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Showing posts with label Estradiol. Show all posts
Showing posts with label Estradiol. Show all posts

Thursday 23 July 2020

How to increase Oxytocin (OT) effects in the autistic brain? OT nasal spray, L. reuteri DSM 17938, Magnesium, Estradiol, Nicotinamide riboside …



 Struggle to make friends? Consider Oxytocin



Today’s post was going to be about FMT super-donors, but instead we have a post about new insights into using oxytocin to treat autism.  From personal experience I can say that you really can target oxytocin receptors to affect mood/behavior; I have no personal experience of FMT (fecal microbiota transplants), but thousands of people use it for many conditions.  The FMT post will be next.

Oxytocin and vasopressin are two hormones, made in the hypothalamus, that are established targets for autism treatment. They are released into the bloodstream where they carry out their best-known functions, but they are also released from the hypothalamus directly into the brain where these hormones have entirely different functions.

Both oxytocin and vasopressin can be given as nasal sprays to enter the central nervous system (CNS) rather than just the blood stream.  This means you get the brain effects of the hormone, also known as the “central effects”.

As was discussed previously in this blog and is highlighted more recently in the article below, you can use certain bacteria in the gut to signal to the hypothalamus to produce more oxytocin.  This is really clever and it works in humans, not just research animals.  It also has the advantage of producing a more continuous effect than is found using the intranasal method to deliver oxytocin. 

When you sever the vagus nerve, the bacteria in the gut continues to produce the required chemicals, but the signal to the brain has been lost. The hypothalamus no longer produces increased oxytocin and so the behavioral/mood effect is lost. This has been proven in the research.

Gut microbes may treat social difficulties in autism mice


In science speak, “the results suggest that a peptide or metabolite produced by bacteria may modulate host oxytocin secretion for potential public or personalized health goals”.  It also appears that oxytocin improves wound healing. So perhaps old people with leg ulcers, which never seem to get better, might benefit from a daily dose of L. reuteri DSM 17938, it also might make them feel better due to those central effects.


Oxytocin in the brain acts via oxytocin receptors

As we learned years ago in this blog, you can increase the effect (turn up the volume) of receptors using a PAM (positive allosteric modulator).  Interestingly, magnesium is a PAM of the oxytocin receptor (OTR).  Many people with autism are supplementing magnesium, perhaps those using intranasal oxytocin should join them. 

A very recent paper has investigated in detail how oxytocin receptors function.


The peptide hormone oxytocin modulates socioemotional behavior and sexual reproduction via the centrally expressed oxytocin receptor (OTR) across several species. Here, we report the crystal structure of human OTR in complex with retosiban, a nonpeptidic antagonist developed as an oral drug for the prevention of preterm labor. Our structure reveals insights into the detailed interactions between the G protein–coupled receptor (GPCR) and an OTR-selective antagonist. The observation of an extrahelical cholesterol molecule, binding in an unexpected location between helices IV and V, provides a structural rationale for its allosteric effect and critical influence on OTR function. Furthermore, our structure in combination with experimental data allows the identification of a conserved neurohypophyseal receptor-specific coordination site for Mg2+ that acts as potent, positive allosteric modulator for agonist binding. Together, these results further our molecular understanding of the oxytocin/vasopressin receptor family and will facilitate structure-guided development of new therapeutics. 

Magnesium and mood disorders: systematic review and meta-analysis



Another consequence of ERβ under-expression in autism

Also interesting to those following autism research, is the role of ERβ (estrogen receptor beta).  It is well known that in the brains of those with autism, there is a lack of ERβ.  A lack of ERβ is likely to lead to lower oxytocin in the brain and CSF (spinal fluid).  In many types of autism, we know that the level of oxytocin in CSF is reduced.

If you activate ERβ you both increase expression of oxytocin receptor (OTR) and also increase the level of oxytocin measured in the CSF.  You can activate ERβ with estrogens, like estradiol or even phytoestrogens like soy.  The ideal therapy to use would be DHED.


The cheap diuretic spironolactone may very well indirectly increase the level of oxytocin in CSF.

Oxytocin and Estrogen Receptor β in the Brain: An Overview

Oxytocin (OT) is a neuropeptide synthesized primarily by neurons of the paraventricular and supraoptic nuclei of the hypothalamus. These neurons have axons that project into the posterior pituitary and release OT into the bloodstream to promote labor and lactation; however, OT neurons also project to other brain areas where it plays a role in numerous brain functions. OT binds to the widely expressed OT receptor (OTR), and, in doing so, it regulates homeostatic processes, social recognition, and fear conditioning. In addition to these functions, OT decreases neuroendocrine stress signaling and anxiety-related and depression-like behaviors. Steroid hormones differentially modulate stress responses and alter OTR expression. In particular, estrogen receptor β activation has been found to both reduce anxiety-related behaviors and increase OT peptide transcription, suggesting a role for OT in this estrogen receptor β-mediated anxiolytic effect. Further research is needed to identify modulators of OT signaling and the pathways utilized and to elucidate molecular mechanisms controlling OT expression to allow better therapeutic manipulations of this system in patient populations.






NAD and Nicotinamide Riboside to boost Oxytocin

Today we see that recent research from Japan shows that in those people with autism who have reduced NAD, they may well be able to improve behavior/mood by increasing the level of their oxytocin using Nicotinamide Riboside (NR).

Nicotinamide riboside (NR) is a special form of vitamin B3, sold as an expensive supplement.  The FDA say it is safe for use in humans.


Nicotinamide riboside supplementation corrects deficits in oxytocin, sociability and anxiety of CD157 mutants in a mouse model of autism spectrum disorder


Oxytocin (OT) is a critical molecule for social recognition and memory that mediates social and emotional behaviours. In addition, OT acts as an anxiolytic factor and is released during stress. Based on the activity of CD38 as an enzyme that produces the calcium-mobilizing second messenger cyclic ADP-ribose (cADPR), CD157, a sister protein of CD38, has been considered a candidate mediator for the production and release of OT and its social engagement and anti-anxiety functions. However, the limited expression of CD157 in the adult mouse brain undermined confidence that CD157 is an authentic and/or actionable molecular participant in OT-dependent social behaviour. Here, we show that CD157 knockout mice have low levels of circulating OT in cerebrospinal fluid, which can be corrected by the oral administration of nicotinamide riboside, a recently discovered vitamin precursor of nicotinamide adenine dinucleotide (NAD). NAD is the substrate for the CD157- and CD38-dependent production of cADPR. Nicotinamide riboside corrects social deficits and fearful and anxiety-like behaviours in CD157 knockout males. These results suggest that elevating NAD levels with nicotinamide riboside may allow animals with cADPR- and OT-forming deficits to overcome these deficits and function more normally.

