Monday 30 October 2023

eIF3f-related neurodevelopmental disorder



I recently received an email from a mother in New Zealand asking about what might help her adult son, recently diagnosed with an extremely rare type of “autism” called elF3f - related neurodevelopmental disorder.

This post is just based on a preliminary investigation, I think much more would be possible if a serious full-time review was made. This applies to all the other single gene autisms that are “untreatable”.


eIF3f (eukaryotic translation initiation factor 3 subunit f)

elF3f is one of the more complicated genes/proteins with multiple functions. In layman’s terms it is involved in making all the other proteins.

eIF3f is a subunit of the eIF3 complex, hence the “f” on the end. It is required for several steps in the initiation of protein synthesis.

We saw how elF4 plays a role in how Fragile X causes intellectual disability. eIF4 is another translation initiation factor that plays a key role in the initiation of protein synthesis.

The eIF4 complex and the eIF3 complex interact with each other to form the translation initiation complex. This complex is responsible for bringing together the mRNA, the ribosome, and the initiator tRNA, which allows protein synthesis to begin.  I did warn you it gets complicated!

eIF4 and eIF3 are both essential for the initiation of protein synthesis.

eIF3f is also involved in the regulation of cell growth and proliferation, making it a target gene in cancer therapy, where eIF3f can be overexpressed or under-expressed.


In spite of what the Simon’s Foundation’s Searchlight project

Simons Search - Partnering with families. Understanding genetic changes.

Driven by science. United by hope

In order to create scientific breakthroughs for rare genetic neurodevelopmental disorders, families and scientists must come together. Simons Searchlight‘s mission is to shed light on these disorders by collecting high-quality, standardized natural history data and building strong partnerships between researchers, industry and families. Families like yours are the key to making meaningful progress.


and others say that “at this point, there are no medicines designed to treat the syndrome”, there certainly are potential treatment strategies available.

The mother did question whether there are similarities with Rett syndrome.  You can apparently reduce expression of eIF3f using the common supplement EGCG (Epigallocatechin Gallate). EGCG has been found to benefit Rett syndrome.

I think what is likely required for eIF3f-related neurodevelopmental disorder is the exact opposite, which is to increase expression of eIF3f.


Sources of data:-


GeneCards - EIF3F Gene - Eukaryotic Translation Initiation Factor 3 Subunit F

RGD - EIF3F (eukaryotic translation initiation factor 3 subunit F) Homo sapiens


The above two sites do provide a great deal of information, but I think a lot is auto-generated and there are mistakes.

What we are looking for are safe substances that change expression of the gene eIF3f.

According to GeneCards there is only one substance - quercetin.

According to RGD there is a long list.  This did look very promising, but when I looked at the linked references I did not always find that the supporting data exists.  This is a problem with AI (artificial intelligence), it can make things up.

Sometimes you have to go back to the basic science.

There is evidence that activating the PI3K/AKT/mTOR signaling pathway will increase eIF3f expression.

One known was to do that would be via increasing IGF-1 – insulin-like growth factor 1. You can inject IGF-1 and it has even been trialed in autism.

In New Zealand there is an OTC supplement called CGPMax that claims to increase IGF-1.

I checked and indeed there is some evidence that CGPMax may also increase the expression of eIF3f.

“There is some evidence that CGPMax may also increase the expression of eIF3f. In a study of ER-positive breast cancer cells, CGPMax was shown to increase the expression of eIF3f mRNA and protein. This was thought to be due to the inhibition of CDK4/6, which led to the activation of the PI3K/AKT/mTOR signaling pathway.”

AI generated

Since our reader is in New Zealand and wants a supplement rather than a drug, I think CGPMax is a good fit and certainly worth a trial.

One of the substances suggested by the RGD site was valproic acid.  This looked great news because valproic acid, an anti-epileptic drug (AED), is often used to safely treat even young children.

Why does Valproic acid apparently increase eIF3f mRNA?  That would highly likely be down to it being an HDAC inhibitor which causes it to make epigenetic changes that turn on/off our genes.

