NORD gratefully acknowledges James E. Goldman, MD, PhD, Columbia University, for assistance in the preparation of this report.
Alexander disease is an extremely rare, usually progressive and fatal, neurological disorder. Initially it was detected most often during infancy or early childhood, but as better diagnostic tools have become available has been found to occur with similar frequency at all stages of life. Alexander disease has historically been included among the leukodystrophies--diseases of the white matter of the brain. These diseases affect the fatty material (myelin) that forms an insulating wrapping (sheath) around certain nerve fibers (axons). Myelin enables the efficient transmission of nerve impulses and provides the "whitish" appearance of the so-called white matter of the brain. There is a marked deficit in myelin formation in most early onset patients with Alexander disease, and sometimes in later onset patients, particularly in the front (frontal lobes) of the brain's two hemispheres (cerebrum). However, white matter defects are sometimes not observed in later onset individuals. Instead, the unifying feature among all Alexander disease patients is the presence of abnormal protein aggregates known as "Rosenthal fibers" throughout certain regions of the brain and spinal cord (central nervous system [CNS]). These aggregates occur inside astrocytes, a common cell type in the CNS that helps maintain a normal CNS environment. Accordingly, it is more appropriate to consider Alexander disease a disease of astrocytes (an astrogliopathy) than a white matter disease (leukodystrophy).
Alexander disease is named after the physician who first described the condition in 1949 (WS Alexander).
Historically, three forms of Alexander disease have been described based on age of onset, Infantile, Juvenile and Adult; but an analysis of a large number of patients concluded that the disease is better described as having two forms, Type I, which generally has an onset by age 4, and Type II, which can have onset at any age, but primarily after age 4. Each type accounts for about half of the reported patients. Symptoms associated with the Type I form include a failure to grow and gain weight at the expected rate (failure to thrive); delays in the development of certain physical, mental, and behavioral skills that are typically acquired at particular stages (psychomotor impairment); and sudden episodes of uncontrolled electrical activity in the brain (seizures). Additional features typically include progressive enlargement of the head (macrocephaly); abnormally increased muscle stiffness and restriction of movement (spasticity); lack of coordination (ataxia); and vomiting and difficulty swallowing, coughing, breathing or talking (bulbar and pseudobulbar signs). Nearly 90% of infantile patients display developmental problems and seizures, and over 50% the other symptoms mentioned; however, no single symptom or combination of symptoms is always present.
Patients with type II Alexander disease rarely show delay or regression of development, macrocephaly or seizures, and mental decline may develop slowly or not at all. Instead, about 50% display bulbar/pseudobulbar signs, about 75% have ataxia and about 33% spasticity. Because these symptoms are not specific, adult Alexander disease is sometimes confused with more common disorders such as multiple sclerosis or the presence of tumors. (For information on these diseases, see the related disorders section of this report.)
The two different forms of Alexander disease are generalizations rather than defined entities. In actuality there is an overlapping continuum of presentations; a one year old could present with symptoms more typical of a 10 years old, and vice-versa. However, in all cases the symptoms almost always worsen with time and eventually lead to death, with the downhill course generally (but not always) being swifter the earlier the onset.
About 95% of Alexander disease cases are caused by mutations in a gene called GFAP for a structural protein called glial fibrillary acidic protein that is found exclusively in astrocytes in the CNS. The cause of the other 5% of cases is not known.
The GFAP mutations are dominant. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. Thus, Alexander patients have one mutant copy and one normal copy of the GFAP gene. The abnormal gene can be inherited from either parent or can be the result of a new mutation (change in the DNA of the gene). Most Alexander patients have a new mutation, indicating that neither of their parents has the mutation, but the mutation arose at some point during the development of sperm or ova or an embryo. As the disease becomes better diagnosed, familial cases, in which the disease is passed from one generation to the next, are being increasingly recognized. The risk of transmitting the disorder from an affected parent to an offspring is 50 percent for each pregnancy. The risk is the same for males and females.