NR elevates brain NAD+ and cerebrospinal OT

Social preference deficit and anxiety of CD157KO males are best corrected at a relatively low dose of NR

The results demonstrated that the daily oral administration of NR rescued the social behavioural impairments observed in male CD157KO mice. NR had essentially no effects on social behaviour in wild-type male mice. The beneficial effects of NR appear to depend on restoration of CSF OT levels because the NR-induced OT elevation was only detected in CD157KO mice, which have a CSF OT deficit.


In the course of identifying a nutritional intervention for CD157KO mice, we reproduced the anxiety-like and social-avoidance-like deficits reported previously. Reproducibly lower levels of CSF OT in male CD157KO mice make these mice an attractive model of autism, anxiety disorder, or social avoidance in neurodegenerative diseases. Significantly, this model responds to both OT and NR as a treatment.
The challenge of polygenic diseases of incomplete penetrance is that they are difficult to understand mechanistically. Multiple genetic and environmental (biochemical) factors may converge to dysregulate pathways that are altered in common conditions such as ASD. We note that one potentially hopeful point when studying polygenetic diseases is that brain systems are redundant, and thus, it may be possible to increase normal functions that are only partially encoded by genetically damaged circuitry.
NAD+ is consumed by CD38 in formation of cyclic ADP-ribose. It then participates in OT release in the hypothalamus. In our study, ADP-ribosyl cyclase activity was maintained at a similar range as that in wild-type animals (data not shown). A recent study suggested that NR supplementation did not change CD38 expression. However, in vitro studies have shown that NAD+ applied to the mouse hypothalamus leads to OT release. It is reasonable to assume that an elevation in NAD+ levels by NR in the hypothalamus is responsible for repair of the OT release.

Future work will probe CD38 dependence and the cell-type dependence of the beneficial effects of NR on CD157KO behaviour, the potential benefits of NR in other ASD models, and the potential of NR to become a safe nutritional intervention, in addition to OT, for at least some types of ASD in human populations.



NAD+ is reduced in older people

There is a lot of research into combating the effects of aging.  It is agreed that the older you get, the less NAD+ you have and so research has looked at numerous ways to raise it.

The CD157KO mice model of autism does feature reduced NAD+, but nobody knows how common reduced NAD+ is in autism.

If you have low levels of NAD+ there will be negative consequences.

I think you can consider NAD+ depletion in a similar way to oxidative stress, both are inevitable and damaging features of aging.

Most healthy younger people are likely wasting their time and money worrying about oxidative stress and NAD+.  These are the people with “detox” diets and juices.

However, most old people and some young people with autism really stand to benefit from correcting oxidative stress and any reduced NAD+.
  

Therapeutic potential of NAD-boosting molecules: the in vivo evidence





Hallmarks of NAD homeostasis
NAD+ is not merely a redox co-factor, it is also a key signaling molecule that controls cell function and survival in response to environmental changes such as nutrient intake and cellular damage. Fluctuations in NAD impact mitochondrial function and metabolism, redox reactions, circadian rhythm, immune response and inflammation, DNA repair, cell division, protein-protein signaling, chromatin and epigenetics.
There are many ways to boost NAD+.

NAD+ Precursors              
Niacin/ nicotinic acid (NA), Nicotinamide riboside (NR) Nicotinamide (NAM) etc.

CD38 Inhibitors                 
Flavonoids (Quercetin, Luteolin, Apigenin, fisetin, rutin and naringin)             
Luteolinidin.  Kuromanin/ Chrysanthemin, an anthocyanin (food pigment)    

PARP Inhibitors    
BGB-290, Olaparib, Rucaparib, Veliparib, CEP-9722, E7016, Talazoparib, Iniparib, Niraparib, PJ34, DPQ, 3-aminobenzamide
                       
SARM Inhibitors
XAV939                    

NAMPT Activators
P7C3 



Conclusion

Some readers of this blog do give intranasal oxytocin as a therapy.  There have been numerous studies on children with autism, some discussed in earlier posts.  Oxytocin needs to be kept chilled, not to lose its potency.

Eleven previous posts in this blog refer to Oxytocin.


As to whether stimulating oxytocin receptors is going to be worthwhile in your case of autism, you will just have to try it and see.
I found that the Biogaia Protectis probiotic (L. reuteri DSM 17938) had very clear effects, which were very much hallmark effects of oxytocin.  This is easy and inexpensive to try.
Some readers of this blog do use Nicotinamide Riboside (NR), which we saw today can increase oxytocin by increasing NAD+.
There are very many reasons why you do not want to be lacking in NAD+, other than oxytocin, but if you already have plenty NAD+ you will unlikely see a benefit from yet more.
Magnesium is a very common autism supplement; it is often given with vitamin B6; both can be used to treat stress.

Superiority of magnesium and vitamin B6 over magnesium alone on severe stress in healthy adults with low magnesemia: A randomized, single-blind clinical trial







Thursday 3 October 2019

Elevated Prenatal Estradiol in Mothers/Babies – a protective reaction to stress that also predicts who will develop Autism? Time for Fetal Medicine?


There has been little mention in this blog about fetal medicine, but it is an area that does hold great promise.  At the Children’s Hospital of Philadelphia, they have been surgically treating babies with spina bifida prior to their birth for nearly twenty years. Early surgical intervention to the spine even allows for malformation of the brain to be self-repaired and this is visible on MRI scans. Such prenatal treatment can be 100% successful, resulting in there being no physical disability in adulthood. 

The more you read about neuroscience the more you realize how little we really know and so encouraging the brain to self-repair may indeed be the best strategy.  This is an avenue of research and not just with stem cells.  A similar approach is proving successful in treating skin cancer, you do not attack the cancer with drugs, you modify the immune system with a drug so it "wakes up" and does its job and kills the cancer cells.

        Skin cancer: Half of people surviving advanced melanoma

Hormones are an often-ignored area of autism research, but they are they on my Venn diagram simplification of autism.



We have seen how female hormones can be highly neuroprotective and that the estradiol/testosterone balance affects a key “switch” that controls gene expression RORalpha.

Today we see that researchers in Utah suggest that stress in the developing fetus with autism causes an increase in estradiol, as a protective mechanism, and this increase in estradiol can then be measured in the mother’s blood. They propose that this elevated estradiol is an advance warning of a baby with autism.



University of Utah researchers have discovered a link between increased levels of a type of estrogen in babies in their second trimester and risk for autism, according to a new study.

The findings could eventually help doctors identify babies at risk of autism early in their mothers’ pregnancies and monitor them more closely, as well as provide early interventions to ensure the children’s well-being, said Dr. Deborah A. Bilder, the study’s first author.

