cases are rare. All three forms of ALX are unified by the presence of Rosenthal fibers (RF), microscopic protein aggregates that are found in astrocytes in the brain and spinal cord. Though Rosenthal fibers are associated with other conditions, the numbers and distribution of RF-containing astrocytes are unique to Alexander disease. ALX is one of the leukodystrophies, a group of disorders characterized by imperfect formation or maintenance of white matter, the myelin sheath (insulation) that covers the nerves in the brain and spinal cord. Patients with ALX usually display loss of white matter, most prominently in the frontal lobes of the brain.
Alexander disease is thought to be quite rare with approximately 200 cases described. Although there are no known prevalence estimates, the disease has been reported in both males and females and in various ethnic and racial groups.
Causes and symptoms
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.
In the infantile form of the disease, average age of onset is six months, with a range of birth to two years. Affected children tend to have progressive physical and mental retardation with loss of previously attained milestones. Head size becomes increasingly large and the forehead appears prominent as a result of megalencephaly (enlarged head and brain). Other disease manifestations include seizures , spasticity (stiffness of the arms and legs), quadriparesis, feeding problems, and ataxia (poor coordination). Hydrocephalus may also occur, especially in children with early onset of symptoms.
The juvenile form of ALX usually presents between age four and the early teens. Patients may develop some or all of the following symptoms: speech problems, difficulty swallowing, frequent vomiting, spasticity of the legs, ataxia, gradual intellectual decline, seizures, megalencephaly, or breathing problems. White matter abnormalities in the juvenile form are less prominent than in the infantile form.
The adult form of ALX represents the most variable and least common form of the disorder. Patients with the adult variant may have symptoms that mimic multiple sclerosis , or may display symptoms similar to the juvenile form of the disease, except with later onset and slower progression. White matter changes may or may not be present. Some adult cases have been discovered by chance when an autopsy reveals Rosenthal fibers, a characteristic finding of this disease.
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.
Management of ALX usually involves the services of multiple medical specialists. In addition to primary health care professionals, patients may require the care of specialists in neurology, neurosurgery, physical therapy, occupational therapy, social services, orthopedics, and gastroenterology. A genetic specialist, such as a clinical geneticist or a genetic counselor, may be helpful to the patient and family, especially at the time of diagnosis or prior to genetic testing. Families may also benefit from psychological counseling and contact with other families affected by ALX or another leukodystrophy .
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.
Recovery and rehabilitation
Given the rarity of ALX, the potential for rehabilitation in this disorder is unknown. Depending upon the type, severity, and rate of progression of symptoms in a given individual, interventions such as physical, occupational, and speech therapy may be recommended for management of disease-related complications. In severe cases of ALX, consideration may be given to placement in a residential care facility that can provide 24-hour care and support services.
As of 2003, there were no clinical trials for patients with Alexander disease. As more is learned about how mutations in the GFAP gene cause disease, it is hoped that new therapies may be developed in the future. As of December 2003, two laboratories were conducting research on the GFAP gene; both accept contact from patients and families. They are the Children's National Medical Center—Center for Genetic Medicine (202-884-6065 or <[email protected]>) and the University of Alabama at Birmingham, Michael Brenner Research Lab (608-263-9191 or <[email protected]>).
The course of Alexander disease is generally one of regression and progressive neurologic degeneration. Prognosis varies according to the form of the disease. Lifespan for patients with the infantile from is significantly reduced; affected individuals live anywhere from one to 10 years of age. For the juvenile form of the disease, survival ranges from several years after onset to the late teens, with rare cases living several decades. Due to the rarity of the adult form, little is known about the prognosis for this ALX variant.
Johnson, Anne B. "Alexander disease." Chapter 34. In Handbook of Clinical Neurology, Vol 22 (66), edited by Hugo Moser. Amsterdam: Elsevier Press, 1996.
Johnson, Anne B. "Alexander Disease: A Review and the Gene." International Journal of Developmental Neuroscience 20 (June–August 2003): 391–394.
Li, R., A. Messing, J. E. Goldman, and M. Brenner. "GFAP Mutations in Alexander Disease." International Journal of Developmental Neuroscience 20 (June–August 2002): 259–268.
Schiffmann, R., and O. Boespflug-Tanguay. "An Update on the Leukodystrophies." Current Opinion in Neurology 14 (December 2001): 789–794.
The National Institute of Neurological Disorders and Stroke (NINDS). Alexander Disease Information Page. (February 18, 2004). <http://www.ninds.nih.gov/health_and_medical/disorders/alexand_doc.htm>.
The Waisman Center. Alexander Disease Project. (February 18, 2004). <http://www.waisman.wisc.edu/alexander/index.html>.
Dawn J. Cardeiro, MS, CGC