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Friday 9 October 2020

A Deep Dive into Closely Interacting Genes/Proteins that Account for Numerous Autism/Epilepsy Syndromes – (all Calcium or Sodium ion channels)

Even I thought this post was rather a long slog, but I kept finding more and more evidence to support the basic premise, so I covered all the genes that came up for completeness.

I have been going on about the relevance of calcium channels in autism for years. I have also pointed out that while you can have severe autism for a single mutated gene, you can also “just” have a miss-expression of that same gene, without any error in the code in your DNA. You can have a little bit of that severe autism phenotype.  You can even have the opposite dysfunction, which would usually be over-expression of that gene. 

Once you have miss-expression of a gene it will cause a cascade of other effects.

This means that while you may not be able to correct the initial genetic dysfunction, you may well be able to treat what comes further down the cascade.

I like to look for associations, so I skip quickly through the research papers, but take note when I see links to things like:- 

·        Epilepsy / seizures

·        Headaches, particularly episodic

·        Mental retardation / intellectual disability

·        Mathematical ability

·        High educational attainment

·        Big Heads

·        Epilepsy / seizures

·        Pain threshold

·        Speech development (or lack thereof)

·        Sleep disturbance

·        IBD (Inflammatory Bowel Disease)


It is very easy to look up the significance of any gene.

Open the site below and just type in the name of the gene.

https://www.genecards.org/

Today’s post does touch on complex subjects, but you can happily read it on a superficial level and get the key insights.

You have about 20,000 genes in your DNA and each gene encodes a protein.  That protein could be something important like an ion channel or a transcription factor.  Today we are mainly looking at ion channels, the plumbing of the brain.

These 20,000 genes/proteins interact with each other and clever people called Bioinformaticians collect and map this data.  These maps can then show you the cascade of events that might happen if one gene/protein is miss-expressed, perhaps due to a mutation.

Today I start with 2 genes CACNB1 and CACNA1C.

CACNB1 was only recently identified as an autism gene

Genome-wide detection of tandem DNA repeats that are expanded in autism


CACNA1C is the gene that encode the calcium ion channel Cav1.2.  It is the gene behind Timothy Syndrome and the gene that I followed to Verapamil, a key part of my son’s PolyPill therapy.

The reason the gene/protein interactions are important is that the same therapy can be applied to different dysfunctional genes/proteins. A person with a genetic defect in a sodium ion channel might get a therapeutic benefit from a drug targeting a calcium ion channel.

 

The top 5 interactions with CACNA1C (in red):



 Note CACNB1 (in blue) 

There is already  lot in this blog about the calcium channel Cav1.2 (encodeded by CACNA1C).

CACNA1C is associated with Autism, schizophrenia, anorexia nervosa, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), Tourette syndrome, unipolar depression and bipolar disorder. 

Today we look at the “new” autism gene CACNB1. 

It is actually much more interesting that you might imagine, especially if you have to deal with epilepsy or periodic headaches at home.  You also might also have some Math Whizz back there in your family tree.

We know that brainy people, particularly mathematicians, have elevated risk of autism in their family.  Having a maths protégé in the family may not be good for your kids.

We also know that bright mathematicians are very likely to have some feature’s of Asperger’s.

The chart below expresses the top 25 interactions with the gene CACNB1 which encodes voltage-dependent L-type calcium channel subunit beta-1. It is the pink circle in the middle.

Click on the link for a higher resolution image, or on the image itself.


https://version11.string-db.org/cgi/network.pl?taskId=KBcDrcBSd4X6

 


If you look at the above chart you can spot the genes that relate to calcium channels, they start with CAC.

At the top of the chart we 6 genes starting with SCN. These genes relate to sodium ion channels.

 

SCN9A

It was interesting to me that the gene SCN9A, which encodes the ion channel Nav1.7 is associated with insensitivity to pain.  Reduced sensitivity to pain is very common in autism.  This is a feature of Monty’s autism.

A mutation in SCN9A can also cause epilepsy. Often these seizures are fever associated.

Local anesthetics such as lidocaine, but also the anticonvulsant phenytoin, mediate their analgesic effects by non-selectively blocking voltage-gated sodium channels. Nav1.7.

Other sodium channels involved in pain signalling are Nav1.3, Nav1.8, and Nav1.9.

You would think that SCN9A would encode Nav1.9, but it seems to really be Nav1.7.  Nav1.9 is encoded by the gene SCN11A, just to see who is paying attention.

 

SCN8A

The SCN8A gene encodes the sodium ion channel Nav1.6. It is the primary voltage-gated sodium channel at the nodes of Ranvier. 



The channels are highly concentrated in sensory and motor axons in the peripheral nervous system and cluster at the nodes in the central nervous system.

If you have a mutation is in SCN8A you may face Cute syndrome.  You will have some severe challenges including treatment resistant epilepsy and may include autism and intellectual disability.


 https://www.thecutesyndrome.com/about-scn8a.html


Not such a cute syndrome.