Both the control group and the group of mothers whose children had autism were selected so that 50% of each group had an exposure to a condition such as gestational diabetes, hypertension and preeclampsia. Previous studies have shown links between those conditions and autism risk.

The researchers looked at several different steroids in the blood samples. Bilder said she expected to find increased levels of steroids that were known to be associated with the conditions, like testosterone. She found those steroids, but they did not reach a statistical significance, according to Bilder.

Bilder also expected progesterone and testosterone in the kids who developed autism to be elevated.

“But that’s not what I found. Instead, what I found, is estradiol being elevated in the children who developed autism,” she said.

Estradiol is a type of estrogen. Lower levels of estradiol in a baby usually indicate a concern with the baby, and high estrogen levels are not currently associated with abnormal conditions.

But as the researchers looked at the steroid hormones that were measured, “what we realized is that the higher estrogen levels being produced by the placenta actually may be stimulating the baby’s development of his or her stress response.”
Usually, a baby’s stress response takes time so that when the pregnancy reaches full term, the baby has developed its own stress response. But elevated levels of estrogen cause the baby’s stress response to develop early, Bilder said.
That prepares babies, when there is an issue, to survive outside the mom. It causes early growth of the lungs, gut and skin so that if the baby doesn’t make it all the way through pregnancy, it’s more likely to survive, she said.

The findings indicated that in the babies with autism, something set off their stress response early.

Studies have shown that children with autism have an abnormal stress response, according to Bilder. She believes the mechanism that triggers the early stress response during pregnancy may still be affecting children with autism past delivery.

Bilder doesn’t think doctors should target the higher estradiol levels or try to lower them. Instead, because it signals a “protective mechanism, that baby is surviving,” doctors should target something that doesn’t jeopardize the baby’s survival.

“By being able to have a way of looking at the baby’s well-being in that regard, I think that opens up the door to considering how can you reduce the stress on that baby?” Bilder explained.
                                                                                 
The full paper:-

Early Second Trimester Maternal Serum Steroid-Related Biomarkers Associated with Autism Spectrum Disorder


Epidemiologic studies link increased autism spectrum disorder (ASD) risk to obstetrical conditions associated with inflammation and steroid dysregulation, referred to as prenatal metabolic syndrome (PNMS). This pilot study measured steroid-related biomarkers in early second trimester maternal serum collected during the first and second trimester evaluation of risk study. ASD case and PNMS exposure status of index offspring were determined through linkage with autism registries and birth certificate records. ASD case (N = 53) and control (N = 19) groups were enriched for PNMS exposure. Higher estradiol and lower sex hormone binding globulin (SHBG) were significantly associated with increased ASD risk. Study findings provide preliminary evidence to link greater placental estradiol activity with ASD and support future investigations of the prenatal steroid environment in ASD.


Fig. 1 The placenta produces estradiol from DHEA of both maternal and fetal origin and shunts over 90% of estradiol into the maternal circulation. The volume of DHEA substrate determines placental estradiol production and subsequently maternal serum estradiol levels. DHEA exists primarily in its conjugated form DHEAS


This is interesting as are some other findings linking steroid hormones to future autism. Another paper highlights a mechanism where maternal stress only has damaging effects on the male fetus (Placental adaptation in response to PNMS is sex-dependent, leading to an increased risk of adverse neurodevelopmental effect in male compared to female).

This paper looks at the effect of maternal stress on serotonin and another group of hormones (Glucocorticoids).

Effects of prenatal maternal stress on serotonin and fetal development

Fetuses are exposed to many environmental perturbations that can influence their development. These factors can be easily identifiable such as drugs, chronic diseases or prenatal maternal stress. Recently, it has been demonstrated that the serotonin synthetized by the placenta was crucial for fetal brain development. Moreover, many studies show the involvement of serotonin system alteration in psychiatric disease during childhood and adulthood. This review summarizes existing studies showing that prenatal maternal stress, which induces alteration of serotonin systems (placenta and fetal brain) during a critical window of early development, could lead to alteration of fetal development and increase risks of psychiatric diseases later in life.




`


         Fig. 1. Proposed mechanism of fetal programming of psychiatric disorders involving placental serotonin system. Cortisol and placental serotonin are essential for fetal brain development. Prenatal maternal stress alters glucocorticoid (11b-HSD2, GR and CRH) and serotonin (SERT, 5-HT1A and 5-HT2A) systems as well as serotonin and glucocorticoid interaction in the placenta. These placental alterations lead to adverse neurodevelopment and programming leading to psychiatric disorders later in life. Placental adaptation in response to PNMS is sex-dependent, leading to an increased risk of adverse neurodevelopmental effect in male compared to female. 11b-HSD2: Type 2 11-beta hydroxysteroid dehydrogenase, GR: Glucocorticoid receptor, CRH: Corticotrophin releasing hormone, SERT: Serotonin transporter, 5-HT1A: Serotonin 1A receptor, 5-HT2A: Serotonin 2A receptor


Conclusion    
         
It should be noted that estradiol is supposed to be elevated during pregnancy. Indeed, this elevation is suggested to explain why females with ADHD have far less symptoms during pregnancy (estradiol is good for ADHD). The study is highlighting a level of estradiol during pregnancy that is even higher than that normally expected.

Spina bifida is normally detected by ultrasound before 18 weeks of pregnancy. This is around the same time that in autism there appears to be elevated estradiol.  Hopefully other biomarkers will also be found.

Given this advance warning, there is potential for fetal medicine.

Only very recently was the first person in the UK treated for spina bifida using fetal surgery, almost two decades after the first operations in the US.

Fetal medicine for autism would not be surgical, rather pharmacological.  In mouse models it has already started.

Estradiol has many effects and I did write about DHED, an orally active, centrally selective estrogen and a biosynthetic prodrug of estradiol. DHED is estradiol just for the brain, without affecting the rest of the body.  I think many people would benefit from DHED, across the range from ADHD to TBI (Traumatic Brain Injury).

DHED, delivering Estradiol only to the Brain, also Lupron and Spironolactone


Estradiol may indeed prove to be a fetal biomarker for autism and DHED might be a useful drug for someone with autism (via ERβ and RORalpha).









Thursday 24 May 2018

An Autism Case History - EpiphanyASD in a Pill





It is not quite that easy!


Initials:                        LT
Age:                           14 years old

Year
of Birth:              2003

Sex:                            Male

Date:                           24 May 2018

Diagnosis      
LT was diagnosed with autism in January 2007, at a multi-disciplinary assessment in London, at the age of 3 years 6 months.  At that time, LT was non-verbal but had some emerging vocalization. No tics, no seizures, no unusual physical features, no self-injury, no sleep disorder, no feeding disorder. Toilet trained. Very limited attention span. No imaginative play. Liked to jump.

