Author: Gabor Varga

EHBOS has been called by various names: deletion 22q13, mutation 22q13, mutation Shank3, deletion Shank3, Phelan-McDermid Syndrome etc. It was first described by Watt et al.:

Originally, it was assumed that a single gene Shank3 was responsible for the majority of mental manifestations of this disease. The most important features of this genetic syndrome are:  developmental delay, intellectual disability, ASD-like features and speech abnormalities.

Shank3 is one of the most important genes causing mental problems, however, without the damage or deletion of the Shank3 gene, deletion or interstitial deletion 22q13 can lead to severe mental disability, similar to the disease also caused by Shank3 involvement:.

This could implicate that the solution for genetic diseases involving several genes (either deletions or mutations, post translational modifications, epigenetic disturbances, etc.) would have to target common key molecular pathways leading to severe mental disabilities, instead of targeting isolated genes. Supporting this implication, recent research has shown that Shank3 is also involved in various common mental disturbances without inborn genetic defects, including bipolar disorder, schizophrenia, Alzheimer’s disease, environmental pollution-caused autism, autism in general, mental problems caused by aging, maternal deprivation and intellectual damages caused by stress, brain inflammation caused by aluminum, traumatic brain injury,  etc.

Scientists suggest that abnormal dendritic spine (tiny protrusions on neural brain cells) maturation and signaling is the cause of autism, implicating common pathways and leading to abnormal signaling.

Indeed, Shank3 is involved at the core of dendritic spine signaling and its expression or function may be affected by other genetic or epigenetic disorders.

Resolving Shank3-related problems is necessary but is sometimes an insufficient requirement for rescuing the mental defects of EHBOS. We know the upstream signaling that should be activated to compensate for Shank3 failure (Rac1-PAK-LIMK-Cofilin phosphorulation/inactivation). This should necessarily be fulfilled by a drug indicated for this disease. As downstream targets, the specific manifestations of EHBOS should lead us to find the optimal solution. My suggestion is that proinsulin C-peptide fulfills the conditions for a full scale remedy of EHBOS. Upstream C-peptide activates the pathway suggested by scientists:

Downstream one should go deep into the details of the symptoms of EHBOS.

First: proinsulin C-peptide is increasing insulin signaling.

This fact is important because intranasal insulin clinical trials are available for the investigation of its therapeutic effects. The author initiated the first clinical trial for intranasal insulin for EHBOS. As the most important immediate positive effect, the unstable hypothalamus of his son G.V., afflicted by EHBOS, has started to stabilize and the diabetes insipidus-like symptoms – also observed in other cases of EHBOS -

- have vanished. His weight, due to water retention, increased from 12kg to 15kg within a few months and his relatively high NaCl values decreased to an optimal mid-level (unpublished observation). His continuous pains that had been treated with adult pain killer medications stopped.

Because EHBOS is prone to develop early into Alzheimer’s disease, intranasal insulin treatment has been a true milestone for EHBOS, potentially preventing or at least delaying this degenerative process. This is also supported by other clinical trials for Alzheimer’s:

The molecular pathways making EHBOS prone to diabetes insipidus or unstable hypothalamus-hormonal problems may include – Rac1-PAK-LIMK – cofilin hypophosphorulation related-NMDA hypofunction:

This shows that insulin can also modulate this pathway, although with significantly less effectiveness than proinsulin c-peptide. full

Insulin can only induce immature dendritic spines, or filopodia: by probably also involving Shank3:

Proinsulin C-peptide can induce mature dendritic spines (in vivo unpublished observations by the author). This is important, because EHBOS is characterized by immature dendritic spine development.   

Partial restoration of synaptic deficits by intranasal insulin could restore vasopressin regulation and induce other significant improvements in EHBOS symptomatology.


Second: Proinsulin C-peptide seems to rescue many of the specific symptoms of EHBOS according to common downstream pathways leading to them.

  1. Carpal and/or ulnar tunnel syndrome-like phenomena. It is not mentioned in the scientific literature (overlooked), but often described and shown in pictures by parents in support groups. It is caused by inflammatory and nerve-degenerative, fibrotic pathways. TGF-beta and NF-kB are involved:
    C-peptide is able to curb these disease pathways that may lead to this phenomenon:

    Interestingly, in type 1 diabetes (lacking C-peptide) the occurrence of carpal tunnel syndrome is significantly increased:

