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Alexander Disease
NORD is very grateful to Michael Brenner, PhD, University of Alabama at Birmingham, for assistance in the preparation of this report.
Synonyms of Alexander Disease
- 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
Disorder Subdivisions
- No subdivisions found.
General Discussion
Alexander disease is named after the physician who first described the condition in 1949 (WS Alexander). It 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 cases of Alexander disease, and sometimes in later onset cases, particularly in the front (frontal lobes) of the brain's two hemispheres (cerebrum). However, white matter defects are sometimes not observed in later onset cases. Instead, the unifying feature among all Alexander disease cases 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 in astrocytes, a particular 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).
Symptoms
The infantile form of Alexander disease, defined as having an onset in the first two years of life, accounts for about half of the reported cases. Symptoms associated with this 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 retardation); 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, 75% seizures, and over 50% the other symptoms mentioned; however, no single symptom or combination of symptoms is always present.
Juvenile Alexander disease generally refers to cases with an onset between two and 12 years of life. Symptoms may be similar to the infantile form, but generally these are only about half as frequent as in the infantile form. Exceptions are ataxia, which remains near 50%, and bulbar and pseudobulbar signs, which rise to near 90%. Mental decline may develop slowly or not at all.
Patients presenting with Alexander disease after their 13th birthday are said to have the adult form. These cases almost never show delay or regression of development, macrocephaly or seizures. Instead, all patients thus far reported 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.)
As just described, the symptoms of Alexander disease tend to depend on the time of onset. However, the different forms are historical generalizations rather than defined entities. An analysis currently in progress suggests that Alexander disease is better described as having two forms, an early onset form most commonly presenting by four years of age, and a later onset form generally presenting after age four. 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, for all forms of the disease 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.
Causes
About 95% of Alexander disease cases are caused by mutations in a structural protein called glial fibrillary acidic protein (GFAP) that is found almost exclusively in astrocytes. 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. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Most individuals with Alexander disease have a new mutation. 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 offspring is 50 percent for each pregnancy. The risk is the same for males and females.
GFAP is a component of Rosenthal fibers, but how the mutations produce Alexander disease is not known. The Rosenthal fibers usually accumulate throughout the surfaces of the brain (cerebral cortex), 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 their precursors. It is not known what this toxic effect is; since astrocytes perform many critical functions in the CNS, there are many possible processes that could be affected.
No metabolic defect has been identified as a cause of Alexander disease. "Metabolism" refers to all the chemical processes in the body, including the breakdown of complex substances into simpler ones (catabolism), usually with the release of energy, and processes in which complex substances are built up from simpler ones (anabolism), usually resulting in energy consumption. Metabolic disorders are characterized by abnormal functioning of specific enzymes that catalyze the chemical reactions in the body.
Affected Populations
About 200 cases of Alexander disease have been described in the literature, but no precise estimates of incidence or prevalence are available. Based on human mutation rates, a likely frequency is in the range of 1 in 20,000 to 1 in 100,000 births. No racial, ethnic, geographic, or sex preference has been observed, nor is any expected given the de novo 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. Since the mutations are dominant, there is a 50% chance that the child of an affected adult will have the disease.
Related Disorders
Symptoms of the following disorders can be similar to those of Alexander disease. Comparisons may be useful for a differential diagnosis:
Hydrocephalus is a condition in which the normal flow of cerebrospinal fluid (CSF) is restricted and the spaces in the brain (ventricles) become abnormally enlarged. Fluid accumulates beneath the skull and puts pressure on the brain. Hydrocephalus is characterized in children by an abnormally enlarged head (megalencephaly). The scalp may be thin and transparent, and the forehead may bulge (frontal bossing). Other symptoms of hydrocephalus may include convulsions, abnormal reflexes, a slowed heartbeat, headache, vomiting, weakness and/or problems with vision. (For more information on this disorder, choose "Hydrocephalus" as your search term in the Rare Disease Database.)
Multiple sclerosis is a chronic disorder of the central nervous system (CNS) that causes the destruction of the fatty covering on nerves (demyelination). The symptoms of this disease vary greatly and may include visual impairment, double vision and/or involuntary rhythmic movements of the eyes (nystagmus), impairment of speech, numbness or tingling sensations in the arms and legs, muscle weakness and/or difficulty walking. The symptoms of Multiple Sclerosis may be similar to those of adult-onset Alexander disease. (For more information on this disorder, choose "Multiple Sclerosis" as your search term in the Rare Disease Database.)
Astrocytomas are brain tumors that can be either benign or malignant and are composed of large, star shaped cells (astrocytes). Symptoms may vary according to the size, location, and growth rate of the tumor. Frequently the first symptom is a recurrent headache that is typically a result of increased pressure within the skull due to the growth of the tumor. Headaches may be accompanied by vomiting and/or personality changes. Other symptoms of benign or malignant astrocytomas may include irritability, emotional instability, memory loss, intellectual impairment, convulsions, paralysis, and/or seizures. (For more information on this disorder, choose "Astrocytoma" as your search term in the Rare Disease Database.)
Adrenoleukodystrophy is a form of leukodystrophy. It is a rare inherited metabolic disorder characterized by the accumulation of very long chain fatty acids (VLCFA) in the brain that causes the progressive loss of the fatty covering (myelin sheath) on nerves within the brain. This disorder also causes progressive degeneration of the adrenal gland (adrenal atrophy). Symptoms of the childhood form of adrenoleukodystrophy, which affects almost exclusively males and is inherited from the mother, may include loss of previously acquired intellectual skills, poor memory, loss of emotional control, a jerky uncoordinated walk (ataxia), and/or muscle weakness on one side of the body. Other symptoms may include difficulties with speech, hearing loss, and/or visual impairment. (For more information on this disorder, choose "Adrenoleukodystrophy" as your search term in the Rare Disease Database.)