IQ not tested.
No CARS (Childhood Autism Rating Scale) assessment.
TEACCH and PECS were recommended as therapy.
Further medical testing or referrals – none recommended (standard practice in the UK) 

LT has an older brother who is intelligent, multilingual and highly social.
Comorbidities
GI disease:                   None
Epilepsy:                       None
Asthma:                        Yes, mild asthma from early childhood
Allergy:                         Pollen
Sleep disorder:             None 

General Health          
Very healthy and almost never ill. When visiting his GP at the age of 14 the doctor commented how she had not seen him for three years, whereas she has seen his older brother twice a year.

Born via a planned caesarean section, without complications, APGAR score was 10.


Growth                      
Body is well proportioned, no obvious macro/microcephaly. No physical features of any syndromes/metabolic anomalies.

However, LT was initially on the 90th percentile for height and dropped to the 20th by the time he was 5 years old. He was a very muscular baby.  At the age of 10 his bone age (X ray of left hand) was estimated to be two years delayed.  IGF-I was normal, FT3 was slightly above the reference range.

At birth he fitted the research description of hyperactive pro-growth signaling pathways, even though there was no macrocephaly.

Regression at age 8              
Aged 8, a big regression took place with self-injurious behavior (SIB) and aggression to others. He would slam his head into walls, other people, car windows, punch himself etc, but he was still small enough to be physically controlled/restrained by larger adults. He could not be controlled by smaller/older adult family members.

This aggression could occur immediately on waking until finally falling asleep at night, it was not predictable.  At that time in the afternoons, LT had a male 1:1 assistant with experience from a school for severe autism and in the mornings a very firm-minded tall female 1:1 assistant. LT’s father imposed a policy of zero acceptance of any SIB, to avoid it becoming a permanent acquired behavior. SIB was physically blocked.
The regression was triggered by the departure of his long time full-time 1:1 female assistant. It was an emotional trauma.  Occasional visits from her just made the situation worse.  In response no drugs were used, just a consistent firm behavioral approach. Over a ten month period the situation slowly stabilized, but skills were lost and bad habits (SIB) were acquired.  LT subsequently did see his assistant again and sees her regularly to this day.
Throughout this time his classmates and teacher at school were remarkably understanding. He was never excluded from school. His assistant ensured nobody at school got hurt.
Since assistants will inevitably come and go, from the age of 8 LT has had two part-time assistants rather than one full time.  As and when subsequent assistants have left, he has not had any troubling emotional reaction. 

Summer-time raging and loss of cognitive function
Summertime raging with self injurious behavior and aggression to others developed from the age of 9.

Later it became clear that in addition there was a loss of cognitive function during the summer months. This became evident once it was possible to teach mental math, from aged 9 onwards.  For example, at the age of 11, simple verbal tasks like 7 x 8 = ?, that had previously been mastered, could not be answered in the summer months.

The raging and cognitive loss were ultimately treatable.

Winter-time raging

Summertime raging was resolved and then winter-time raging developed. This was traced back to the cytokines released to signal reabsorption of milk teeth roots (a proves that takes months) and the eruption of permanent teeth. It was not tooth ache, i.e. pain. LT has retarded bone age and apparently this applied to his teeth development as well.

He lost his later milk teeth always in the winter.

The winter time raging did not respond to his summertime therapy, but responded very well to a low dose of ibuprofen. Summertime raging does not respond to Ibuprofen 

PANS-like episode aged 13
At Christmas time, following a minor viral infection, LT developed acute onset profound verbal tics. LT does not have Tourette’s type autism and had never exhibited such behavior previously. The tics were treated as a PANS/PANDAS flare-up with 5 days of prednisone. Over a two week period the tics faded away and have never returned.

Intellectual disability 
IQ was never measured, LT’s ABA consultant said there was no point, but the very much more rigorous ABBLS was completed, see below. Evidently, prior to pharmacological treatment at the age on 9, there was a 5 year developmental delay.
With hindsight, IQ pre-treatment was probably in a similar range to Down Syndrome (DS) meaning less than 70.

At the age of 14, LT’s academic performance now puts him in the top half of his class of 12 year old neurotypical peers. His grades are mainly As, with maths and computing being particular strengths. 

Other testing:    No genetic testing, MRI or EEG.

Family History:          

LT has a 7 years younger, very distant cousin who is non-verbal with autistic disorder. They have shared great great great maternal grandparents. The cousin has parents who are both doctors and were high academic achievers as medical students.

The father’s family has a large number of Cambridge-educated doctors on both the grandmother's and grandfather's side; one gave his name to the scale still used to assess severity of Ulcerative Colitis and helped develop the first H2 anti-histamine drug. The father and uncle are engineering graduates from top universities. One distant cousin was a math’s protégé at Oxford University.  One distant cousin has bipolar. One uncle has type-1 diabetes.

The mother is an academic alpha female in a stressful creative profession. The maternal grandmother was a teacher and grandfather was an army Colonel.
The maternal grandmother and her children all had premature hair greying, which may be linked to Bcl-2 expression and Wnt signaling, both implicated in autism. Thickness and greying of hair share biological mechanisms, which overlap with those controlling development of dendritic spines. LT and his father have very dense hair, mother has thin hair.
Maternal grandparents both smoked and the grandfather has COPD (Chronic Obstructive Pulmonary Disease). Oxidative stress is a core feature of COPD, because anti-oxidant genes are silenced; these effects are known to be heritable via epigenetic tags. 
The family fits the high IQ  type of autism (some autism genes are linked to intelligence and some bipolar genes are linked to creativity, which helps explain why some actors/artists are bipolar) with oxidative stress raised during pregnancy, anti-oxidant response possibly weakened, no oxytocin surge during delivery and no microbiota transfer at birth (C-section delivery).  No pets at home during pregnancy (a good source immuno-stabilizing bacteria).  No obesity in the family.