We know that some single gene autism can be treated by HDAC inhibitors, at least in mouse models. The potent HDAC inhibitors are now used to treat cancer. One parent I met at the Thinking Autism conference was desperate to access one of these potent drugs for her child’s single gene autism, similar to Kabuki syndrome.

Broccoli sprouts produce an HDAC inhibitor, called sulforaphane.

I could not find any supporting data why valproic acid was listed, the linked reference did not actually refer to eIF3f.

Nonetheless it is harmless to try broccoli sprouts.



Another common product popped up in my brief review and that was Quercetin. I had not expected to find that. There is a reaction between quercetin and eIF3f. It is not fully understood. 

Quercetin is a widely available OTC product and simple to trial.



It is known that estradiol can increase the expression of eIF3f.

The effect of estradiol on eIF3f expression is likely mediated by the estrogen receptor alpha (ERα).  We have seen that estrogen receptor beta (ERβ) is under-expressed in autism.

Increasing estradiol, or indeed reducing testosterone, has been proposed as an autism therapy. This is not a simple strategy.  In cancer therapy radical steps are taken to reduce sex hormones, because it is the only way to stop the growth of certain types of cancer.

Disturbing the level of male/female hormones will have body-wide effects.  The “men” who currently take large doses of female hormones are going to have consequences later in life.

There is dietary therapy in the form of phytoestrogens that is known to be safe.  The Japanese eat a lot of soy products.

Soy is a particularly good source of phytoestrogens, especially a type of phytoestrogen called isoflavones. Isoflavones are similar in structure to estrogen, but they are much weaker.

Incorporating more soy products into diet would seem a reasonable strategy.



There is some evidence that the antibiotic gentamicin can activate the gene eIF3f.  It is given by injection.

Among the list of substance that can increase eIF3f mRNA are some quite toxic substances like BPA found in plastic packaging.  Another interesting option was listed under “anti-rheumatic drugs”, this actually refers to tocilizumab. This is an anti-arthritis drug given to people over the age of two.  Since it ends in -mab, we can infer that it contains monoclonal antibodies, in this case to interleukin-6.

Tocilizumab would likely be helpful in many people with other kinds of autism with a strong auto-immune component.


eIF3f-specific treatments vs treat as idiopathic autism

We know from readers with children with different single gene autisms, that are supposed to be untreatable, that these children often respond well to therapies in use for autism of unknown origin (idiopathic autism).

Almost all autism features neuroinflammation, activated microglia etc. Most autism features oxidative stress.  Most autism features impaired myelination. Much autism features mitochondrial dysfunction.

There are specific insights that a genetic diagnosis does give you.  In the case of eIF3f, we are dealing with hypo-active (REDUCED) pro-growth signaling. That means the opposite to the kids born with macrocephaly (big heads).


This excellent framework was explained in this old post

IGF-1 was mentioned earlier as a possible therapy.  Note that growth hormone (GH) is made in the anterior pituitary gland, it is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body.

More IGF-1 would lead to more growth. Even in an adult you can increase the density of dendritic spines.

As shown in the chart above on the lower right, in today’s disorder we have decreased protein synthesis.

Now back to the science and the basics of this syndrome. 

eIF3f-related neurodevelopmental disorder (EIF3F-RND) is a rare genetic disorder that causes a variety of neurological and developmental problems. It is caused by mutations in the eIF3f gene, which provides instructions for making a protein that is involved in protein synthesis. It has to be inherited from both parents.

If both parents are carriers, there is a 25% chance that each child will have EIF3F-RND, a 50% chance that each child will be a carrier, and a 25% chance that each child will not have EIF3F-RND and will not be a carrier.

If only one parent is a carrier of the mutated gene, there is a 50% chance that each child will be a carrier, and a 50% chance that each child will not be a carrier and will not have EIF3F-RND.