How the GFAP mutations produce Alexander disease is not known. The Rosenthal fibers, which contain GFAP, accumulate throughout the surfaces of the brain (cerebral cortex), in the white matter of the brain, and in the lower regions of the brain (brainstem), and the spinal cord, and primarily appear under the innermost of the protective membranes (meninges) surrounding the brain and spinal cord (pia mater); under the lining of the fluid-filled cavities (ventricles) of the brain (subependymal regions); and around blood vessels (perivascular regions). Studies in mice indicate that the mutations act by producing a new, toxic effect, rather than by interfering with the normal function of GFAP. This toxic effect may be due to the presence of the Rosenthal fibers, or to the very large, abnormal amounts of GFAP that accumulate in Alexander astrocytes, or both. Astrocytes perform many critical functions in the CNS, and several of these are affected by the GFAP mutations, but the importance of these changes to the disease is not yet known.
Alexander disease has been estimated to occur at a frequency of about 1 in 1 million births. No racial, ethnic, geographic, or sex preference has been observed, nor is any expected given the de novo (new) nature of the mutations responsible for most cases. Although initially diagnosed primarily in young children, it is now being observed with similar frequency at all ages.
For many years a brain biopsy to determine the presence of Rosenthal fibers was required for the diagnosis of Alexander disease. However, even this procedure can be ambiguous, because Rosenthal fibers are also found in certain other disorders, such as tumors of astrocytes. More recently, MRI criteria have been developed that have a high degree of accuracy for diagnosing typical Type I (early onset) disease. These criteria have been less useful for some of the Type II cases, which have little or no white matter deficits in the brain, although abnormalities in the brainstem, cerebellum, and spinal cord can suggest the diagnosis. Accordingly, when making a diagnosis of Alexander disease, more common diseases that have similar symptoms for which tests are available should first be ruled out. These include adrenoleukodystrophy, Canavan’s disease, glutaricacidurias, Krabbe leukodystrophy, Leigh syndrome, metachromic leukodystrophy, Pelizaeus-Merzbacher and Tay-Sachs disease. A definitive diagnosis of Alexander disease rests on the identification of a GFAP mutation in the patient’s DNA, which can be obtained from a blood sample or a swab of the inside of the cheek. DNA analysis is provided by several commercial and research laboratories. However, since no GFAP mutation has been found in about 5% of known cases, a negative result does not completely rule out the disease. Presently, Alexander patients without a GFAP mutation can be definitively diagnosed only at autopsy by the presence of disseminated, large numbers of Rosenthal fibers.
Treatment is symptomatic and supportive. Genetic counseling may be of benefit for patients and their families. Fetal diagnosis is an option for a couple who have had a previously affected child.
A few treatments have been performed on individual patients, but there have been no trials performed to determine if they are truly effective.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
Current research on Alexander disease is focused on identifying the genetic change in all cases and investigating the mechanism of how the mutations in the GFAP gene lead to the disease. Also being investigated is the exact composition of the Rosenthal fibers and the factors responsible for their formation and growth. Research is also underway to try to find ways to prevent the mutant GFAP from being made or accumulating. Together, these studies may eventually lead to new methods of diagnosis and, in time, to the development of new treatments for Alexander disease.
Families and individuals wanting to participate in studies on Alexander disease should contact the United Leukodystrophy Foundation (ULF) at (800) 728-5483.
Contact for additional information about Alexander Disease:
Albee Messing, VMD PhD
Professor of Neuropathology
University of Wisconsin-Madison
1500 Highland Avenue, Rm. 713
Madison, WI 53705-2280
Tel: (608) 263-9191 (office)
Cell Phone: 608-469-7315
Fax: (608) 263-4364
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Alexander Disease Website. Waisman Center, University of Wisconsin-Madison. Last Update January 11, 2016..Available at: http://www.waisman.wisc.edu/alexander/index.html Accessed February 1, 2017.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Alexander Disease. Entry No: 203450. Last Edited March 12, 2015. Available at: http://omim.org/entry/203450 Accessed February 1, 2017.
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