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It is becoming more common to have ANE patients and their families tested for a gene mutation. It is important to note, however, that even with the gene mutation, not all mutations will result in ANE. The actual trigger has yet to be determined. Probability of recurrence after the first episode, is 50% on trigger activation (ie. Influenza; HSV) and then 25% after a second episode. Note that triggers vary from one patient to the next. Some patients will only have 1 trigger while others will have multiple.

At least three mutations in the RANBP2 gene have been found to increase the risk of developing acute necrotizing encephalopathy type 1 (ANE1). These mutations change single protein building blocks (amino acids) in the gene’s protein resulting in the production of a protein that cannot function properly. The mutations do not cause health issues on their own; it is not clear how they are involved in the process of a viral infection triggering neurological damage.

These genes are inherited in an Autosomal Dominant manner.

Autosomal dominant inheritance pattern

In an autosomal dominant disorder, the mutated gene is a dominant gene located on one of the nonsex chromosomes (autosomes). You need only one mutated gene to be affected by this type of disorder. A person with an autosomal dominant disorder — in this case, the father — has a 50 percent chance of having an affected child with one mutated gene (dominant gene) and a 50 percent chance of having an unaffected child with two normal genes (recessive genes).

Each child of an individual with susceptibility to infection-induced acute encephalopathy 3 (IIAE3) / ANE1 has a 50% chance of inheriting the genetic mutation. Penetrance is incomplete (this means that you may have the gene but never have ANE). Forty percent of people with the mutation for RANBP2 mutation will manifest an episode of acute necrotizing encephalopathy (ANE); 50% of such episodes occur before age two years. A first episode becomes less likely with age, but can occur in adulthood.

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.