Acute necrotizing encephalopathy type 1, also known as susceptibility to infection-induced acute encephalopathy 3 or IIAE3, is a rare type of brain disease (encephalopathy) that occurs following a viral infection such as the flu.

Acute necrotizing encephalopathy type 1 typically appears in infancy or early childhood, although some people do not develop the condition until adolescence or adulthood. People with this condition usually show typical symptoms of an infection, such as fever, cough, congestion, vomiting, and diarrhea, for a few days. Following these flu-like symptoms, affected individuals develop neurological problems, such as seizures, hallucinations, difficulty coordinating movements (ataxia), or abnormal muscle tone. Eventually, most affected individuals go into a coma, which usually lasts for a number of weeks. The condition is described as "acute" because the episodes of illness are time-limited.

People with acute necrotizing encephalopathy type 1 develop areas of damage (lesions) in certain regions of the brain. As the condition progresses, these brain regions develop swelling (edema), bleeding (hemorrhage), and then tissue death (necrosis). The progressive brain damage and tissue loss results in encephalopathy.

Approximately one-third of individuals with acute necrotizing encephalopathy type 1 do not survive their illness and subsequent neurological decline. Of those who do survive, about half have permanent brain damage due to tissue necrosis, resulting in impairments in walking, speech, and other basic functions. Over time, many of these skills may be regained, but the loss of brain tissue is permanent. Other individuals who survive their illness appear to recover completely.

It is estimated that half of individuals with acute necrotizing encephalopathy type 1 are susceptible to recurrent episodes and will have another infection that results in neurological decline; some people may have numerous episodes throughout their lives. Neurological function worsens following each episode as more brain tissue is damaged.

Mutations in the RANBP2 gene have been found to increase the risk of developing acute necrotizing encephalopathy type 1. The RANBP2 gene provides instructions for making a protein that interacts with a protein complex known as the nuclear pore. The nuclear pore is a channel that allows transport of molecules in and out of the cell's nucleus. The RANBP2 protein helps regulate the transport of proteins and other molecules through the nuclear pore and helps modify proteins coming into or out of the nucleus. In addition to its functions at the nuclear pore, the RANBP2 protein also plays multiple roles during cell division and helps transport materials within cells.

RANBP2 gene mutations that are associated with acute necrotizing encephalopathy type 1 result in the production of a protein that cannot function normally either due to altered shape or because it cannot get to the nuclear pore where it is needed. These mutations do not cause health problems on their own; it is unclear how they are involved in the process by which a viral infection triggers neurological problems. Researchers suspect that prolonged inflammation in response to the infection may be involved in the development of acute necrotizing encephalopathy type 1, although the role of the altered RANBP2 protein in this process is unknown. Inflammation is a normal immune system response to injury and foreign invaders (such as viruses). However, excessive inflammation can damage the body's tissues. Additionally, certain inflammatory proteins can be toxic to nerve cells when present in large amounts. It is suspected that the combination of the altered RANBP2 protein and the abnormal immune response play a role in individuals' susceptibility to recurrent episodes of acute necrotizing encephalopathy type 1. In people with acute necrotizing encephalopathy type 1, the virus is not found in nerve cells in the brain or spinal cord (central nervous system), so it is likely that the immune reaction, rather than the infection itself, accounts for the neurological signs and symptoms.

Influenza is the most common virus found in people with acute necrotizing encephalopathy type 1; other viruses that are known to trigger this condition include human herpesvirus 6, coxsackie virus, and enteroviruses. In rare cases, the bacterium Mycoplasma pneumoniae is involved. Because the signs and symptoms of acute necrotizing encephalopathy type 1 do not vary significantly among the different infections, it is likely that the type of infection is less important than the occurrence of an infection to trigger the condition.

Some people with signs and symptoms of acute necrotizing encephalopathy type 1 do not have an identified mutation in the RANBP2 gene. In these cases, the gene involved is unknown.

Normal Function

The RANBP2 gene provides instructions for making a protein that typically associates with a protein complex known as the nuclear pore. The nuclear pore is embedded within the membrane that surrounds the cell's nucleus (called the nuclear envelope), forming a channel that allows transport of molecules in and out of the nucleus. The RANBP2 protein is attached to the nuclear pore outside of the nucleus, where it helps regulate the transport of proteins and other molecules through the nuclear pore and also helps modify proteins coming into or out of the nucleus.

