NORD gratefully acknowledges Gregor Kuhlenbaumer, MD, PhD, Department of Neurology, University of Munster, Germany, for assistance in the preparation of this report.
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 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.
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.
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.
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 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.
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