The Role of Genetics

A genetic predisposition (also called genetic susceptibility) is an increased likelihood of developing a particular disease based on a person’s genetic makeup. A genetic predisposition results from specific genetic variations that are often inherited from a parent. These genetic changes contribute to the development of a disease but do not directly cause it. Some people with a predisposing genetic variation will never get the disease while others will, even within the same family.

It is becoming more common for ANE patients and their families to be tested for a RanBP2 variant. It is important to note, however, that even with the gene mutation, not all mutations will result in ANE. 40% of RanBP2 carriers will experience an episode of ANE after a viral illness. 50% of episodes occur before the age of 2 years.

The probability of recurrence after the first episode, is 50% and then 25% after a second episode. Note that triggers (preceding viral illness) vary from one patient to the next. Some patients will only have 1 trigger while others will have multiple.

RanBP2 Genetic Variations


RAN binding protein 2 is listed as a “major susceptibility factor in Familial Acute Necrotizing Encephalopthy” ORPHA:88619 on Orphanet, (portal for rare diseases and orphan drugs).

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.

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 (above), 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 into 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 (cytokine storm). 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.



Carnitine Palmitoyltransferase 2 is listed on Orphanet (portal for rare diseases and orphan drugs) as a “candidate gene tested in Acute Necrotizing Encephalopathy of Childhood ORPHA:263524”.
Carnitine palmitoyl transferase 11 is associated with multiple syndromes of acute encephalopathy with various infecious diseases.

HLA Genotypes

Atypical immune responses on individual HLA genotypes may contribute to ANE.
Specific HLA genotypes confer susceptibility to Acute Necrotizing Encephalopathy



ribonuclease inhibitor (RNH1)

In summary, the clinical, genetic, and neuroradiological data in this study provide evidence that biallelic variants in RNH1 confer a variably penetrant predilection to an acute viral/febrile encephalopathy that overlaps ANE and ANE1; because of salient distinguishing features, it likely represents a recognizable subtype, and we propose it be referred to as ANE2.

Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy.



It is suspected that other, unknown genetic variations are yet to be discovered as a contributing factor of ANE.

Very rare cases of recurrent ANE without  RANBP2 missense mutations have also been reported.

Familial Acute Necrotizing Encephalopathy: Evidence from Next Generation Sequencing of Digenic Inheritance

“Variants in RANBP2 and CPT2 have been individually known to be associated with IIAE3 and IIAE4, respectively. Segregation analysis revealed that the RANBP2 variant was inherited from the father and the CPT2 variant from the mother. This case qualifies to be the first of its kind where digenic inheritance (ie, DNA sequence variants in 2 genes are required for the pathogenic phenotypes) appears to cause a lethal class of acute necrotizing encephalopathy. ”

Iyer G, Utage P, Bailur S, Utage A, Srirambhatla A, Hasan Q. Familial Acute Necrotizing Encephalopathy: Evidence From Next Generation Sequencing of Digenic Inheritance. J Child Neurol. 2020;35(6):393-397. doi:10.1177/0883073820902308

What’s in a name? –

The term “acute necrotizing encephalopathy” (ANE) continues to be used for ANE that is sporadic (i.e., a single occurrence in a family of unknown cause).

Infection-induced acute encephalopathy 3 (IIAE3) is reserved for ANE with a documented RANBP2 pathogenic variant.

The infection-induced acute encephalopathy (IIAE) series describes genetic predispositions to CNS dysfunction following infections:

  • IIAE1, IIAE2, IIAE5, and IIAE6 refer to genetic variants that allow herpes simplex virus to invade the CNS.
  • IIAE3 refers to non-neuronopathic infections of different types that can trigger encephalopathy without evidence of direct CNS invasion.
  • IIAE4 refers specifically to influenza-mediated encephalopathy, also without CNS invasion factor.


de novo mutation –

A genetic alteration that is present for the first time in one family member as a result of a variant (or mutation) in a germ cell (egg or sperm) of one of the parents, or a variant that arises in the fertilized egg itself during early embryogenesis. Also called de novo variant, new mutation, and new variant.