Education
LT has attended the same mainstream international school, following the English curriculum, since the age of 3. Class sizes are very small, about 12 pupils. From the age of 4 he has had a 1:1 assistant eight hours a day, throughout the year.
LT commenced a parent-managed ABA (Applied Behavioral Analysis) inspired home program shortly after diagnosis.  Both parents attended a 2 day training program to learn the use of PECS (Picture Exchange Communication System).  PECS was applied and shortly thereafter LT became partly verbal at the age of 4, speaking single words.
1:1 assistants were recruited mainly from the local University and trained to apply ABA, with elements from Floortime and the Canadian Hanen Program. There was some supervision from US-trained Behavioral Consultants that would fly in for training. A large collection of specialist training material was acquired from the US. 
Extensive use was made of professional (i.e. expensive) special needs language teaching software (Laureate Learning) from the age of 4 until 8 years old.
Later, web-based reading software (Headsprout) was used and years later special maths teaching software (Math Wizz). Neither are made for special needs, but both are very compatible with an ABA approach.
LT spent an extra year in kindergarten and in primary/junior school was held back 2 years at the age of 9, following a request from the parents.
In primary school (English system) he went Year 1, Year 2, Year 3 (started bumetanide) then back to Year 2, then Year 3, Year 4, Year 5, Year 6 and currently attends Year 7 in secondary/high school
The equivalent in the US system would have been, he went K, 1st, 2nd, then 1st, 2nd 3rd, 4th etc.
From the age of 13, LT attended school full time, prior to that he attended only the morning and then went home after lunch to work 1:1 with his assistant for three hours.
During school holidays LT has a 1:1 home learning program.
LT learnt to read and write at home as result of the unrelenting efforts of his assistant. He started to learn maths from the age of 8, prior to that he could not master the basic concepts, or understand the relevant vocabulary.
From the age of 9, LT has been able to keep up with his new peer group at school, two years his junior.
At the age of 14, in a class with 12 year old neurotypical children, LT takes the same assessments as the rest of the class and his grades currently place him in the top half of the class. He is now particularly good at things like arithmetic, algebra, coordinates, spelling and has neat handwriting (very unusual in autism). He is still clearly autistic and his speech is limited to what he wants to say; there is no small talk.
LT started to learn the piano aged 8. He progressed from an extremely basic level and a desire to hit his teacher to his current level 4 of the popular Faber Music piano course (there are just 5 levels). When he plays in public people are very surprised, he does not play like someone with any cognitive impairment. His peers as school have asked “how can he play like that?” 

Motor Skills
Like many people with classic autism LT had problems with both fine and gross motor skills as an infant. After a great deal of 1:1 therapy, motor skills are now normal.
LT started to learn to ski at the age of 5 with a special needs instructor. Progress was initially slow, but 9 years and one broken collar bone later, LT can confidently ski on red slopes and deal with all the various types of lifts you encounter in the Alps.
Stamina improved considerably after starting to take Agmatine, which is evident at school where they are timed to run 2.5 km (1.5 miles) and when swimming.

Behavioral Treatment (age 3- 8)
From diagnosis aged three, until nine years old, therapy was exclusively based on behavioral interventions. Extensive use of ABA (Applied Behavioral Analysis) and VB (Verbal Behavior) with 40 hours a week with a 1:1 Assistant.
At the aged of 9, LT had mastered almost all the skills in the very extensive ABBLS (Assessment of Basic Language and Learning Skills) assessment. The language skills and other basic learner skills that are tracked by this tool are those that are acquired by most typically developing children by the time they reach four to five years of age. LT’s elder brother had acquired these while he was three years old.
LT’s skill acquisition to the age of eight was seen by the ABA consultants as nothing unusual in someone with classic autism. There was slow but continuous progress. 
All learning was taking place at home with school attended mainly for socialization.

Pharmacological Treatment (age 9 onwards)
In late 2012 a small clinical trial was published by Ben Ari and his clinical associate Lemmonier; it showed the benefit of the NKCC1/2 blocker bumetanide in autism. This paper was studied by LT’s father and contact has been maintained for several years with Dr Ben Ari, who originated and patented this therapy.
Bumetanide (1mg per day) was commenced just before Christmas December 2012, unknown to the school, or LT’s assistants.
On returning to school in January 2013 the Head Teacher summoned LT’s father and asked what had happened to LT. He was “so joyous” and “like a different child”.
At the suggestion of his original ABA consultant, LT’s father had been asking LT every school day for 5 years “what did you have for lunch at school today?”. The usual answer would be no answer, the wrong answer, but sometimes a brief correct answer. From now on LT would say precisely what he had eaten “peas, potatoes and chicken – cake for dessert”. The assistant was there to confirm what had really been eaten for lunch. 
LT’s 1:1 assistant at that time described the effect of bumetanide as making him “more present”. Since his assessment at the age of 3, it was always noted that LT had a very short attention span and would not be able to focus on the class teacher for more than a couple of minutes. LT was never hyperactive, quite the opposite. He was physically present but not mentally.
Later on it would be realized that the most potent effect of long term bumetanide use in strictly defined autism (SDA) is enhanced cognition, which leads to accelerated acquisition of new skills.  IQ has long been seen as the best predictor of more favorable outcomes in autism.  
Bumetanide use has continued for five years, with occasional pauses to confirm it still works.  Different doses were tested and currently the dose is 2mg once a day.
When stopping bumetanide for a week and returning to his web-based maths learning program, LT was unable to complete previously mastered tasks, no matter how many times he tried. Having recommenced bumetanide, the same maths problems were attempted a week later and could be solved. 
Blood potassium levels were checked regularly at the beginning, but were always high normal (5.0 mmol/L).  Bumetanide is taken with 250mg of K+ per 1mg of bumetanide. Diet is rich in potassium, with bananas and other fruit.
Dehydration, another potential problem, is entirely self-regulated with LT drinking more water. Total consumption is 2.5 to 3 liters per day.
Diuresis occurs mainly within one hour of taking bumetanide and has never caused a problem at home or school. LT takes his bumetanide at least an hour before leaving home for school.
Bumetanide’s suggested mode of action is lowering intracellular chloride via blocking NKCC1 cotransporters in the brain.  Bumetanide crosses the blood brain barrier very poorly and many researchers are dubious it can have any effect. Bumetanide is a partial solution.
A new drug is being developed by Dr Ben Ari that will cross the blood brain barrier more effectively than bumetanide and have less effect on NKCC2, so producing less diuresis.
An alternative strategy discussed in the literature is to improve the pharmacokinetics of bumetanide, by slowing its excretion via OAT3 (organic anion transporter 3) and thus increasing plasma concentration. There are many OAT3 inhibitors, the best known and most potent is probenecid, used to treat gout by increasing the excretion of uric acid. Some foods are OAT3 inhibitors. One readily available substance is chlorogenic acid (more precisely 1,3- and 1,5-dicaffeoylquinic acid) which is sold as a coffee-based weight loss supplement. Interestingly, coffee, but not caffeine, has been shown to reduce the risk of gout.
Little is known about exactly how bumetanide is transported/excreted across the blood brain barrier.
Bumetanide’s autism benefit appears to be from lowering intracellular chloride and hence making GABAA become more inhibitory. Excitatory-Inhibitory (E/I) imbalances are widely believed to be at the core of autism.  An E/I imbalance during so-called Critical Periods, will result in permanent changes to the developing brain, nonetheless it appears that correcting an E/I imbalance in later years can still be highly beneficial, though not curative. 
Another experimental therapy also makes GABAA become more inhibitory. This uses very low doses of clonazepam to modify the behavior of GABAA receptors that contain the α3 sub unit.  In LT the effective dose of clonazepam is just 0.03mg, which might be considered sub-clinical, but as predicted by Professor Catterall, it does have a beneficial effect (a bumetanide-like effect). It has no side effects and there is no tolerance develops at this tiny dose, after four years of use.
At the time low dose clonazepam was introduced, LT would go swimming at 5pm most days. He was not really interested to do much independently in the water, he was very passive. This passive behavior was notably changed once the effective clonazepam dose had been found. He became more like a typical child playing in a swimming pool. Instead of sitting on the steps he wanted/demanded interaction/play with the attending adult.  The effect was not as profound as that seen in the first months of bumetanide, but noticeable nonetheless.
After 4 years of bumetanide the effect was still there, but there was a desire to accelerate skill acquisition to keep up with neurotypical school peers.
A new strategy was adopted to further reduce intracellular chloride, this time using a method first documented in the 1850s, when potassium bromide (KBr) was used to treat epilepsy. Reading old case studies from Great Ormond Street Hospital in London it appeared to LT's father that some children with epilepsy, MR/ID and undiagnosed autism improved behaviorally and developed age-appropriate play when treated with KBr. Lack of age-appropriate play is a hallmark of autism.  Modern research shows that bromide ions compete with chloride ions to enter cells and the result is a lower intracellular concentration of Cl-. The limiting factor in the use of KBr is that it increases mucous secretions and so causes acne (and can make asthma worse), in a dose dependent fashion. At a low dose of 400mg per day there is a cognitive gain without significant spots. KBr is still used at high doses to treat pediatric epilepsy in Germany and Austria. Some leading US neurologists regret they cannot prescribe it; technically they could ask the FDA for permission on a patient by patient basis.