 

SCN4A

The Nav1.4 voltage-gated sodium channel is encoded by the SCN4A gene. Mutations in the gene are associated with hypokalemic periodic paralysishyperkalemic periodic paralysisparamyotonia congenita, and potassium-aggravated myotonia.

I have covered hypokalemic periodic paralysis and hypokalemic sensory overload previously in this blog.  I showed that I could reduce Monty’s sensitivity to the sound of a baby crying by giving a modest potassium supplement. 

Mutations in SCN4A are also associated with abnormal height and abnormalities of the head, mouth or neck.

 

SCN3A

The Nav1.3 voltage-gated sodium channel is encoded by the SCN3A gene

It has recently been shown that speech development is affected by this ion channel.  Many people with severe autism never fully develop speech.




  

Sodium channel SCN3A (NaV1.3) regulation of human cerebral cortical folding and oral motor development

Channelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated sodium channel NaV1.3. Pathogenic NaV1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (NaV1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.

 

 SCN2A

The Nav1.2 sodium ion channel is encoded by the SCN2A gene.

Mutations in this gene have been implicated in cases of autisminfantile spasms bitemporal glucose hypometabolism, and bipolar disorder and epilepsy.

  

SCN1A

 The Nav1.1 sodium ion channel is encoded by the SCN1A gene.

Mutations to the SCN1A gene most often results in different forms of seizure disorders, the most common forms of seizure disorders are Dravet Syndrome (DS), Intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC), and severe myoclonic epilepsy borderline (SMEB).

Mutations are also associate with

·        Febrile seizures up to 6 years of age

·        MMR-related febrile seizures

·        Sleep duration

·        Educational attainment

 

 

Now the Calcium ion channels:-


CACNB1

The gene CACNB1 encodes the Voltage-dependent L-type calcium channel subunit beta-1.

CACNB1 regulates the activity of L-type calcium channels that contain CACNA1A, CACNA1C or CACNA1B.  Required for functional expression L-type calcium channels that contain CACNA1D.

The gene is associated with headaches, asthma, mathematical ability and acute myeloid leukemia


CACNB2

The gene CACNB2 encodes the Voltage-dependent L-type calcium channel subunit beta-2.

Mutation in the CACNB2 gene are associated with Brugada syndromeautismattention deficit-hyperactivity disorder (ADHD), bipolar disordermajor depressive disorder, and schizophrenia.

 

CACNB3

The gene CACNB3 encodes the Voltage-dependent L-type calcium channel subunit beta-3.

Diseases associated with CACNB3 include Headache and Lambert-Eaton Myasthenic Syndrome.

Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by muscle weakness of the limbs.


CACNA1A

The Cav2.1 P/Q voltage-dependent calcium channel is encoded by the CACNA1A gene.

Mutations in this gene are associated with multiple neurologic disorders, many of which are episodic, such as familial hemiplegic migraine, movement disorders such as episodic ataxia, and epilepsy with multiple seizure types.

 

CACNA1B

The voltage-dependent N-type calcium channel subunit alpha-1B is encoded by the CACNA1B gene. Diseases associated with CACNA1B include Neurodevelopmental Disorder With Seizures And Nonepileptic Hyperkinetic Movements and Undetermined Early-Onset Epileptic Encephalopathy.

 

CACNA1C (covered earlier in this blog)

The CACNA1C gene encodes the calcium channel Cav1.2.   Cav1.2 is a subunit of the L-type voltage-dependent calcium channel.

 

CACNA1S

The CACNA1S gene encodes Cav1.1 also known as the calcium channel, voltage-dependent, L type, alpha 1S subunit.

This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysisthyrotoxic periodic paralysis and malignant hyperthermia susceptibility.

Mutations are associated with inflammatory bowel disease (IBD) and ulcerative colitis.

Note that Rezular or R-Verapamil was a drug developed to treat IBD.

 

CACNA1D

The CACNA1D gene encodes Cav1.3.

Cav1.3 is required for proper hearing.

Some mutations in CACNA1D) cause excessive aldosterone production in aldosterone-producing adenomas (APA) resulting in primary aldosteronism, which causes treatment - resistant arterial hypertension. These mutations allow increased Ca2+ influx through Cav1.3, which in turn triggers Ca2+ - dependent aldosterone production. The number of validated APA mutations is constantly growing. In rare cases, APA mutations have also been found as germline mutations in individuals with neurodevelopmental disorders of different severity, including autism spectrum disorder.

Recent evidence suggests that L-type Cav1.3 Ca2+ channels contribute to the death of dopaminergic neurones in patients with Parkinson's disease

Inhibition of L-type channels, in particular Cav1.3 is protective against the pathogenesis of Parkinson's in some animal models

CACNA1D is highly expressed in prostate cancers compared with benign prostate tissues. Blocking L-type channels or knocking down gene expression of CACNA1D significantly suppressed cell-growth in prostate cancer cells

 

CACNA1E

CACNA1E encodes the calcium channel Cav2.3 , also known as the calcium channel, voltage-dependent, R type, alpha 1E subunit.

These channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death.

Mutations are associated with epilepsy, acute myeloid leukemia, mathematical ability and having a big head.

 

CACNA1F

The gene CACNA1F encodes Cav1.4.

Mutations in this gene can cause X-linked eye disorders, including congenital stationary night blindness type 2A, cone-rod dystropy, and Aland Island eye disease

Mutations are associated with astigmatism and other eye conditions.

 

CACNA2D1

The CACNA2D1 gene encodes the voltage-dependent calcium channel subunit alpha-2/delta-1.

Alpha2/delta proteins are believed to be the molecular target of the gabapentinoids gabapentin and pregabalin, which are used to treat epilepsy and neuropathic pain. 

Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability


CACNA2D2

The CACNA2D2 gene encodes the voltage-dependent calcium channel subunit alpha2delta-2 is a protein that in humans is encoded by.

The Calcium Channel Subunit Alpha2delta2 Suppresses Axon Regeneration in the Adult CNS


CACNA2D3

The CACNA2D3 gene encodes the Calcium channel alpha2/delta subunit 3.

Cacna2d3 has been associated with CNS disorders including autism.

Synaptic, transcriptional and chromatin genes disrupted in autism


CACNA2D4

Calcium channel, voltage-dependent, alpha 2/delta subunit 4 is a protein that is encoded by the CACNA2D4 gene.

Mutations in CACNA2D4 are associated with mathematical ability and educational attainment.

 

CACHD1


CACHD1 (Cache Domain Containing 1) is not well researched, it may regulate voltage-dependent calcium channels.  It is moderately associated with anxiety.

 

CACNG1

The CACNG1 gene encodes the Voltage-dependent calcium channel gamma-1 subunit

Diseases associated with CACNG1 include hypokalemic periodic paralysis, type 1 and Malignant Hyperthermia.

 

REM1

The protein encoded by this gene is a GTPase and member of the RAS-like GTP-binding protein family. The encoded protein is expressed in endothelial cells, where it promotes reorganization of the actin cytoskeleton and morphological changes in the cells.

Recall my posts about RASopathies and MR/ID.

Diseases associated with REM1 include Mental Retardation and late onset Parkinson’s disease.

 

NALCN

NALCN (Sodium Leak Channel, Non-Selective) gene encodes a voltage-independent, nonselective cation channel which belongs to a family of voltage-gated sodium and calcium channels that regulates the resting membrane potential and excitability of neurons.

It is highly associated with an abnormality in the process of focusing of light by the eye in order to produce a sharp image on the retina.

It is associated with mental or behavioral disorders and unusual body height.

 

GEM

GEM encodes a protein that belongs to the RAD/GEM family of GTP-binding proteins.

It is associated with heart disease.

 

Conclusion

I was really surprised just how many autism/epilepsy genes are so closely related to the newly recognised autism gene CACNB1.

I hope you can see that a child without a mutation in CACNB1 can be affected by several of today's genes.  What matters is differentially expressed genes (DEGS).

In my simplification of autism, I have a category called channelopathies and differentially expressed genes (DEGS).  I did add the DEG part a while back, but this chart has stood the test of time.

I think many people with severe autism are affected by the genes in today’s post.

Headaches and epilepsy are an integral part of autism and better not considered as comorbidities. The same is true with big/small heads and indeed high/low IQ.




 

If you do invest in genetic testing, you would be well advised to look up any affected genes yourself. From what I have seen, do not rely on your DAN Doctor to do this thoroughly.





58 comments:

  1. My daughter has auburn hair, making her stand out genetically. She gets it from her aunt. Long before science confirmed it, we have been aware through my sisters experience that redheads don’t get any numbing from lidocaine. What do you make of that in light of the above described channels? https://scienceforecastoa.com/Articles/JOF-V2-E1-1003.pdf

    ReplyDelete
    Replies
    1. tpes, the pigment driving hormone is called MSH. MSH is derived from something called POMC.

      Pain relieving endorphins are also derived from POMC.

      People with red hair have an altered version of the gene MC1R and seem to have an altered receptor for both the pigment hormone MSH and for endorphins.

      Endorphins play a major role in the body's inhibitory response to pain.

      Laughter may also stimulate endorphin production and elevate one's pain threshold

      Endorphin production can also be triggered by vigorous aerobic exercise and contributes to a phenomenon known as a "runner's high”

      I think the fact that your daughter responds well behaviourally to the "wind in the hair" kind of sensory input might relate in part to an altered response to endorphins.

      The role of sodium ion channels in pain seems to be limited to the detection of pain by nerves in the peripheral nervous system, rather than what your brain does with these inputs. If you put lidocaine cream on your skin it just makes that part of your skin do numb, because you have blocked the signal from the sodium ion channels in that part of your body.