    TGF-beta overactivation may be the consequence of integrin overactivation and/or Rac1 hypoactivation due to Shank3 failure, because Shank3 seems to limit integrin and increase Rac1 activity.
  2. Synovitis of the hip. It happens more often than you think (overlooked by scientific publications). B and T cell-related immune cell disturbances can be seen as causative for this problem as a consequence of Shank3 failure. As we have seen above, Shank3 limits the activity of Rap1 and Ras:
    But then, Rap may overactivate cofilin. Thus, the brake for the immune system may be damaged. „This biomechanical brake may serve to prevent inappropriate responses to antigen in the absence of optimal co-stimulation:” In:
  3. Dystonic cerebral palsy/parkinsonism. (Overlooked by the literature) Essentially, there seems to be a severe Na,K pump failure in EHBOS, also in cases where only Shank3 is affected, no other genes. The explanation for this phenomenon seems to be very simple. Cofilin in EHBOS – as we have seen – is overactivated, that is, its phosphorulation is impaired and phosphorulated cofilin provides about 30% energy/fuel for the high energy consuming Na,K pump in the brain:

    This, at least, should not have been overlooked by neuroscience!
    Interestingly, C-peptide is not only an effective cofilin phosphorulator, but can also increase Na,K pump expression: (Overlooked by neuroscience)
  4. Gastroparesis. It is common in EHBOS. By activating the parasympathetic pathway it can be ameliorated. (unpublished observation) Its occurrence is increased in autoimmune gastritis with autonomic nerve dysfunction. in:
    Interestingly, its appearance is correlated with decreased c-peptide levels in diabetes mellitus:
  5. Lymphedema. TGF-beta dysregulation can cause this „mysterious” phenomenon.
    Interestingly, it is also common in diabetes mellitus. Experts are perplexed by the cause of it. For explanation of TGF-beta overactivation in EHBOS, see point 1.
  6. Enlarged/dilated aortic root or aortic root aneurysm. Caused by overactivated cofilin in EHBOS.
    It should not have been overlooked!
  7. Cystic fibrosis. It also happens, caused by TGF-beta dysregulation.
    See point 1. in explanation for EHBOS.
  8. Pulmonary hypertension. It may happen in EHBOS. 
    PPARg agonist may ameliorate the problem.
    C-peptide is a PPARg agonist.

    Interestingly, activating the parasympathetic pathway – which can be done by central c-peptide (nasal spray) administration – is ameliorating the problem:

    Indeed, central c-peptide administration may be the ultimate solution for this potentially fatal phenomenon. For the role of c-peptide in autonomic nervous system regulation see:
  9. Cyanosis is characterized by bluish, purplish discoloration of the lips or skin, caused by low blood oxygen level. EHBOS is vulnerable to this problem; it happens relatively often. This may be caused by impaired ATP release of red blood cells which can be ameliorated by c-peptide.

    Breath holding also happens in EHBOS, which may contribute to cyanosis. A typical description of this is: “She is sort of holding her breath and then blowing it out.” or “X is holding her breath for 3-10 seconds between each breath...been going on for a few hrs at this point. Her tongue is kind of hanging...she's not coughing or wheezing.” Or “Can I ask if any of your children pause between breathing? Y seems to take between 4 of 5 seconds between each breath??” This is characterized by autonomic dysfunction.
    The problem may also be ameliorated by central/brain/intranasal C-peptide administration as it is regulating autonomic functions.
  10. Temperature dysregulation, febrile seizures, brain oxidative stress. Recurrent low fever is sometimes an issue for EHBOS. This may result from central temperature dysregulation due to oxidative stress. Oxidation in the brain can increase body temperature in an NMDA receptor (brain excitatory receptor)-dependent manner. Nitrotyrosine is a brain oxidative stress marker, which is elevated in EHBOS, in a Shank3-dependent manner.
    Brain oxidation can increase seizure susceptibility and also implicates mitochondrial dysfunction . Interestingly, c-peptide can decrease nitrotyrosine and oxidative stress:
  11. Inappropriate immune reactions in the brain, cortical atrophy, and regressions Overactivated cofilin makes the immune cells (in the brain microglia) prone to induce inflammation in an NF-kB dependent manner.
    This may also increase seizure susceptibility, and contribute to the cortical atrophy experienced in older subjects with EHBOS. Overactivated cofilin is also susceptible to oxidation (in Cysteine residue):
    This may be the reason why regressions often happen after a swimming course: contact with or inhaling chlorine triggers oxidation of overactivated cofilin, inducing apoptosis of neurons. Increased oxidative stress and inflammation susceptibility makes regressions often happen.
  12. Behavioral disturbances, heart arrhythmias: Parasympathetic regulation in autism is impaired which can be measured with Respiratory Sinus Arrhythmia, which is indicative of behavioral disturbances:
    Brain heart interaction is impaired in EHBOS .
    Bradycardia and tachycardia are often consequences of autonomic dysregulation in EHBOS.
    It is not surprising that children with type 1 diabetes who lack c-peptide have also increased behavioral dysregulation:
  13. Hypotonia.  Cofilin plays some role in muscle development and muscle contraction.
    Cofilin-dependent muscle contraction may happen by the LIMK-cofilin phosphorulation pathway
    or independently of it: . Because this pathway is impaired in EHBOS, it may be one of the reasons for hypotonia. Interestingly, type 1 diabetes is also characterized by fatigue and impaired muscle strength:
  14. Increased gut permeability and resulting bowel problems. Shank3 failure leads to damaged intestinal barrier function.
    Interestingly, inflammatory bowel disease is more common in diabetes mellitus type 1 with c-peptide deficiency:
    What's more, in t1d the gut junctions seem to be damaged, the gut mucosa and microbiota are prone to inflammation:
    More specifically, in gut microbiota abnormalities there is a striking similarity between the microbiota characteristics in autism and in t1d: „significant increase in the Firmicutes/Bacteroidetes ratio in autistic subjects due to a reduction of the Bacteroidetes relative abundance.” In:
    Until now, gut microbiota similarity between t1d and autism has also been  overlooked by science. Of course, in autism, there is no c-peptide deficiency, but most probably, a c-peptide signaling failure. It would be also interesting to look into why „SHANK3 expression correlated with ZO-1 and PKCε in colonic tissue of patients with Crohn's disease”
    In: ,
    because c-peptide is able to increase PKCε phosphorulation:
  15. Alzheimer’s. EHBOS, as we have seen, increases the risk of early Alzheimer’s, which seems also to be the case for Type 1 diabetes:

    Indeed, one of the most important inevitable early hallmarks of Alzheimer’s is cofilin hyperactivation which cannot be counter-regulated even by endogenous LIMK compensatory overactivation.

    The relationship between t1d and EHBOS/autism seems to be intricate because of early exposure to c-peptide deficiency in t1d; during gestation, it incresases the probability of autism diagnosis in the offspring by 250% compared to healthy controls:
  16. Nail and skin problems. Nail and skin abnormailities, sensitivity to stress factors may be explained by cofilin-dependent Golgi-related aberrations:

    Nail bed problems in t1d:
  17. Individuals suffering in EHBOS seem to be more susceptible to develop cancer. One subtype of deletion 22q13 is ring chromosome 22/Ring22. Ring chromosomes are unstable and are prone to loose the NF2 gene that may lead to Neurofibromatosis type2. We know this from parents that this is a real danger. My son has also Ring22. According to recent research neurofibromatosis type 2 can be effectively treated by suppressing the hyperactivated signalling of TGF-beta specifically by inhibiting receptor 1 of TGF-beta: Proinsulin C peptide can inhibit receptor 1 of TFG-beta: I have seen its therapeutic effect in vivo: it saved the sight of someone. It is a real therapeutic possibility for this „untreatable” disease. This therapeutic possibility has been overlooked by science.   
  18. Bipolar disorder, optic nerve atrophy, glaucoma: In point 3 we have seen that Na K pump impairment may play an important role in EHBOS (dystonic parkinsonism). Na K pump failure can not only increase the susceptibility to depression but can also lead to manic like behaviours what is often seen in individuals affected by EHBOS. For example one decription of a mother :
    “I absolutely HATE this MANIC crap!!!!! The laughing and the energy never ends.” Another: “Anyone else struggling with the full moon? S. is completely manic, loud, laughing, hyper and won't sleep. Ugh I hate this.” Another: “ When A. is manic all she does is go, go , go, and increasing her meds always seems to make it worse. ” The descriptions refer to individuals with deletion or mutation of the chromosome 22q13. This problem is discovered by the scientific literature but its cause (Na K pump failure) has been overseen:

    Optic nerve atrophy happens also in a few individuals with EHBOS. One typical description „So E. also has optic nerve hypoplasia. His optic nerve is super tiny.” Comlete sight loss happens also athough this occurs rarely. These two conditions may be caused also by Na K pump failure: Glaucoma is accompanying sometimes EHBOS (overseen by the literature). The probable cause of this may be hyperactivated TGF-beta. (See for the explanation of TGF hyperactivation point 1.):