Another strategy to reduce intracellular chloride is to target chloride ions that enter neurons via the AE3 exchanger, this is possible using Acetazolamide (Diamox). This therapy does seem to work for some people, but was not tolerated by LT, it caused reflux.
KBr has a very long half-life and so it takes 4-5 weeks to reach the maximum effect. 
Bumetanide took about two weeks to lower chloride and show behavioral and cognitive improvements.
Low dose clonazepam takes three days, as was predicted by its half-life.
The cognitive loss in severe autism has parallels with that in Down Syndrome (DS). Bumetanide has been patented as a therapy for DS by Ben Ari, based on the results from mouse studies.
In mouse models of Down Syndrome both a negative allosteric modulator and a selective inverse agonist of α5 sub-unit of the GABAA receptor improve cognition. 
Mouse research has shown that poor learners have greater GABRA5 expression than good learners and that in mice GABRA5 expression can be normalized by eating cinnamon, or its metabolite sodium benzoate (NaB); this makes a poor learner become a good learner, at least in mice.
So it may be that increasing the effect of α3 sub-unit of the GABAA and reducing the effect of the α5 sub-unit of the GABAA can both improve cognition. For the moment the latter remains unproven. NaB is an approved food additive, E211. Ceylon cinnamon, which is safe for long term consumption, is metabolized to NaB. People who are histamine intolerant have to avoid DAO inhibitors such as cinnamon and NaB. 

Summertime raging and loss of cognitive gains
From the aged of 8 it became apparent that summer provoked behavioral deterioration. At this point there was no obvious allergy, but behavior improved when moving to the mountains in summer. At first, OTC mast cell stabilizers were investigated; some common H1 antihistamines are partial mast cell stabilizers. Rupatadine, azelastine, ketotifen, loratadine and cetirizine were all tried, as was the flavonoid quercetin.
Some of the above did indeed help reduce the summertime self injury, but not to a satisfactory level.
A final solution was found in a small dose of the Cav1.2 blocker, verapamil. 
When mast cells degranulate, one step requires activation of an L-type calcium channel. This is why most mast cell stabilizers are actually calcium channel blockers.
It should be noted that mutation in the CACNA1C gene, which encodes the Cav1.2 ion channel, leads to a severe kind of autism called Timothy Syndrome. Because Cav1.2 is widely expressed in the heart those affected have a very poor prognosis.
In addition, verapamil blocks the potassium ion channel Kv1.3.  Potassium channels, Kv1.3 and KCa3.1, have been suggested to control T-cell activation, proliferation, and cytokine production. Kv 1.3 is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases.  Research has shown that peptides from parasitic worms that suppress the body's immune response do so by blocking Kv1.3. A drug therapy based on these peptides is being developed.
Verapamil also upregulates autophagy, which is impaired in many neurological disorders, such as Huntington’s. Lack of autophagy has been linked to the synaptic pruning deficits found in autism.
Verapamil has a short half-life of about 3 hours. Only a small dose is required to prevent the onset of SIB and the preceding agitation (described by LT as “spray the fire in my head”).
From the age of 10, LT’s summertime raging has been treated with 40-80 mg of Verapamil split into 2-3 doses from May until late November.
On the occasions that he has missed his 1pm dose in the peak allergy period, he has repeatedly developed aggression and self-injury by 4 or 5pm.
When he has taken verapamil there has never been any aggression and or self-injury.
Once self-injury was removed as a concern, learning progressed during the long summer school holidays. It became clear that during summer cognition was reduced as if bumetanide was no longer working.
It has been shown that the expression KCC2, the cotransporter that allows Cl- to leave neurons is affected by inflammatory cytokines like IL-6. It therefore appears plausible that the histamine and IL-6 released directly and indirectly by mast cell degranulation was causing an increase in neuronal Cl- and thus undoing the good work being done by bumetanide. Inflammation also increases α5 GABAA receptor activity and can thus reduce cognitive function.
At this point, the bumetanide dose was raised from 1mg once a day to 2mg in the morning and on occasion 1mg in the late afternoon.
The combination of an increased dose of bumetanide and the use of verapamil, cetirizine and azelastine has produced a very favorable result (no SIB and minimal summertime cognitive decline). Perhaps of note is that cetirizine is an eosinophil stabilizer, which may also be helpful and not just for asthma.
OTC therapies that have a helpful effect in summer are L-histidine, curcumin and L. reuteri DSM 17938 (sold as Biogaia Protectis). The amino acid histidine is a precursor to histamine and it seems that the body’s feedback loops can be tricked into not degranulating mast cells by slightly increasing the level of circulating histidine. The immunomodulatory effects of L. reuteri DSM 17938 have been well studied; the effect however does not continue after prolonged use. Curcumin is a very widely studied natural substance that performs much better in vitro than in vivo, due to very poor bioavailability. Modified versions of curcumin have been developed and there is a marginal benefit. Histidine is extremely cheap and easy to administer. Modified curcumin and L. reuteri are quite expensive.
It is reported by others that at a higher dose verapamil is as effective as an H1 antihistamine in treating allergy. 