      Delete
  2. I actually came here to ask you in which blog post you talked about morning crankyness and sugar levels. I looked already but could not find it.

    ReplyDelete
    Replies
    1. I think discussion of a low glycemic diet has mainly been in the comments.

      It is referred to in this post, which may be the one you are looking for.

      https://epiphanyasd.blogspot.com/2019/12/dietary-autism-therapy-it-clearly-works.html

      In the approach used by Dr Kelley for mitochondrial disease he suggested giving a starchy food in the evening, that takes a long time to digest, so the child does not wake up in the morning with low blood sugar. You just do not want to give the child reflux during the night from a late meal.

      Delete
  3. Hello Peter.
    I'm in the process of having my DNA sequenced.
    I'm trying to understand once I have the raw data, what format does it need to be in and how I would proceed to analyze it? I see there are more resources in the GeneCards website.

    Have done this yourself and can recommend sources,
    or can point me to good reliable literature how to go on about this?

    Thank you

    ReplyDelete
    Replies
    1. You would normally receive a list of genes that have an anomaly and a code that identifies the anomaly.

      You then just look up these genes in GeneCards or elsewhere.

      We all have these anomalies and often you would submit your sample for DNA testing and ask for report covering just autism. If the entire exome has been sequenced, you can as for the extended report which would cover the genes the lab do not think relate to autism. Labs do not always know which the relevant genes are, so if you pay a lot of money for your genetic testing you might as well see the full set of results.

      Normally you test the person of interest and both their parents.

      There are some much cheaper genetic tests that will not cover all the autism genes, but might tell you something of interest nonetheless.

      I have looked up genes on many occasions, but not from my own DNA.

      Delete
  4. Hello Peter, Ling, Friends, and Community!

    I know it's been a while, but COVID has had me incredibly busy on multiple fronts (especially work and also a child home from school for 6 months), but I have just changed roles to one that has a far better work / life balance and hope to be back here more often.

    Peter - this was a wonderful post! Parents who are just learning the science behind the brain / ASD will greatly benefit from learning about the various ion channels (especially if relevant to their case). The Genecards tool is also a wonderful way to try to identify the relevant pathways if one knows the mutated gene in question. One issue that I've come up against is that the gene I'm dealing with has multiple isoforms (due to alternative splicing), and by knowing the location of the mutation, I was able to at least eliminate one isoform but have a couple left to deal with, each of which may contribute to my daughter's phenotype.

    Peter and community - Given that I have time again to research and post, I wanted to share something that may be of benefit to any parents dealing with NF1 mutations:

    https://onlinelibrary.wiley.com/doi/10.1002/npr2.12144

    The research was done in cell cultures (iN cells), and it may either not work in people or it may only work if applied very early (or during certain windows of neurodevelopment) but I wanted to share just in case it helps someone whose child is dealing with NF1.

    Please note that something that may help someone with NF1 may not help those with any other types of ASD.

    Your friend with (finally!) more work / life balance in the cooling North (AKA Canada),

    AJ

    ReplyDelete
  5. Due to my issues with attention and also often time zone issues, I do not attend online conferences on autism that much, though many are quite good. This years Synchrony conference however is really quite amazing, so I will definitely have to attend and recommend everyone take a look at the line up.

    ReplyDelete
    Replies
    1. tpes, I am presenting at the Synchrony autism conference. I did receive an email just now with a discount code for anyone who is interested to participate. Our reader Agnieszka gave a presentation at this event last year.

      Dr Ben Ari is going to talk about Bumetanide and I am talking about 8 years of using Bumetanide.

      Here’s the coupon code for readers of this blog:-

      EPIPHANY

      Here’s the link to the conference. Early bird pricing ends Oct 15th.

      https://synchronysymposium.com/

      The coupon code applies only to Early Bird and Regular Price, not to the Day Pass.

      Delete
    2. Great, thanks! :-)

      /Ling

      Delete
  6. Hi Peter

    I would highly recommend this Simon Baron Cohen youtube video – understanding sex differences in Autism. Most of us are aware of his extreme male brain theory by now but he also makes a compelling case for what happens with “non-genetic autism” & how Testosterone & other damaging hormones in the womb over masculinises the brain to the point of disability.

    From here there is a clear path for developing drugs / therapies to counter these hormones in pregnant mothers & for the prevention of autism in the womb. It’s a long shot but maybe a therapeutic avenue as well.

    https://www.youtube.com/watch?v=WjTR-VJNm3w

    ReplyDelete
    Replies
    1. Ross, what many men do not notice/know/remember is that in this day and age, a significant number of women get treated with hormones during pregnancy. I just remembered I was told to take progesterone for the first trimester, and look here - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252360/
      https://molecularautism.biomedcentral.com/articles/10.1186/s13229-018-0225-5

      I don’t think doctors understand just how little they know. I knew my pregnancy was going well and I only took it for about 6-7 weeks in the first trimester. Then they wanted me to take it later on, but I just lied to them that I was and they were very impressed with the stability of my pregnancy, praising the progesterone at every visit :-).