The incidence of EIF3F-related neurodevelopmental disorder (EIF3F-RND) is unknown. However, it is estimated to be a very rare disorder, affecting less than 1 in 100,000 people. This is likely due to the fact that EIF3F-RND is caused by mutations in a single gene. In order for a child to be affected, both parents must carry a copy of the mutated gene. If only one parent is a carrier, the child will be a carrier, but will not be affected.

The incidence of EIF3F-RND may also be underestimated, as it is a relatively newly identified disorder. As more people are diagnosed with the disorder, the incidence rate may increase. 

EIF3F-RND is caused by under-expression of the eIF3f protein.

Symptoms of EIF3F-RND can vary widely from person to person, but may include:

  • Intellectual disability
  • Developmental delay
  • Seizures
  • Hypotonia (low muscle tone)
  • Microcephaly (small head size)
  • Autism spectrum disorder
  • Facial dysmorphism





Interactions with other genes/proteins 

One feature of the GeneCards website is that you can see a representation of which are the most important interactions of a gene/protein.

This can sometimes suggest a possible therapy, since one of these related genes might be easier to treat.

In the case of eIF3f almost all the interactions are with other elF-somethings.

The RPS-somethings below are all genes that translate mRNA into proteins.

So, everything below is part of the machinery cells have to make proteins.




EIF3F-related neurodevelopmental disorder research

The EIF3F-NDR research is still in its infancy.

There need to be a models made that can suggest which downstream genes are affected and hence might be treatable.

An eIF3f activator is a drug or other compound that can increase the expression or activity of the eIF3f protein.

Currently, there are no known eIF3f activators that are approved for clinical use. However, researchers are developing a number of different approaches to activating EIF3F, including:

  • Small molecule drugs: Researchers are screening libraries of small molecules to identify compounds that can bind to eIF3f and increase its activity.
  • Gene therapy: Gene therapy could be used to deliver a working copy of the eIF3f gene to cells in the nervous system.
  • CRISPR gene editing: CRISPR gene editing could be used to correct mutations in the eIF3f gene.

In addition to the above approaches, there are a number of other things that could potentially be done to activate eIF3f, such as:

  • Identifying and targeting upstream regulators of eIF3f: Researchers could identify and target other proteins or genes that regulate the expression or activity of eIF3f. This could lead to the development of new drugs or other therapies that could be used to activate eIF3f indirectly.
  • Understanding the role of eIF3f in different cell types: Researchers are still learning about the role of eIF3f in different cell types in the nervous system. This knowledge could be used to develop targeted therapies that activate eIF3f in the specific cell types where it is needed most.


EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum



An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients.


21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals’ facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype–phenotype correlation.


Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.


The cancer research

Cancer research is much more advanced and better funded than autism research.

As you can see in the table below, decreased expression of eIF3f is feature of several common cancers. If you can upregulate eIF3f you might have a viable cancer therapy.

As in many types of autism, the potential exists to repurpose cancer drugs as and when they get developed and approved. HDAC inhibition is perhaps the best example. So far people are too scared to try the new potent HDAC inhibitors in human single-gene (monogenic) autism.


Alternatively, an indirect regulation of the activity of eIF3 is performed by association of its subunits with other proteins involved in the regulation of protein synthesis. For example, the subunit eIF3e binds p56 in interferon-treated or virus-infected mammalian cells, and inhibits the translation in vitro and in vivo [43, 44]. The subunit eIF3g interacts with Paip1, a Poly (A)-binding protein and stimulates translation initiation [45] whereas the subunits eIF3h and eIF3f interact with TRC8, a ubiquitin E3 ligase, and inhibit protein synthesis, possibly through ubiquitilation of eIF3 or some other translational components [46]. These mechanisms and interacting partners render eIF3 a pivotal player in controlling the protein synthesis and degradation. 

All these data confirm that eIF3f has a multileveled control of multiple functions in the cells, outside its usual function in translation. Keeping it in mind, targeting eIF3f may be a strategy to reorganize different intracellular pathways and alter the basis of the balance between cell proliferation and apoptosis. Thus, eIF3f represents a lead candidate to use for biotherapeutic applications both for inhibiting the growth of cancer cells or muscle atrophy and thus preventing its progression into irreversible cachexia.