Canavan leukodystrophy is another rare, inherited form of leukodystrophy characterized by the progressive deterioration of the central nervous system. Symptoms of this disorder may include floppiness, the loss of previously acquired mental and motor skills, poor head control, an abnormally enlarged head (megalencephaly) and/or blindness. As Canavan leukodystrophy progresses, there may be spastic muscle contractions in the arms and legs and paralysis. This disorder is caused by a chemical imbalance in the brain and symptoms typically appear in early infancy. It is autosomal recessive, so that one affected gene is inherited from each parent, and it is most common in individuals of Jewish background. (For more information on this disorder, choose "Canavan Leukodystrophy" as your search term in the Rare Disease Database
Metachromatic leukodystrophy is a rare inherited leukodystrophy characterized by the abnormal accumulation of a fatty-like substance (sphingolipid) in the brain and other tissues of the body. Symptoms of this disorder may include muscle rigidity, visual impairment, and/or convulsions. Previously acquired physical and intellectual skills may be lost. This disorder may begin in infancy, adolescence, or adulthood. It is an autosomal recessive disorder. (For more information on this disorder, choose "Metachromatic Leukodystrophy" as your search term in the Rare Disease Database.)
Pelizaeus-Merzbacher brain sclerosis is a very rare inherited leukodystrophy characterized by the degeneration of the brain caused by the loss of the fatty myelin sheath covering the nerves (demyelination). This disorder may begin in infancy or adulthood. The first symptoms in an infant include failure to thrive, developmental delays, muscle spasms, unsteadiness, weakness, and/or visual impairment. Deformities of the bones and convulsions are sometimes seen. It is usually inherited from the mother and is most common in boys. (For more information on this disorder, choose "Pelizaeus-Merzbacher" as your search term in the Rare Disease Database.)
Standard Therapies
Diagnosis
For many years a brain biopsy to determine the presence of Rosenthal fibers was required for diagnosis of Alexander disease. However, even this procedure can be ambiguous, because these aggregates 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 early onset disease. These criteria have been less useful for some of the later onset cases which have little or no white matter deficits, and instead only show atrophy of the brainstem, cerebellum or spinal cord. Accordingly, when making the diagnosis, more common diseases that have similar symptoms for which tests are available should first be ruled out. These include Canavan's disease, Leigh's encephalopathy, adrenoleukodystrophy, metachromic leukodystrophy, Krabbe leukodystrophy, Tay-Sachs, glutaric aciduria and Pelizaeus-Merzbacher. Definitive diagnosis of Alexander disease can be provided by identification of one of the known GFAP mutations in the patient's DNA, which can be obtained from a blood sample or a swab of the inside 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 rule out the disease. Presently cases without a GFAP mutation can be definitively diagnosed only at autopsy by the presence of disseminated Rosenthal fibers.
Treatment
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.
Investigational Therapies
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
Email: prpl@cc.nih.gov
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
Current research on Alexander disease is focused on identifying the genetic change in all cases and investigating the mechanism of how the mutations 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. 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), (800) 728-5483.
Contact for additional information about Alexander Disease:
Albee Messing, VMD PhD
Professor of Neuropathology
Waisman Center on Mental Retardation
& Human Development and Department of Comparative Biosciences
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
E-mail: MESSING@Waisman.Wisc.Edu
Organizations related to Alexander Disease
References
TEXTBOOKS
Flint, D. and Brenner, M. (2011) Alexander disease, In Leukodystrophies. Raymond, G.V., Eichler, F., Fatemi, A., and Naidu, S., Mac Keith Press, London; 2011:106-129.
Brenner M, Goldman JE, Quinlan RA, Messing A. Alexander disease: a genetic disorder of astrocytes. In Astrocytes in Pathophysiology of the Nervous System, ed. V Parpura, PG Haydon, pp. 591-648. Boston: Springer; 2009:591-648.
Adams RD, et al., eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill Companies, Inc.; 1997:945.
Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:1727.
JOURNAL ARTICLES
Van der Knaap MS, et al. Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord. Neurology 2006;66:494-498.
Hagemann TL., et al. Alexander disease-associated glial fibrillary acidic protein mutations in mice induce Rosenthal fiber formation and a white matter stress response. J Neurosci 2006;26:11162-11173.
Li, R, et al. Propensity for paternal inheritance of de novo mutations in Alexander disease. Hum. Genet. 2006;119:137-144.
Van der Knaap MS, et al. Unusual variants of Alexander disease. Annals Neurol. 2005;57:327-338.
Li R, et al. GFAP mutations in infantile, juvenile and adult forms of Alexander disease. Annals Neurol. 2005;57:310-326.
Li R, et al. GFAP Mutations in Alexander Disease. Int. J. Dev. Neurosci. 2002;20:259-268.
Van der Knaap MS, et al. Alexander disease: diagnosis with MR imaging. Am. J. Neuroradiol. 2001;22:541-552.
Brenner M, et al. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nature Genetics 2001; 27:117-120.
Borrett D. Alexander's disease. Brain. 1985;108:367-385.
Alexander WS. Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. Brain. 1949;72:373-381.
INTERNET
Alexander Disease Website. Waisman Center, University of Wisconsin-Madison. Available at: http://www.waisman.wisc.edu/alexander/index.html. Updated March 23, 2011. Accessed June 6, 2011.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Alexander Disease. Entry No: 203450. Last Edited November 10, 2009. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed June 6, 2011.
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Report last updated: 2011/06/07 00:00:00 GMT+0
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