Alexander Disease

Alexander Disease

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Alexander Disease is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • 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

  • None

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.

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

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.

Resources

March of Dimes Birth Defects Foundation

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United Leukodystrophy Foundation

224 N. 2nd St.

Suite 2

DeKalb, IL 60115

Tel: (815)748-3211

Tel: (800)728-5483

Email: office@ulf.org

Internet: http://www.ulf.org/



ELA - European Association Against Leukodystrophies

2, rue Mi-les-Vignes

54521

Laxou Cedex, 61024

France

Tel: 33383309334

Fax: 33383300068

Email: ela@ela-asso.com

Internet: http://www.ela-asso.com



NIH/National Institute of Neurological Disorders and Stroke

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Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/



Hunter's Hope Foundation, Inc.

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6368 West Quaker Street

Orchard Park, NY 14127

Tel: (716)667-1200

Fax: (716)667-1212

Tel: (877)984-4673

Email: info@huntershope.org

Internet: http://www.huntershope.org



Genetic and Rare Diseases (GARD) Information Center

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Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

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Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Let Them Hear Foundation

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East Palo Alto, CA 94303

Tel: (650)462-3174

Fax: (650)462-3144

Email: info@letthemhear.org

Internet: http://www.letthemhear.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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