      Delete
    2. Thanks again tpes, for valuable insights!
      In hindsight, what would your best pregnancy tips be to avoid ASD or similar disorders?

      Delete
    3. Get yourself checked out, whether you have Aspergers. Count all autoimmune and allergic issues in immediate family. Look at the age of the male. Go on a grainfree organic diet 3 months before. Avoid tickbites and contact with animals. Check out your viral values before pregnancy, resolve all herpes issues you might have. Same for hormonal issues. I am pretty mad at my therapist - I was in therapy for several years before oregnancy and he never once told me that he considered me on thr aspie side ‘because a lot of his clients lean that way and it’s not a therapists job, its a psychiatric evaluation’. There isn’t enough awareness that having Aspergers is not a fun quirk in TV shows but rather a genetic thing you need to know about. funnily, when you ask the world for treatment for asd/aspergers, that awareness is very readily available.

      Delete
  7. Hello Peter, Ling, Friends, and Community!

    I wanted to share an update with you, which may be helpful to some of you.

    My daughter was really fixated on my wife and I buying her a contraption that would allow her to fly (e.g. jetpack, a helicopter belt, wings, etc) and despite our repeatedly telling her that this wasn't available, would repeatedly ask - constantly. And she was not a happy camper with our answer.

    It was to the point that we really had to do something as she want not moving on from her demands to other activities. We did try methods to divert her attention, worked with our behavoural therapist on methods to reduce her demands for things that don't exist, but to no avail. I finally relented about 6 weeks ago and decided to trial Lithium Orotate.

    Given that one never knows if a new treatment will help or make things worse, I started with what I considered a microdose (~160mcg/day) and have since titrated up to 320mcg/day. To get to such microdoses, I basically divided the contents of a 5 mg capsule evenly multiple times to get to the approximate dosage.

    It's been night and day - no more excessive demanding, better attitude, and I think we are seeing improvements in other areas as well (eye contact has been off the charts, more back and forth communication too).

    I can't say with 100% certainty it's the Lithium Orotate, but I would say it's 75% likely given that the trajectory of improvement (especially behavioural) increased noticeably soon after starting the Lithium Orotate.

    Please note, it's always N=1, others may not benefit from Lithium Orotate, and some may worsen. But I did want to share my experience just in case someone else is experiencing behavioral issues that are creating challenges.

    I hope this is helpful!

    AJ

    ReplyDelete
    Replies
    1. That is awesome news AJ! I've been interested in lithium orotate for some while due to the effect on GSK3beta, but I can't find where to get it here in Europe. Maybe it is considered a drug(?)
      Do you find it decreasing edginess or aggression?
      Great to have you back on the forum! :-)

      /Ling

      Delete
    2. AJ, that is interesting to hear. The research uses lithium carbonate and there is no consensus about the equivalent dose using lithium orotate. You would think you could just calculate the lithium content of the two, but they may not both be absorbed to the same extent.

      The limiting factor with lithium carbonate at the standard doses is the side effects. Maybe some people do not need these doses?

      We were also told Suramin was not suitable for autism, due to side effects and yet now they are developing it for autism.

      Regular dose Lithium Carbonate is used for Bipolar (900 to 1800 mg a day)

      Low dose Lithium Carbonate is used in Huntington's disease (150 mg a day)

      In the autism study below lithium carbonate was given at 6 mg/kg twice per day (with a 12 h interval) for 3 months.

      "In summary, low-dose lithium treatment was well tolerated and improved cognitive performance and adaptive behavior in children with ID without causing severe or irreversible side effects."

      https://www.frontiersin.org/articles/10.3389/fnmol.2018.00425/full

      Delete
    3. Hi Ling! :-)

      It's great to be back, and I'm really looking forward to having some work life balance in the new role. And very importantly, back to doing as much research as I used to.

      In terms of where I get it from, it's not sold in Canada so I order it from the US. For those who are not in the US or Canada, a re-shipping service (like Shipito) can be useful. I've used them for a few items from the US that didn't ship to Canada directly. They'll ship from the US to anywhere. Some of my go to stores include Swanson Vitamins, iHerb, and Piping Rock.

      As far as its effect, it definitely seems to have reduced the "crankiness" and my daughter's penchant for becoming fixated on certain items and not being able to move on. Her mood has definitely improved.

      Honestly, she has been great the last 6 weeks, no excessive demanding, and even her sense of humour has seemed to improve. She seems to laugh a lot more at funny things. The 2 items I would say have improved the most have been the excessive demands and crankiness, but there may be improvements in other areas as well (I am seeing a lot more eye contact - the eye contact avoidance has dramatically decreased and she looks into my eyes a lot more).