IPR3
It appears that aberrant calcium channel signaling is a key feature of much autism. Gargus has suggested that IP3R is a nexus for different dysfunctions that lead to autism. IP3R controls the release of calcium stored within cells (the endoplasmic reticulum).
Excessive calcium within cells is known to be damaging. L-type calcium channels that remain open will raise intracellular calcium and the same is true with IP3R. Caffeine can be used to inhibit calcium release via IP3R.
Gargus has not proposed an IP3R therapy.  


RORα

RORα is another proposed nexus where different dysfunctions  that lead to autism may converge. One potential RORα agonist is estradiol.  We know that in much autism there is elevated testosterone and reduced estradiol; we also know that estrogen receptor beta is under-expressed. Estradiol is known to be highly neuroprotective and may help protect females from developing autism. Females lacking in estradiol, for example in Turner Sydrome, may exhibit features of autism. A logical therapy would be to either use estrogens, or reduce testosterone (effectively the same thing). Ideally you would do this just in the brain; a brain selective pro-drug of estradiol, called DHED, actually exists. Less ideal therapies range from estradiol itself, to phytoestrogens or a high soy diet, to drugs reducing testosterone, like spironolactone; these will have effects beyond the brain.

Wintertime raging
Having solved summertime raging, wintertime raging appeared. As expected, verapamil had no effect.
Ultimately the likely trigger was traced back to the very slow loss of milk teeth and eruption of permanent teeth. Both reabsorption of roots and the eruption new teeth is signaled using pro-inflammatory cytokines.
Moderate use of Ibuprofen, as and when behavior began to deteriorate, resolved the problem. Ibuprofen has no effect on summertime raging.

PANS-like episode aged 13
PANS (Pediatric Acute-onset Neuropsychiatric Syndrome) and PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) are infection-induced autoimmune conditions that disrupt a patient’s normal neurologic functioning, resulting in a sudden onset of Obsessive Compulsive Disorder (OCD) and/or tics and cognitive loss.
The import part is acute-onset; behavior changes overnight.
LT exhibits the classic traits of autism including stereotypy/stimming but never tics, which are a feature of Tourette’s-type autism.
Just before Christmas LT was recovering well from what presented as mild viral infection that had not warranted any medical intervention. He suddenly developed very loud verbal tics.
It is well known in PANS that delayed treatment severely affects prognosis. The sooner the patient is treated, the more complete recovery will be. Diagnosis is based on a very specific set of laboratory tests, only available in the US.
LT was treated from the third day of the tics as if he had PANS flare-up. He was treated with 40mg of prednisone for 5 days, requiring no taper.
Over a two week period the tics faded away. There have been no more tics.

Use of antioxidants
A recurring feature in autism research is oxidative stress. Two clinical trials have shown the benefit of the antioxidant NAC (N-acetylcysteine) in autism.
In LT the effect of NAC is the immediate disappearance of stereotypy and a type of anxiety. Without NAC, LT always wants to know what is happening next, to the point of obsession.
Oxidative stress has been shown to vary throughout the day and LT’s therapy is tailored to match it. Oxidative stress causes a cascade of further disruptions and causes many of the side effects of type-1 diabetes, for example.
LT takes 2,400 mg of NAC per day (a dose slightly lower than in the clinical trials). He has 600mg immediate release NAC at 7am, 600mg sustained release at 7am and then 600 mg sustained release at 1pm and 5pm. 
There have been no side effects after more than 4 years. 

Anti-inflammatory
Numerous studies (e.g. Ashwood) show elevated pro-inflammatory cytokines and reduced  anti-inflammatory cytokines as a feature of autism; but specific subgroups exist. Activated microglia is another feature of autism, which also suggests chronic inflammation.
Numerous anti-inflammatory strategies have been researched.
Atorvastatin has potent anti-inflammatory effects that are very well studied. It also affects the autism/cancer proteins RAS, PTEN and BCL2.
RASopathies are associated with MR/ID and indeed autism. Mutations in PTEN generally cause loss of function in PTEN and are associated with macrocephaly, enlarged corpus callosum, MR/ID and autism. Loss of function of PTEN is also found in some cancers, for example prostate cancer.
Because autism is polygenic and hundreds of genes are over/under expressed, it is not necessary to have a mutation to have misexpression. The mutation is just the extreme case (be it Cav1.2 or PTEN).
The effect of Atorvastatin is visible from the first dose and fades away the next day if therapy is stopped. The effect is very specific, it releases cognitive inhibition; it is as if the person with autism has the desire and capability to do something, but some barrier prevents him from doing it.
In broader severe autism, this is very important, Why does a child with autism who can verbalize never speak?
At the age of 9, LT was having piano lessons at home twice a week. He would practice the piano only if his assistant or father sat beside him. He never played independently.
After taking 10mg Atorvastatin for the first time, the next day LT went himself to his piano and started playing, without any prompting of any kind. He then began to practice on a daily basis.
As a child aged 3, LT had the habit of coming to the entry of the room with the television and watching from around the corner of the wall. He wanted to watch but could not enter the room. At the time it was thought he somehow just liked the visual sensation of peering around corners.
When he later moved to a multi-level house, LT would not come downstairs by himself; he would wait at the top of the stairs for someone to lead him down, every morning.  With atorvastatin not only did this behavior disappear, but it reappeared the day after Atorvastatin was withdrawn.
During one test withdrawal of the treatment, he got “stuck” in the kitchen and could not leave the room.

Sulforaphane Nrf2 and HDAC
In 2014, and again in 2017, Talalay/Zimmerman published research that sulforaphane from broccoli showed a benefit in autism. Sulforaphane is an HDAC inhibitor and thus has potential epigenetic properties, like some cancer drugs. Sulforaphane may also activate the Nrf2 redox “switch” and so be protective in conditions associated with oxidative stress.
LT’s father did contact the researchers and shortly after the first research was published LT started to take a broccoli sprout supplement. It did produce a very obvious effect and within 30 minutes; LT was laughing so much, be went to look at himself in the bathroom mirror. The more general effect was an unmissable increase in speech.
After three years of use the positive effect of sulforaphane/broccoli is no longer visible, even trying alternative brands.
In the 2017 clinical trial the authors found one responder retained the benefit of sulforaphane after the trial ended. They suggest an epigenetic switch may have been activated.  

