Giant axonal neuropathy
Giant axonal neuropathy is an exceptionally rare congenital disorder with a wide range of debilitating symptoms that affect voluntary and involuntary muscle control. Giant axonal neuropathy involves abnormalities of axons which are the parts of neurons that deliver impulses. It affects both the central nervous system (the brain and the spinal cord) and the peripheral nervous system.
Definition & Facts
Giant axonal neuropathy (GAN) is a rare, inherited genetic disorder that is an early-onset and fatal disease that slowly causes impairment and the degeneration of the peripheral as well as central nervous systems. It is a neurodegenerative disorder that results in the loss of basic functions. Giant axonal neuropathy begins at infancy and most people with this disease do not live past their twenties.
Unfortunately because this condition is so rare, funding for research into this disease is less robust than it is for more common diseases.
Symptoms & Complaints
- Gait abnormality
- Physical clumsiness
- Inability to control one’s body and coordinate movements (ataxia)
- Dysmetria, a form of ataxia in which a person cannot judge distances and coordinate them with muscle movement.
- Increased muscle weakness
- Little to no feeling in the arms and legs
- Occasional seizures
- Oculomotor apraxia – the inability to control eye movement.
- Nystagmus, which is the rapid back and forth movement of the eyes from left to right
- Vision loss and hearing loss
- Neurogenic bladder (e.g. overactive bladder syndrome or underactive bladder) and constipation
- Intellectual disability can occur in some cases.
As symptoms persist and worsen, most individuals with GAN will become wheelchair dependent in their early to mid 20s. Wheelchair dependence tends to further weaken the body and increased muscle atrophy occurs rapidly as a result, rendering most patients bedridden and immobile. Most patients with this disorder pass away by their thirties typically due to respiratory failure.
Giant axonal neuropathy is caused by genetic mutations of the GAN gene which make a protein called gigaxonin. There are 20 different genetic mutations associated with this condition. Gigaxonin is a cytoskeletal protein. These mutations result in fewer gigaxonin which increases the amount of neurofilaments which are typically broken down by gigaxonin. These neurofilaments overcrowd the axon cells which results in their destruction. Restricted movement and depleted sensation result from the deterioration of the axons.
The mutations that cause this disorder are inherited through the autosomal recessive inheritance pattern. This means that the child has to inherit two copies of the genetic mutation from genetic carriers who themselves do not have the disease; both parents must be carriers.
Diagnosis & Tests
Diagnosis will involve an intake of medical history and physical history as well as a physical examination. One common physical trait of those with giant axonal neuropathy is that they tend to have extremely curly hair even when their parents do not. They may also be pale, have red hair, and a high forehead.
Giant axonal neuropathy is also diagnosed professionally with a series of tests and can be detected in a variety of different ways, including:
- The measuring of nerve conduction velocity through a nerve conduction study
- A magnetic resonance imaging (MRI) of the brain
- A peripheral nerve biopsy, which involves the removal of a small portion of the nerve tissue (a biopsy) for extensive examination of engorged axons. Other types of cells will also be swollen with excessive neurofilaments.
- A brain biopsy will show that the white matter appear diseased.
- Genetic testing can detect the genetic mutations responsible for this disorder.
Giant axonal neuropathy is detected when results from a nerve conduction studies show moderate to low speeds of conduction, indicating that the axons are heavy and weighed down with dense cell material and are unable to function.
Treatment & Therapy
There is no definitive treatment for giant axonal neuropathy. However, there are therapies that can help ease the side effects of giant axonal neuropathy. It is recommended that families work together with a medical team that includes the following team of professionals:
- Pediatric neurologist
- Orthopedic surgeon
- Speech therapist
- Occupational therapists
Speech therapy, physical therapy, occupational therapy, psychotherapy, and counseling all play a role in improving the quality of life of a patient with giant axonal neuropathy. Hearing aids and eyeglasses will be used to address the hearing and vision problems associated with this condition. Special education may also be necessary for children with learning disabilities and cognitive deficits caused by this condition.
According to Hannah's Hope Fund, a charity that raises money for research into giant axonal neuropathy clinical trials are underway in which a virus is used to transmit a healthy GAN gene into nerve cells. This process involves the virus binding to the surface of the cell. The DNA of the virus will invade the nucleus of the nerve cell and express the missing protein. The first patient to undergo this form of gene therapy occurred in 2015. Though still highly experimental, such clinical trials offer hope for patients and families with this exceptionally rare and deadly disease.
Prevention & Prophylaxis