  19. Children’s early death. Seizure, heart, pulmonary and inflammatory problems are common in EHBOS. Early death cases are frequent in EHBOS. Loosing a child is probably the most painful event in life. Seizure seems to be often fatal in EHBOS and autism besides heart, lung and inflammatory problems: The majority of early death cases may be prevented by increasing the parasympathetic tone by intranasal c-peptide, because it is a potent stimulator of the vagus nerve. (See ) Vagus nerve stimulation has been applied for intractable seizures for a long time:

    The anti-inflammatory properties of the parasympathetic nervous systhem can be exploited by intranasal c-peptide for preventing early death cases due to inflammatory diseases such as pulmonary infections: (For the activation of the parasympathetic nerves by c-peptide see but also zinc is necessary for the signalising functions of proinsulin c-peptide:

    It is not an accident that autism is characterised by autonomic imbalance and a higher sympathetic activity:

  20. Stroke like events may occur in EHBOS. One description of it: „It was suspected that my daughter had mini stroke when she was 13. Lost use on her right side ”

    Inflammation, oxydative stress and Blood Brain Barrier breakdown (as a consequence of Shank3 failure) may be among the causes of strokes.

    Proinsulin c-peptide is able to strenghten the vascular barrier in stress situations:
    Vagus nerve activation (by c-peptide) may prevent ischemic brain injury by lowering inflammation, oxydative stress and may confer neuroprotection by improving BBB integrity. Vagus activation may also prevent strokes by regulating the autonomic nervous function and blood pressure what is also often dysregulated in EHBOS according to parent’s descriptions.

  21. Dangerous drugs approved by FDA: The brain of a person suffering in EHBOS is vulnerable. In this situation challenging the central nervous system by inappropriate drugs may be dangerous and even may lead to life threatening conditions. Among the commonly used drugs, approved also for intranasal use by the authorities like the FDA, the so called sympathomimetic pills and nasal sprays may be especially problematic. The mother of a 2y old girl suffering in EHBOS using heavily a sympathomimetic nasal spray, containing oxymetazoline described the state of her child as following: „...when she had very high fever we had to go to hospital cause her right arm started to shake, she was not able to use it. After 20min the shaking stopped, but her arm was still weak for a week. .....our neuro prof said it was epilepsy. We had EEG but was negative.” After two months the girl had mild fever and the shaking returned again. At this point the mother stopped the administration of the nasal spray containing the sympathomimetic substance and the symptoms described above settled within 3 days.

    That oxymetazoline like sympathomimetic substances are dangerous especially for children has been well known by the medical literature for decades. It was administered for a 2y old child and caused cardiac arrest. He was successfully resuscitated.

    Naturally, for neonates sympathomimetics may be also life threatening causing coma.

    In small children among the side effects are epileptiform convulsive attacks, tachycardia, vasoconstriction, insomnia, frightening hallucinations.

    These over the counter cold remedies (sympathomimetics ) are also for adults not safe. They may cause cerebral vasoconstriction, headache, retinal artery branch occlusion, hypertension, tonic convulsion, cardiac arrythmia/arrest and even ischemic and hemorrhagic stroke, cerebral infarction, trembling, weakness, bradycardia, angitis, convulsions, tachycardia, paranoid psychosis, hallucinations, agitation, anxiety, sudden speech disturbances.

    Sympathomimetic drugs activate the so called alpha (1,2) –adrenergic receptors increasing the activity of the sympathetic nervous system and so making the body and the brain more susceptible to inflammation by activating the proinflammatory mediator interleukin (IL)-1beta.

    Unfortunately the activation of interleukin (IL)-1beta promotes the induction of febrile seizures and generally epilepsy.

    This may be the mechanism why fever could induce trembling and convulsion, stroke like symptoms in the case of the 2y old girl mentioned above.

    Interesting that patients afflicted by type 1 diabetes mellitus lacking proinsulin c peptide have autonomic disfunction characterised by increased sympathetic activity. Autism is also characterised by autonomic disfunction. Because the autonomic nervous system is indispensable for an appropriate host defence it is not surprising that also patients with type 1 diabetes and EHBOS are more vulnerable to infectious diseases than the general population.

  22. PCOS - Polycystic ovary syndrome is a common trait of both EHBOS and type 1 diabetes. A mother of a girl describes a case in a support group as follows: „It’s been mentioned about ovarian cysts on here!!! E. has three and looking like surgery in the next few hours!!!”

    Patients with type 1 diabetes have a 25% chance for having PCOS. In the general population this number is about 4-8%. The lack of proinsulin c peptide may increase inflammation and hormonal dysregulation (hyperandrogenism). According to the  scientific literature „insulin resistance is apparently not the major contributor to androgen excess in these women.”