Mitochondria and Microvasculature
A distinct type of autism has been characterized by Kelley at Johns Hopkins, Autism Secondary to Mitochondrial Disease (AMD). Kelley suggests that almost all regressive autism is caused by mitochondrial dysfunction and usually deficiency of the rate-limiting complex 1.
By stabilizing the mitochondria with antioxidants and then trying to stimulate more complex 1, a gradual improvement can occur.
Mitochondrial disease effectively starves the brain and body of energy (ATP), so lack of exercise endurance is exhibited in people with a genuine mitochondrial dysfunction.
One feature of autism is that growth factors (BNDF, IGF-1, NGF, VEGF etc) are disturbed, but the disturbance varies greatly by the type of autism.  Vascular endothelial growth factor (VEGF) in particular and its receptors are known to be disturbed and this has implications for microvasculature. Studies suggest that unstable, rather than reduced blood flow occurs in autistic brains.
In sports medicine, exercise endurance is a key target and it can be raised by improving the energy production from mitochondria and by improving the circulation of blood throughout the body by targeting eNOS (Endothelial Nitric Oxide Synthase) and NO (Nitric Oxide).
In Mild Cognitive Impairment (MCI) studies have shown the benefit of improved cerebral blood flow using cocoa flavanols to indirectly affect NO and hence improve memory.
Studies show that eNOS and NO can be safely increased by Agmatine and NO can be increased  using L-citrulline, which then produced more L-arginine. These supplements are widely used by sportsmen and women.
A small dose of Agmatine (1 g) has a near immediate substantial effect on LT, making him far more energetic.  It moved him from being rather passive physically, to being active. This has been very evident from his performance at school during physical activities, where it has been widely noted. At home LT started trampolining before breakfast and late in the evening.

Sensory Overload and Sensory Gating
An apparent over-sensitivity to sensory stimuli is a common observation in autism and is often the precursor to behavioral problems. In some younger children these can be trivial, but in more severe autism it can produce profound behavioral problems that never fade away.
Hypokalemic sensory overload and hypokalemic periodic paralysis are described in the literature. LT had sound sensitivity as a young child, in particular an inability to cope with the sound of crying. Tests were carried out to establish whether LT’s tolerance to the sound of crying improved after oral potassium. He consistently tolerated a high volume of a recording of this sound, when played 20 minutes after 250mg of potassium. Following ABA, he was purposefully exposed to this sound and taught to understand why people cry and modify his response, to the extent that his response changed to laughter, which again has to be modified towards empathy. 
Aged 10, LT developed a phobia to traveling in elevators/lifts. This was because the elevator he regularly used to visit his Grandparents was the old-fashioned type, with an internal sliding gate that you close by hand, which is extremely noisy.  He refused to use the elevator from that point on.  People with autism very easily form habits, or are allowed to form them, following the path of least resistance.  Elevators are a part of modern life and hard to avoid.
After a few weeks of this behavior, LT was given 500mg of potassium and half an hour later willingly entered the elevator and coped with the ride. The behavior has never recurred.
Sensory gating is another common issue in autism and schizophrenia, the individual is not able to filter out repetitive background sounds, like a clock ticking or the sound of a noisy eater. Sensory gating can be measured by looking at the P50 response on an EEG. α7 nicotinic acetylcholine receptor (α7 nAChR) agonists, like nicotine, can correct impaired P50 gating. A low dose of a PDE4 inhibitor is another suggested therapy
LT does exhibit was presents as impaired P50 gating. It is really only evident when his pharmacological therapy is halted for a few days. Then he finds all kinds of unavoidable noises very annoying, even the sound of a person sitting next to him eating. 

Typical Psychiatric Drugs
LT has never been treated with any of the usual antipsychotics, stimulants, anti-depressants, or anti-anxiety drugs sometimes prescribed in autism. His use of clonazepam is at a dose far below its standard clinical use.

Current status
In September 2017 LT moved to secondary/high school where some of the teachers recall how he used to be 10 years previously. Initially there was some trepidation and the view by some that a boy with classic autism should not be there. The school does have a boy with Asperger’s. However, LT surprised his new teachers, achieving grades placing him in the top half of his class. He is now extremely attentive in class, no attention deficit anymore, and has clearly not reached his intellectual limit. He has likely already far surpassed his intellectual limit, had he remained untreated.
As the end of the first year of high school approaches, LT continues to keep up academically with his peers. His agmatine-boosted physical performance has been maintained and he competes very well in long distance running and swimming.
LT is still intellectually far away from the trajectory followed by his older brother, but LT is keeping up academically with many of his classmates who are neurotypical, with average IQs.
A significant number of people diagnosed very young with autism do indeed make dramatic progress by the age of 6.  Zappella proposed his Dysmaturational Syndrome that he says applies to about 6% of early childhood autism, but they all have Tourette’s type autism (with tics).   There is an additional group without tics that also achieve what Fein calls Optimal Outcome, essentially they lose their autism diagnosis. In total it is 10-15% of cases that seem to “get better” all by themselves, regardless of intervention. As more diagnosis takes place even before 2 years of age and autism threshold grows ever wider, Optimal Outcome may become even more common.  
The definition of autism has been greatly watered down in recent years (DSM3 to DSM5). LT started with DSM3-type autism and by the age of 8 he still had it. DSM5 autism includes very much milder variants, some of which are trivial.
Each therapy used by LT has been found to be reversible based on careful withdrawal trials.



People with strictly defined autism (SDA) start to acquire skills with a delay compared to NT peers and thereafter acquire skills at a slower rate and hence fall ever further behind, making inclusion at school a delusion. The aim is to have similar skills to NT peers to make inclusion effective.
People with SDA often leave high school with an educational level of a 7 to 10 year old.

From the age of 12, LT ceased having any autism-specific learning curriculum; he just follows the curriculum of his mainstream school.  

Anecdotal Evidence
LT’s piano teacher exclusively teaches people with disabilities (mainly severe autism and a few with Asperger’s) and so has great experience of the disorder. She says while she has taught people who learnt to play as well as LT does today, this has never happened before with a child who started in his kind of condition at 8/9 years old.
The American ABA consultant (with Ph.D. and 20 years of experience) knowing LT from the age of 8, before he started bumetanide, told the family that of all her clients, LT is the one she sees the least but has improved the most and how strange that is. 


Current Therapy

The current therapy, called the Autism PolyPill, may be found in the link below.  

https://epiphanyasd.blogspot.com/p/polypill-for-autism.html

Autism is a highly heterogeneous condition, but there appear to be broad sub-types. At least some people with an autism diagnosis respond to each individual therapy in the PolyPill. Some people respond to almost the entire combination of therapies; other people respond to none.


Future Therapy

Some other interesting therapies remain to be investigated and it is clear that more improvement is possible because short term therapy with the flavones nobiletin and tangeretin produces a marked change in cognition and behaviour. The effect only lasts two or three days.  Tangeretin is a PPAR gamma agonist, among other properties. It reduces cholesterol when used long term, but its autism benefit is transient.  

The ketone Beta-Hydroxy Butyrate (BHB) also looks interesting; it has epigenetic properties amongst its other effects.