When found elsewhere in the cell, the RANBP2 protein plays multiple roles during cell division, including breaking down and forming the nuclear envelope and dividing chromosomes. The RANBP2 protein is thought to associate with cell structures called microtubules, which form scaffolding within the cell to help cells maintain their shape. In conjunction with microtubules, the RANBP2 protein helps transport materials within cells.

In nerve cells in the brain, the RANBP2 protein is likely involved in the regulation of energy and the maintenance of the protective barrier that allows only certain substances to pass between blood vessels and the brain (the blood-brain barrier).

Health Conditions Related to Genetic Changes

Acute necrotizing encephalopathy type 1

At least three mutations in the RANBP2 gene have been found to increase the risk of developing acute necrotizing encephalopathy type 1. This condition, also known as susceptibility to infection-induced acute encephalopathy 3 or IIAE3, is a rare type of brain disease (encephalopathy) that occurs following a viral infection such as the flu. These mutations change single protein building blocks (amino acids) in the RANBP2 protein, resulting in the production of a protein that cannot function normally either due to altered shape or because it cannot get to the nuclear pore where it is needed.

These RANBP2 gene mutations do not cause health problems on their own; it is unclear how they are involved in the process by which a viral infection triggers neurological damage. While individuals with acute necrotizing encephalopathy type 1 frequently have damage to and often lose their blood-brain barrier, the influence of RANBP2 gene mutations is unknown. Researchers suspect that individuals who develop acute necrotizing encephalopathy type 1 produce too many immune system proteins called cytokines in response to the infection. The excess cytokines lead to prolonged inflammation, although the role of the altered RANBP2 protein in this process is unknown. Inflammation is a normal immune system response to injury and foreign invaders (such as viruses). However, excessive inflammation can damage many of the body's tissues. Additionally, certain cytokines can be toxic to nerve cells when present in large amounts. It is suspected that the combination of the altered RANBP2 protein and the abnormal immune response play a role in individuals' susceptibility to recurrent episodes of acute necrotizing encephalopathy type 1. In people with acute necrotizing encephalopathy type 1, the virus is not found in nerve cells in the brain or spinal cord (central nervous system), so it is likely that the immune reaction, rather than the infection itself, accounts for the neurological signs and symptoms.

Cancers

Genetic abnormalities that involve the RANBP2 gene can cause an abnormal growth called an inflammatory myofibroblastic tumor. This type of tumor can be noncancerous (benign) or cancerous (malignant) and can be found in tissues throughout the body. The genetic changes that cause this tumor are somatic, which means that they are acquired during a person's lifetime and are present only in certain cells. These genetic abnormalities result in a rearrangement (translocation) within chromosome 2 that fuses part of the RANBP2 gene with another gene known as ALK. The fusion of these two genes results in production of an abnormal protein that promotes uncontrolled cell growth, which can lead to the formation of a tumor.

Other Names for This Gene

• 358 kDa nucleoporin
• ADANE
• ANE1
• E3 SUMO-protein ligase RanBP2
• IIAE3
• nuclear pore complex protein Nup358
• nucleoporin 358
• nucleoporin Nup358
• NUP358
• P270
• ran-binding protein 2
• transformation-related protein 2
• TRP1
• TRP2

Genomic Location

Acute necrotizing encephalopathy type 1 is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing the disorder following an infection.

In most cases, an affected person inherits the mutation from a parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Some people who have the altered RANBP2 gene never develop the condition, a situation known as reduced penetrance. It is estimated that an individual with a RANBP2 gene mutation has a 40 percent chance of developing acute necrotizing encephalopathy type 1 during his or her lifetime. Additional genetic or environmental factors likely play a role in whether an infection triggers the signs and symptoms of this condition. The health history of the individual, such as nutritional status and number of prior infections, may also influence risk.

Acute necrotizing encephalopathy type 1 is likely a very rare condition, although its incidence is unknown. At least 59 cases of this condition have been reported in the scientific literature.