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Giant Axonal Neuropathy

NORD is very grateful to Gregor Kuhlenbaumer, MD, PhD, Department of Neurology, University of Munster, Germany, for assistance in the preparation of this report.

Synonyms of Giant Axonal Neuropathy

  • GAN

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Giant axonal neuropathy is a rare neuropathy that severely affects the peripheral as well as the central nervous system. The first symptoms appear in early childhood. This disorder is characterized by abnormalities in the peripheral and central nervous systems including low muscle tone (hypotonia), muscle weakness, decreased reflexes, impaired muscle coordination (ataxia), seizures and intellectual disability. Pale, tightly curled hair is frequently seen in those affected. Giant axonal neuropathy follows autosomal recessive genetic inheritance.

Symptoms

Symptoms of giant axonal neuropathy occur in early childhood before the age of seven years. Both the central and peripheral nervous systems are affected. The central nervous system includes the brain and spinal cord and the peripheral nervous system spreads out from the brain and spinal cord to all other areas of the body. Characteristics include low muscle tone (hypotonia), muscle weakness, decreased reflexes, impaired muscle coordination (ataxia), seizures and intellectual disability. In contrast to purely peripheral neuropathies, the reflex of the toes known as Babinski's sign is often positive, indicating involvement of central motor pathways. Most affected children have pale, tightly curled hair unlike their parent’s hair. Cranial nerves may also be affected leading to facial weakness, abnormal eyes and poor vision. An unusual leg posture is present in some affected children. Skeletal abnormalities such as scoliosis and foot deformities have been described and are thought to be a result of the nervous system dysfunction. Mental development is in most cases initially normal, but later in childhood degenerative mental changes (dementia) may occur as the disorder progresses. Giant axonal neuropathy is rapidly progressive, usually leading to dependence on a wheel chair by the second decade of life and death in the second or third decade.

Causes

Giant axonal neuropathy is an autosomal recessive genetic disorder. This condition is caused by an abnormality in the GAN gene located on chromosome 16 at 16q24.1 that codes for the gigaxonin protein. The abnormal gigaxonin protein causes a portion of the nerve cell called the axon to swell up with deposits of tiny threads of protein called neurofilaments, giving the appearance of giant axons. The giant axons cause degeneration and abnormal functioning of the peripheral nervous system.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome16q24.1" refers to band 24 on the long arm of chromosome 16. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits an abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All healthy individuals carry 4-5 recessive abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Affected Populations

Giant axonal neuropathy is a rare disorder that presents in early childhood. This disorder affects equal numbers of males and females. The prevalence of giant axonal neuropathy and the frequency of carriers of one defective copy of the GAN gene is not known, but it is known that giant axonal neuropathy is a very rare disease.

Related Disorders

Symptoms of the following disorders can be similar to those of giant axonal neuropathy. Comparisons may be useful for a differential diagnosis:

Charcot-Marie-Tooth (CMT) hereditary neuropathies are a group of disorders in which the motor and sensory peripheral nerves are affected, resulting in muscle weakness and atrophy, primarily in the legs and sometimes in the hands. In contrast to giant axonal neuropathy, the overwhelming majority of patients with CMT shows no, or only very mild, central nervous system (CNS) involvement. The differential diagnosis between the rather common CMT and giant axonal neuropathy is, therefore, rarely difficult. CMT group hereditary neuropathies affect mainly the peripheral nerves that control many muscles in the body. The nerve cells in individuals with this disorder are not able to send electrical signals properly because of abnormalities in the nerve axon or abnormalities in the insulation (myelin) around the axon. Specific gene mutations are responsible for the abnormal function of the peripheral nerves. Charcot Marie Tooth hereditary neuropathy can be inherited in an autosomal dominant, autosomal recessive or X-linked mode of inheritance. (For more information about this condition, choose "Charcot" as your search term in the Rare Disease Database.)

Seitelberger disease (infantile neuroaxonal dystrophy) is an inherited central nervous system disorder usually beginning before the age of two years. Children with Seitelberger disease may experience difficulty in walking and/or speaking. Coordination may become impaired, and decreased muscle tone ("floppiness"), muscle spasms (spasticity) and/or weakening of reflexes may also occur. In later stages, involuntary rapid eye movements, progressive vision problems and seizures can occur. (For more information on this disorder, choose "Seitelberger disease" as your search term in the Rare Disease Database.)

Menkes disease is a genetic disorder of copper metabolism that is characterized by seizures, intellectual disability, stunted growth, failure to thrive, unstable body temperature, and very unusual color and texture of hair. Menkes disease is inherited as an X-linked recessive trait and is found disproportionately in male children. (For more information about this condition, choose "Menkes" as your search term in the Rare Disease Database.)

Metachromatic leukodystrophy is a rare inherited disorder affecting the white matter of the brain (leukoencephalopathy). It is characterized by the accumulation of a fatty substance known as sulfatide (a sphingolipid) in the brain and other areas of the body. The fatty protective covering on the nerve fibers (myelin) is lost from areas of the central nervous system due to the buildup of sulfatide. Symptoms of metachromatic leukodystrophy may include convulsions, seizures, personality changes, spasticity, progressive dementia, motor disturbances progressing to paralysis, and/or visual impairment leading to blindness. (For more information on this condition, choose "leukodystrophy, metachromatic" as your search term in the Rare Disease Database.)

Toxic substances that affect the nervous system (neurotoxins) such as n-hexane and acrylamide can cause symptoms similar to those found in giant axonal neuropathy but sufficiently severe and/or chronic intoxications with these substances are rare.

Standard Therapies

Diagnosis
Diagnosis of giant axonal neuropathy is made by clinical findings and specialized tests including nerve conduction velocity, brain MRI and peripheral nerve biopsy. The hallmark finding on a peripheral nerve biopsy is the appearance of "giant axons" which are caused by the accumulation of neurofilaments. Molecular genetic testing for abnormalities in the GAN gene is available to confirm the diagnosis. Negative mutation screening of the region of the GAN gene which encodes the protein does not exclude the diagnosis of giant axonal neuropathy.

Treatment
Treatment of giant axonal neuropathy is symptomatic and supportive and often involves a team of professionals including pediatric neurologists, orthopedic surgeons, physiotherapists, psychologists and speech and language therapists. Services for visually and/or mobility impaired people may be of assistance to people with giant axonal neuropathy.

Genetic counseling will be of benefit for patients and their families.

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

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Giant Axonal Neuropathy Resources

Organizations:

References

TEXTBOOK
Vanderver, A and Pearl PL. Giant Axonal Neuropathy. In: The NORD Guide to Rare
Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003: 569.

JOURNAL ARTICLES
Timmerman V, De Jonghe P Van Broeckhoven C. Of giant axons and curly hair. Nat
Genet 2000;26:254-5.

Flanigan KM, Crawford TO, Griffin JW, et al. Localization of the giant axonal
europathy gene to chromosome 16q24. Ann Neurol 1998;43:143-8.

Igisu H, Ohta M, Tabira T, et al. Giant axonal neuropathy, a clinical entity affecting
the central as well as peripheral nervous system. Neurology 1975;25:717-721.

INTERNET
Kuhlenbaumer G, Timmerman V and Bomont, P. Updated:June 21, 2012. Giant
xonal Neuropathy. In: GeneReviews at GeneTests: Medical Genetics Information
esource (database online). Copyright, University of Washington, Seattle, 1997-2013.
vailable at http://www.genetests.org . Accessed:February 5, 2013.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD:
The Johns Hopkins University; Entry No. 256850. Last Update:3/30/12 Available at
Accessed:February 5, 2013.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2013/02/07 00:00:00 GMT+0

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