      I can't say what the impact will be for anyone else, but I started with a microdose. My LO pills are 5mgs each, so I started with ~160mcg/day just to ensure that there were no negative effects, and then when there were none, I moved up to ~320mcg. In theory, I could titrate up to ~500mcg or even ~640mcg, but I'm staying at this dose for now.

      If you do trial it, I really hope you see some good results.

      Have a great day Ling! :-)

      AJ

      Delete
    4. Hi Peter,

      Hope all is well!

      Peter, when I was doing my research on Lithium (as a result of the excessive demanding and crankiness), I saw the same thing you've noted (i.e. Lithium Carbonate vs. Orotate, the relatively high doses LC, and the lack of a clear understanding of how a LC dose might relate to a LO dose due to bioavailability / ability to cross the BBB ).

      Given the research on impact of LC on ASD, and the availability of LO (in much lower doses of Lithium), I decided to trial LO with ~160 mcg as the Lithium dosage is extremely low relative to LC doses, and even low compared to LO doses (which can be 5mgs or 10mgs for adults).

      In fact, we all get some Li in our food, and some people consider it a necessary nutrient for health, so I felt that a trial of ~160 mcgs was worthwhile given the behavioural challenges.

      We have had no negative effects at all, and given all the potential effects of Lithium, it's hard to determine which one or several are resulting in the positive effects we're seeing. I'm hoping the researchers will give me some clues soon, as knowing which pathway(s) I need to focus on would obviate the need for trial and error and allow me to focus on relevant pathways.

      Interestingly, the study you identified was a key study that helped sway me to trial LO. Given the dose of 6mgs/kg X2 in the LC ASD trial, my daughter's dose would be 131mgs of LC X 2 (or 262mgs/day). Assuming that 1mg of LC = 1mg of LO, this means that my current dose of 320mcg is ~800 times smaller than the daily dose of this trial. This made me comfortable in terms of side effects, especially my starting dose of 160 mcg/ day, which is 1/1,600th the dose in the trial (but I use LO vs LC).

      I can't say if it's greater bioavailability of LO, better ability to cross the BBB, or that only a tiny dose is needed in our case to impact the relevant pathway, but based on my experience, I think we only needed a microdose.

      For anyone reading this other than Peter or Ling (who know their stuff), please note that the dose I started with is 160 micrograms, not milligrams, and that my current dose is ~320 micrograms of LO. I say this as I would hate for someone to misunderstand the dosing. A standard capsule of LO has 5 milligrams of LO. My current dose is about one-sixteenth (1/16) of a capsule per day, and my starting dose was 1/32 of a 5mg capsule.

      I'll keep you posted Peter on how things go, but the last 6 weeks on LO have been noticeably different (and much better) than just prior to in terms of crankiness, excessive demanding, and even eye contact.

      Have a great night Peter!

      AJ

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    5. Hi AJ!(Tanya here) Wonderful news about how lithium orotate has helped your daughter . I am a big believer in lithium. However my son is on LC. (We tried LO when he was very young). He was on a low dose, and his blood tests were coming back lower levels. The doctor suggested we increase it when we removed a medicine the hospital rx’d after his manic episode in 2017. We increased the dose and it was like a switch flipped - so appropriately happy and at ease it was remarkable. We check his labs every 6 months (and it’s been almost 3 years since we started) - and never any issues - the doctor actually said his kidney markers looked “beautiful”. Ha! And thyroid markers normal. He is still very thin and athletic as usual. He has been on 900 mg for 2.5 yrs now - and still his labs always show low lithium levels. Anyone have thoughts on why that is? Does his body drain it?
      Glad y’all are doing well - excellent news
      ~Tanya

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    6. AJ, let me add that I'm very impressed you were able to divide capsules into 1/32 parts!

      Tanya, did your son respond to Lithium orotate too when young? Is lithium a normal thing to check for on labs, or was there any specific reason they checked for it?

      It really sounds like Lithium has some essential (anti-depressive) properties, though it's not considered so.

      /Ling

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    7. Here is very readable paper on Lithium.

      Note that even lithium found in some drinking water has an effect.

      Recall that many years ago the drink 7-up contained lithium and was its key selling point. This was in an old post.

      The New News about Lithium: An Underutilized Treatment in the United States
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854802/

      Delete
    8. Hi Tanya, Ling, and Peter,

      @Tanya - Hi Tanya! Thank you, and I'm so glad to hear your son is doing so well on LC :-) Ultimately, I think the key is the Lithium, and once those who will benefit from Lithium find the right dosage of the form they use (i.e. LC or LO), then it can seemingly do some really positive things. In terms of why his labs show low Lithium levels, I can't think of a reason why, other than his body is very good at eliminating it. Most (>90%) of Li is eliminated via urine, so it may just be that your son is better able to eliminate it than others. The great news is that even if the labs aren't detecting much, it's clearly doing the job. I hope all is well with you Tanya!