Personally, I would treat EIF3F-NDR with two parallel approaches:

·        As idiopathic autism with hypo-active pro-growth sigaling autism (small heads/microcephaly)

·        Gene specific with clever ideas targeting the effects of eIF3f under-expression.

Is the cognitive impairment responding to bumetanide?  In the models of Rett syndrome and Fragile-X this is the case. For EIF3F-NDR you could just make your own trial.

For sure there will be oxidative stress in EIF3F-NDR due to the malfunctioning in the protein synthesis “machinery”.  NAC is the antioxidant of choice and is OTC.

EIF3F-NDR can be associated with GI dysfunction, as is much of broader autism.  When treated this often leads to improvements in behavior.

Increasing IGF-1 looks achievable.

Nerve growth factor (NGF) may be upregulated by Lion’s Mane mushrooms, according to the research.

BDNF (brain derived neurotropic factor) can be up regulated. Certain foods and nutrients have been shown to increase BDNF levels. For example, one study found that lutein supplementation increased BDNF levels in the blood. Other foods and nutrients that have been shown to increase BDNF levels include omega-3 fatty acids, magnesium, and zinc.  Some drugs increase BDNF such as lithium, SSRIs, modafinil. Statins such as Simvastatin and Atorvastatin are known to increase BDNF.




  1. Peter you are an indispensable help to asd families. I continue to be grateful that in spite of your son’s success, you press on with sharing your take on the literature and helping families with your analysis of it..

  2. Peter, is Valentina still reading your blog? From the comments, she seems to be the only one who seems to have some experience with using Valproic acid. Valentina, if you are reading this, I’m looking forward to your response

  3. Just a word of caution for readers who are new to hacking molecular pathways to raise a specific protein (the typical case for nonsense mutations in rare genetic disorders).
    Even though some substances actually raise the expression of your protein of choice, it doesn't always mean this is a good therapy option.
    A good example is when the protein is part of the body's response to oxidative stress. Anything that raises oxidative stress will then raise the body's need for and production of that protein. But for a person who can't produce enough of that protein from the beginning, the deficit will be even more pronounced under the load of oxidative stress. For this specific example, you might want to look for substances that lessen the need for (and also production of) your protein, which would be antioxidants.

    Always crossreference substances (drugs or supplements) to see what effects they have, especially in related disorders and other affected body systems.


    1. Thank you for this Ling. We are doing whole exome sequence testing next week. My son was just diagnosed with the complication of excited catatonia. The hits just keeping coming for him unfortunately. Another rare complication not well known. Great. Perfect.

    2. Oh Tanya, I'm really sorry you have to endure this.
      I hope you finally get an answer from the WES, to better understand what you are dealing with.
      Lots of strength to you!

    3. Thanks Ling - I’m a bit worried about what the future holds - hoping treatment works

  4. I have wanted to try Blackcurrant for awhile but I cannot afford CGPMax unless I was doing a one time trial.

    1. It is pretty expensive, but the drug version is likely to be 100x the price.

  5. Hi Peter, I’m meeting with Dr. Frye on Monday. Do you have any specific questions? I would be willing to ask him since you have helped me so much. Thank you


    1. Stephen, good luck with Dr Frye on Monday.

      I did meet him a while back and I don't have any specific questions for him at the moment.

    2. Stephen, I know it was targeted for Peter. But if it's okay for you can you please ask this to him? With such chronic high doses of Leucovorin, are we not risking hyper methylation which can turn off good genes? Another would be, what worked best for his own son's recovery? TIA

    3. Sorry about that second question. I just realized it was Dr. Rossignols child who has Autism and not Dr. Frye's!

    4. No worries Janu, I think that's a definitely worthwhile question to ask. I'll let you know what he says since I have two kids that take Leucovorin.

