What is Acute Necrotizing Encephalopathy?
Acute Necrotizing Encephalopathy
Acute Necrotizing Encephalopathy, as described by the Genetic & Rare diseases Information Center (USA) is a rare disease characterized by brain damage (encephalopathy) that usually follows an acute febrile disease, mostly viral infections. The symptoms of the viral infection (fever, respiratory infection, and gastroenteritis, among others) are followed by seizures, disturbance of consciousness that may rapidly progress to a coma, liver problems, and neurological deficits.
The disease is caused by both environmental factors and genetic factors. Usually, ANE develops secondary to viral infections, among which the influenza A, influenza B, and the human herpes virus 6, are the most common. ANE can be familial or sporadic, but both forms are very similar to each other. Most familial cases are caused by mutations in the RANBP2 gene, and are known as “infection-induced acute encephalopathy 3 (IIAE3)”.
Although the clinical course and the prognosis of ANE is diverse, the characteristic that is specific to the disease is the “multifocal symmetric brain lesions affecting the thalami, brain stem, cerebral white matter, and cerebellum” which can be seen on computed tomography (CT) or magnetic resonance imaging (MRI) exams. The best treatment of ANE is still under investigation but may include corticosteroids and anticytokine therapies, including TNFa antagonists.
“It’s a bit more complicated than “ANE is caused by a mutation in a gene” or “it is caused by a virus” or “it is caused by environmental factors”. In reality it is a combination of all of these. Your genes encode proteins that make up your cells. These proteins have various functions including how your body reacts to viruses and the environment. Disentangling all of this is very complicated. In the lab we can see that cells cannot survive without a RanBP2 protein – so it is likely that ANE-associated mutations do not completely disable the gene but alter it in a very particular way so that the body’s reaction to certain viral infections is altered”.
Alexander F. Palazzo
Brain scans (Computed Tomography – CT and Magnetic Resonance Imaging-MRI) show symmetric multifocal lesions affecting the brain (thalami, brainstem, periventricular white matter and cerebellum are the most common although other areas may be affected). The bilateral thalamic lesions are a distinctive feature of ANE. The spinal cord is rarely involved.
Cerebrospinal fluid (CSF) testing shows elevated protein, but very rarely pleocytosis (increased cell count). Sometimes, pathogens (viruses) responsible for infection are found in the CSF.
Diagnosis is made based on the presence of viral infection before the development of ANE, signs of rapidly neurological deterioration, the results of the brain scans (specifically the symmetric multifocal lesions) and CSF testing and exclusion of resembling diseases.
(How the disease happens).
The exact mechanism of the disease is not yet known. It is presumed to be an immune-mediated process triggered by the viral infection. In other words, people with ANE often may have an exaggerated immune response to various infections.
ANE is not considered to be an inflammatory encephalitis as there are no signs of infection in the CSF or the brain (as seen in autopsies, when performed).
The clinical course and the prognosis vary from patient to patient, ranging from a mild form with complete recovery (10%) to a severe form with a high mortality (30%). Most of the survivors are left with neurological sequelae (e.g. motor deficits, epilepsy, developmental delay). Poor prognosis is associated with delayed diagnosis, involvement of brainstem (part of the brain that connects the brain with the spinal cord and controls the heart and lung functions) and recurrent episodes. Recurrent or familial ANE without the RANBP2 mutation has a more severe outcome and greater predilection for males than that with the RANBP2 mutation. This suggests that there are unknown gene mutations linked to ANE.
ANE has the 2nd in the mortality rates and is another distinct neurological complication of influenza infection with reported mortality rates of 30%–40% second only to historical descriptions of encephalitis lethargica (60%) among neurologic complications of influenza.
There are no set guidelines for treating ANE. Treatment usually includes:
intensive care to help the patient perform their usual bodily functions (breathing machine, tubes and drips),
symptomatic treatment (e.g. antiepileptic drugs), immunotherapies (e.g. IV glucocorticoids, immunoglobulin, and plasmapheresis),therapeutic hypothermia (reduction of the body temperature done on purpose).
Recurrent and Familial Cases- ANE1
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.
Further Information At: https://ghr.nlm.nih.gov/gene/RANBP2#conditions
HLA Genotypes (In Japanese Patients)
Whilst the mutation of the RANBP2 gene has been confirmed to be associated with ANE, the involvement of HLA genotypes has not at this point. However, a recent study confirms the likelihood. ANE has been reported worldwide, but this disease is reported predominantly in children living in East Asian countries. The difference in occurence among various ethnic groups suggests the involvement of host genetic factors in ANE. Using 31 Japanese confirmed ANE patients a study was conducted in Japan and aimed for the first time to investigate genetic background of ANE within this ethnic group. Human leukocyte antigen (HLA) genotypes include HLA class I (HLA-A, -C and -B) and class II (HLA-DR, -DQ and -DP). These molecules play an important role in the immune response. The study focused on HLA genotypes as a predisposing factor to ANE based on the fact that the abnormal innate immune reaction was provoked by a preceding infection. In addition, HLA have been reported to be associated with various diseases susceptibility, such as autoimmune diseases and infectious diseases.
At the conclusion of the study there was enough evidence to support the above but due to the rarity of ANE the availability of statistics were limited. Further similar studies are required to confirm these findings. The data from this particular study suggests that specific HLA Genotypes are involved in the manner of development of ANE.
Read Full Article At: http://www.nature.com/gene/journal/v17/n6/full/gene201632a.html
“It’s so rare that we are not able to give an incidence number. So, in medicine we like to say how common something happens in a certain percentage of a population, say per 1000 or 100,000, but it is so rare that at this point we aren’t able to give it a number”.
Dr Michael Esser
Pediatric Neurologist & Researcher
Cumming School Of medicine
“Acute necrotizing encephalopathy (ANE) is underreported;
the prevalence and incidence of ANE remain unknown. Due to ascertainment bias, it is not possible to estimate the proportion of ANE that results from mutation of RANBP2 (and thus is classified as infection-induced acute encephalopathy 3 [IIAE3])“.
Dr Derek Neilson
genetics & metabolism
Phoenix childrens hospital
What ANE Families Are Saying
“Do not be afraid to ask the Dr’s a million questions. They are always there to help and want the best for your child. They will listen to your concerns. Listen to your gut feelings. You know your child best and be their advocate”.
“Grief will come, and that is ok. Grieving a child is the hardest thing you will do as a parent. You will grieve your child’s losses and your child may grieve some of those losses as well. This will be HARD!“.
“Any progress is good progress xx✨ “.
“Faites confiance à votre enfant ! Parfois, vous aurez l’impression qu’il avance à vitesse « tortue » mais vous verrez que, lorsque la forme est là, il nous surprend à avancer vitesse « éclair » !!!
Un jour à la fois 🙏❤️“
“Fight for everything you feel you need for your child, do not give up and work every step with your child and don’t let the school be ok with only simple things for goals, challenge your child at all times“