      @Ling - LOL, You should have seen me trying to divide the contents of one capsule in half 5 time at my kitchen counter. By the time I was splitting the 1/16th into 1/32nd (using the eyeball method versus any sort of scale), I was pretty close to the limits of my visual acuity. The amounts in each capsule were so small, that it was likely closer to an approximation of 1/32 of a capsule than an exact amount. Oh the things we do for our kids. Hope all is well Ling! :-)

      @Peter - I had forgotten about 7-Up having included Lithium many years ago, and the fact that Lithium is already in our drinking water made me look up the numbers. In the following link, based on US cities / states, the cities listed can range from 20mcg/L to a whopping 649mcg/L:

      https://psycheducation.org/treatment/mood-stabilizers/the-big-three-for-bipolar-depression/lithium/how-much-lithium-in-my-water/

      What is fascinating is the studies, and the recommendation by some scientists that Lithium should be added to drinking water (as it helps reduce suicide rates in places where the Li levels are higher). Have a great day Peter!

      AJ

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    9. Hi Ling! hope you all are well -
      We never tested lithium levels when he was younger. But when prescription lithium is given, there are guidelines for testing levels for therapeutic range also thyroid markers.
      ~Tanya

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    10. Thanks Tanya!
      I have no idea of why lithium could be drained, all I know is that it has an (inhibitory) effect on NMDArs. The link to mania and MAOIs is unknown to me.

      AJ, may I ask what human weight you are dosing against?
      iHerb seems to have 1000 mcg capsules, it might be easier to divide those. :-)

      /Ling

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    11. Hi Ling! My daughter is 48 pounds (22 kg). My intent was to start at a super low dose to ensure that if there any negative effects, I would catch them at a minimal dose (~160mcg). As I've noted, I'm up to what should still be a pretty low dose (~320mcg) at which I believe we are seeing some efficacy.

      Let me know how you do on the low tech eyeball technique - it's ok after the first couple of rounds of dividing the dose in halves, but by the 5th round, it's really hard to split the dose in half any further :-)

      I hope this is helpful Ling!

      AJ

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    12. seems iHerb has a liquid form of LO - and that may makes it easier for dosage control.
      Hows your trial on LO going so far?

      Delete
  8. ling, most parents in Europe use the webshops iHerb, mandymart and spectrumsupplements. They should all have lithium orotate.

    ReplyDelete
    Replies
    1. Yes, I just saw it on iHerb (1000mcg). But if it is a drug it won't enter my country because of customs going through all packages from the US. I once lost a whole order because it contained NAC...
      /Ling

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    2. mandimart and spectrumsupplements are eu

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  9. Hi Peter we just had the whole exome sequencing done on the nhs by genetics for my asd son and me and his dad,do you think all this will show up there .We have been told it will take 12 weeks before we get the result .

    Thanks

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    Replies
    1. Hopefully they will show you the full report, listing any affected genes. There are very many possibilities, the fact you had it done for free might mean they expect a "result".

      Only in a small number of cases is there a single problem gene, in another 25% there is useful information. For most people whole exome sequencing does not really tell you much.

      Whole exome sequencing looks at just 2% of your DNA. There is also the epigenome.

      It is definitely good news that the NHS are doing this for you. It would be great if the NHS did this for everyone with an autism diagnosis.

      It will be interesting to see what the NHS provides you after the results.

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    2. Thanks Peter .I will let you know when the results are out .I actually pushed for it as I heard of a condition where children have creatine deficiency and abnormal GAA levels which makes them present with asd features and they may not actually have autism so he was tested for that too but his GAA levels were okay and then the WES was the next step since his GAA levels and creatine were okay .

      Yes it will be interesting to see what comes up ,I will definitely keep you posted .I will register for the conference too as we are presently in the trial .I am interested in hearing what Ben Ari has to say and you too about the Bumetanide .

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    3. Hi Lady Apinks, I want to push for WGS on the NHS too when this covid dies down, im expecting resistance and to be fobbed off since my boy has already had a micro array test that was negative. There was a big announcement last year that all kids with unknown conditions will be able to get WGS on the NHS, thing is do they class autism as unknown?

      Delete
    4. Hi Ross I have no idea but I saw the peadiatrician and she referred us to genetics as she said she didn’t know what I was talking about .We were sent to guys and the geneticist agreed to do it so I will say you should push for it and don’t take no for answer especially as the micro array didn’t show anything .

      Delete
  10. Hi Peter and readers of this blog,

    Can you recommend a Potassium supplement? All t the options I looked into have a low amount (99 mg : 2% of RDA). Looking for a supplement that offers more us safe to use.

    Thanks,
    V

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    Replies
    1. You can buy potassium supplements in powder form. Look on iHerb. You measure the dose you need and dissolve in a glass of water.

      You do not want to give a huge dose of potassium. My 17 year old son takes a 500mg dose of potassium citrate with his 2mg of bumetanide.