    5. Hey Janu, Dr Frye appointment is over and done. He didn't seem to worried about turning off of good genes. We talked extensively about Leucovorin. I guess there are good quality brand and bad brands in the states. Once I get the brand list I'll send it. Levoleucovorin is not FDA approved so it's not available too buy except in Switzerland. Lastly, nothing secret or cutting edge in ASD best to keep reading Peter's blog.


    6. Thank you Stephen!

  6. Good morning Peter

    Hope you are well.Please what can one use for OCD as we have a really bad case here.My son won't allow you touch him and will push your hands away.if you are teaching him something on the iPad,he won't allow you touch the iPad,chairs in the house have to be placed in a certain way he keeps adjusting it, always adjusting drawers, doors have to be closed in a particular manner by him.He won't allow you hold him to cross the road and has no awareness of danger, wont listen to instructions at the pool.

    Its just draining and I don't know what to do again.He was to walk on specific lines outside and some sort of rituals when we are outside, he has to collect petals and squeeze and getting him indoors is another thing once he sees the flowers and then we have just had this sudden coughing tic that he does all day.What do you think this is and what can we do about it.
    I have contacted the paediatrician but there are no appointments till December ending but I doubt if he will do anything other than to explain it away as autism and increase his dose of ADHD medication.Hes on guafacine 2mg daily.

    Please do you have any advice

    1. Apinke, unless I am mixing you up with another reader, I seem to recall that you once trialled bumetanide and it seemed to work but the school complained about the need for extra toilet breaks.

      If your son did respond to Bumetanide, I would go back to using it again.

      Many young children with autism have stimming/OCD that responds to NAC. Even if you tried it before, try it again and see if it helps with the problem behaviors that you are now experiencing. I would try 1200 mg NAC before school and then 600 mg around lunch and 600mg around 4 or 5m.

      My son used to compulsively pick the wild flowers growing at the side of the pavement. NAC stopped that from the first day.

    2. Hi Peter Thank you so much.yes he responded.What dose would you recommend for me to try him on?Hes weighing about 34kg now.
      Thank you I will start the NAC right away and source for bumetanide as the one I have is out of date..

    3. Apinke, I suggest 1mg of bumetanide once a day.

      If school makes a problem, you could try giving it after school. It has to taken every day.

      As he is a responder, he will then be able to learn more at school and become more aware of dangers. Life will get better.

    4. Apinke, I saw your pain, the child's pain, please try it, if the child is not allergic to plants, nikworm syrup india in a single socket once a day, morning and evening, I don't know how old the child is, for an adult it is 30 ml dim and 30 in the evening, it will immediately calm his OCD and ritual behavior, if it went well, repeat it after 10 days, and then you can administer samento with the pinnela from nutramedix, start slowly, bifdidus probiotics so he doesn't miss it, a small dose of clonazepam, you'll see because it's another child, try it and you'll prove me right.

    5. Thank you Peter and Dragos

  7. In end of august and whole september i was sneezing but NAC worked (I didn't take NAC before). Does this mean my allergy doesn't affect my medication?

    1. This means that NAC resolved a symptom of your allergy, which is a known effect of NAC. NAC has very many well documented beneficial effects.

    2. But you said that medications including NAC don't work in allergy time. That's what i meant. Thank you

    3. Stefan, every case is slightly different. In my son pollen allergy negates the cognitive benefit of bumetanide and triggers aggressive behaviors.

      NAC continues to have its effect in the background but when you have aggression nobody is really interested in whether there is stimming or not.

      Many people with autism are never aggressive. In those people allergy might just cause a cognitive impairment as intracellular chloride rose and wiped out the benefit of bumetanide.

      Some people do not notice small changes in cognition in their child but they certainly will notice a punch to their face.

      NAC is a really good supplement to take if you have autism any chronic condition like diabetes or you are over 50 years old

  8. Hi Peter ,

    I just found your blog last night and really want to read all sharing and comment. It is really great and useful.

    I have an interesting observation on my son, and would like to have your views.