    Excessive androgen hormones may increase the risk of psychiatric disorders, not only autism. Women with PCOS are at a significantly increased risk for bulimia, schizophrenia, bipolar disorder, depressive and anxiety disorders, personality disorders with the highest increased risk for ASD (55%).

    It is well known that elevated levels of prenatal testosterone may increase the risk for autism in the offspring. PCOS itself is sufficient to trigger pathways involved in the development of autism.  As we have seen, the offspring of mothers with type 1 diabetes lacking proinsulin c peptide have an enormously increased risk of autism (250%).

    Proinsulin c peptide in the brain seems to offer protection against PCOS, autism and psychiatric disorders generally.

  23. Symptoms associated with the consequences of stoke or traumatic brain injury:  aspiration, swallowing reflex problems, pneumonia, lung injury, hypertonia, insulin resistance, arrythmia, cardiac dysfunctions. EHBOS seems to cause brain damages reminiscent of the problems an ordinary stroke or TBI can cause. For example aspiration is a common characteristics of EHBOS. It is not sufficient to cause pneumonia but in conjunction with brain defects causing the dysregulation of autonomic nervous system may lead to pneumonia. Hyperactivity of the sympathetic and impaired parasympathetic tone can lead to increased gut permeability, blood pressure and immunosuppression (NK cell and macrophage defects). Increased gut permeability may cause bacterial infection without external pathogens.

    Vagus nerve activation, the potentiation of the parasympathetic nervous system, that can be achieved also by brain proinsulin c peptide administration, may alleviate or resolve the above mentioned problems.

  24. Dangerous FDA approved clinical trials harming EHBOS, particularly individuals with Shank3 failure. One of the most important lessons Shank3 and EHBOS researchers should have learned is that Shank3 cannot be replaced by other proteins because the work of the synapses cannot be compared to computer chips due to their unimaginable complexity. One of the growth factors clinical scientsists try to play with is IGF-1. Although IGF-1 seems to increase the abundance of PDS-95, a protein that increases the number and functionality and strength of synapses, it virtually kills Shank3. As the scientists put it: „Surprisingly, we found that IGF1 caused a dramatic decrease of Shank3 protein expression in the cell body and processes of both control and PMDS neurons…” or 

     Interestingly, IGF1 decreases Shank3 expression and promotes the formation of a class of synapses containing PSD95 but lacking Shank3.”


    Scientists writing this paper have done an excellent investigation but made a pseudoscientific conclusion, because they thought that Shank3 can be replaced by PSD-95. These results published in 2013 should have raised alarm in the head of clinical scientists.

    The possible cause of this result is that the abundance and stability of Shank3 is decreased by a biological process called ERK2 and ERK2 is increased by IGF-1:

    The real dangerous events for the affected are caused by pseudoscientific conclusions and biased clinical researchers leading to FDA approved clinical trials and biased papers like:

    If we look more closely at the side effects of the Shank3 killing drug IGF-1 we find hypoglicemia in most of the subjects participating in above linked the study. Hypolglicemia is a life threatening condition. The authors of the paper seem to be ignorant of this fact. What may hint at the possibility that this treatment is killing the remaining Shank3 in the brains of the EHBOS patients is that most of the patients get sleep disturbance. The cause of it is that Shank3 is a very important sleep regulating protein.
    If you lack it, this may cause problems to fall asleep even when you are sleepy.

    It is very problematic also that mood changes, irritability or lethargy are also occuring at most of the children.

    Such studies may mean for the affected that administering IGF-1 is not life threatening for EHBOS because the drug is legal (approved by FDA). Beside that, most of the individulas with severe brain damages and mental problems are immunologically compromised due to disturbances in the brain-gut neural axis.  That is, they are prone to infections caused by leeky gut that may leed to life threatening pneumonia. In the above mentioned clinical trial most of the children (5) had upper respiratory tract infection. If you decrease shank3 by IGF-1, you cannot expect the improvements of the central nervous sythem that may prevent the leeky gut syndrome as we see the facts in the study.

    The right treatments increasing the functionality of Shank3 and the synapses may save the lives of individuals suffering EHBOS. The right treatment should increase the parasympathetic functions and so decrease the leeky gut problems and prevent seizure activity.

    According to anecdotal evidences, parents telling they epreriences related to the study in question, epileptic activity was also more frequent among the children receiving IGF-1. This may be not surprising, because IGF-1 decreases the threshold of seizures.
    Long-term treatment of IGF-1 to an injured brain is pro epileptic.

    This fact and the anecdotal evidences are not mentioned in the study. This raises many question about this clinical study because a new IGF-1 study is under way. Will it be safe?

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