    Firstly I am a father of an autistic boy of 7 years old. He was diagnosed as mild autism when he was 18 months. And Dr also diagnosed him as ADHD as well when he qas 6. He takes Atomoxetine every day for the ADHD.

    I was really tired of handling his behavior and emotions issues. When my family go for a walk or dine out, my wife and I are nervous for any his behaviour which may impact other people due to his impulse.

    Around a month agao, he started having FMT treatment. He takes 2 FMT capsules and 2 teaspoon of Inulin everyday. And he also takes 20ml lactulose to ease up his constipation. He also stops eating eggs and cheddar cheese due to allergies stated in his Igg report.

    After around 3 weeks, I observed improvement on eye contact, impusive behavior and also emotions. More and active eye contacts, almost no impulsive behaviour. Emotions become stable. His ADHD symptoms look gone.

    From my understanding, FMT and Inulin makes more good bateria in his gut, and the bacteria produce butyric acid which ease up his inflammations. So his symptoms are improved

    Now he is still shy and reluncant to do anything which may make him being a focus of people. E.g. sing a song in the class, and even say "please" in the request.

    And he is still stubborn. In addition to these two, he just behaves like a typical child.

    I just wonder if he should take butyric acid supplement to observe any further improvement.

    And any supplement he can try to improve his stubbornness and shy? /Eddy

    1. Ciao Eddy dove prendi le capsule di fmt?

    2. Eddy, trying sodium butyrate would be worthwhile, it has many good effects.

      There is also a Japanese probiotic used for many decades in both children and livestock called MIYAIRI 588. This contains Clostridium butyricum, which specifically produces butyric acid in the gut.

      If you like probiotics there is also L. plantarum 299v which is good for many types of GI inflammation.

      There is the "psychobiotic" Lactobacillus plantarum PS128, which was shown in the study below to provide some benefit in autism.,28%2Dday%20consumption%20of%20PS128.

      You might want to consult a dietician who treats kids with mild autism or ADHD. They report good results with simple dietary modification.

      You may then find you no longer need Atomoxetine/Strattera.

    3. Just note that MIYARI 588 can make stool harder, which you don't want if your son already has constipation. I vaguely recall that combining it with Bifidobacterium Longum BB536 capsules helped with that.
      Sounds like you should continue the gut route. Check for more alleries/intolerances and add products that have additional effect.
      Good luck!

  9. Hi Peter, my son tried the PS128 before, but I didn't observe any improvement. I stopped it around 4 months before.

    I just ordered butyric acid calcium/magnesium. Will try it next week. Let's see if any miracle will happen. Thanks your suggestion.

  10. Hi Diego,
    I DIY the FMT capaules. I take my younger son's fecal and inject it into capsules. Then I put them in the freezer. I learnt the way from youtube.

  11. Hi Peter,
    My son has had severe toilet regression.He was fully potty trained from 4 to 10 years.He is 12 years

    Two year ago,he started having pee accidents.Initially we thought it was behavior issues.Tried lots of behavior but nothing seems to work.He cannot hold his pee even for 30 min.Doctors prescribed him oxybutynin and Luvox.
    Dr this it might be related to OCD.It worked for a while but never returned to baseline and then stopped working.

    Not sure what to do now.Please suggest.

    1. SB, urinary incontinence is common in autism and indeed in ADHD. It has many completely different causes.

      Your doctor will have considered the common causes like urinary tract infections and in kids with autism it can also be a behavioral consequence of something else, like a change of school or teacher.

      OCD or anxiety could be the problem and that is why you have Luvox.

      It can even be a symptom of PANS-PANDAS, but there would be other symptoms like a reduction in cognition or a long list of other symptoms.

      Oxybutin is to treat an overactive bladder.

      The question is whether the problem is in the bladder or the brain.

      Urinary incontinence could also be a side effect of some drug or supplement he is taking. This is worth considering and just think back to see what you may have changed 2 years ago.

      You could try mild anti-inflammatory therapies like a few days on ibuprofen - assuming a PANS-like issue. If it was OCD-related, you could try NAC 4 times a day.


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