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  11. Hello Peter, Ling, Friends, and Community,

    I just read a very interesting article on gene therapy for certain causes of ASD, and how a parent can really impact the research and potential treatments for their child. This reminds me of a supermom I know ... ;-)

    https://www.sciencemag.org/news/2020/10/gene-therapy-ready-treat-some-forms-autism

    My personal belief is that while in an ideal world, a child is treated either in the womb or soon after birth, that there are always opportunities to improve, and that the human brain has enough plasticity to allow us to later (via treatment) gain some/most/all of the capabilities that were otherwise lost. Translation: Don't give up, there is always hope!

    Your friend from the soon to be frozen north,

    AJ

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    1. Great reading AJ, thank you for sharing hope!
      I find it a bit surprising but very encouraging every time I hear of a genetic condition that can be reversed even in adult mice. It happens rather often, actually. In my daughter's condition, researchers have found there is a post-natal effect on the brain, meaning there is hope even for older individuals.
      That said, I will do as much as I can for damage-control now.

      /Ling


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    2. Hi Ling, hope all is well and my pleasure to share and as I was reading the article, the mom in the article reminded me of you (being very proactive to impact the research on a gene) :-)

      My view of the science is this - just 14 short years ago, the scientific consensus was that a cell's fate could only go in one direction. And then in 2006 Dr. Shinya Yamanaka accomplished the impossible via his Yamanka factors and rewound the clock back and turned adult cells back into a stem cell state. This created Induced Pluripotent Stem Cells (iPSCs) and dramatically changed science forever.

      I bring this up as for some genes / mutations the science today may say that beyond certain critical points (e.g. in the womb, at certain critical postnatal windows, etc.) nothing can be done. I absolutely believe that for at least some cases, solutions will be found such as "re-opening" certain critical windows of time outside of their standard timing, and allowing for corrections to be made.

      It may be that something appears impossible today, but as Dr. Shinya Yamanaka proved, what is impossible today can be possible tomorrow.

      If anyone can move mountains for your gene Ling, and not only do "damage control" but really make a positive impact, it's you.

      Between CRISPR (and my personal favorite right now base-editing), RNA editing (which is a less permanent solution than DNA but may be accessible sooner by virtue of it not being permanent), and the many other incredible platform technologies emerging, I really believe we have a real shot and giving our kids a much better future.

      Have a great day Ling!

      AJ

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  12. I just finally got around to reading a very interesting bit of research on GABA, Astrocytes, and how they interact in the thalamus to control sensory tuning:

    Press Release:

    https://www.sciencedaily.com/releases/2020/09/200908113333.htm

    Paper:

    https://www.cell.com/neuron/fulltext/S0896-6273(20)30644-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627320306449%3Fshowall%3Dtrue

    They also discuss the DAO enzyme which as you well know has a lot to do with histamine in other parts of the body.

    This makes you wonder with regards to how noisy the autistic brain usually is, whether impairments in astrocytic GABA could be a cause of sensory overload in those with autism due to the lack of "GABA tuning" of thalamic neurons via astrocytic regulation.

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  13. Hi Peter .Please I have a few questions

    we are presently on Bumetanide and I have managed to get some verapamil, atorvastatin and clonazepam.My boy is 6 years and weighs 22kg.
    1.Please what dosage would you advise for the 3 especially clonazepam and which one would you advise I start with.He is non verbal but can say a few words when prompted

    2.I read verapamil also helps with behaviours .He is not aggressive or hit or lash out but very disruptive .If he comes into a room he will put all the pillows on the floor,overturn the toy box and try and turn the place upside down.Would this be classed as behaviours ?He does not know how to play with toys just stims with it and knocks it together .Do you think verapamil will help with calming in this kind of situation ?


    3.He also suffers from constipation,he does not go to the toilet daily, maybe once in 3 to 4 days do you think this will help in resolving gut issues .

    4.He is about to be put on Ritalin for calming do you think I should wait and see how he would react to the polypill first.

    Many thanks for your help.I look forward to your response .

    ReplyDelete
    Replies
    1. Apinke, based on the doses I used, the doses would be 0.015 mg of clonazepam, 5mg of Atorvastatin and 15mg of Verapamil.

      You will find it hard to measure such a small dose of Clonazepam. Because the dose is so small there appear to be no side effects at all, at normal doses Clonazepam has issues. I add a tablet to water in a 100ml glass bottle, stir very well and use a syringe to measure the exact dosage. Keep the bottle in the fridge and use a hand held electric frappe mixer to stir it very well each time. It takes 3 days to reach a steady level in your body and only then will there be an effect. If there is an effect, but it is negative, reduce the dose slightly. There is a narrow dosage window where you get the required effect, so a bit of trial and error is needed.

      Atorvastatin may help cognition, but only use it if there is a good reason. If there is a positive effect it appears in the first couple of days.

      Verapamil's effect on behaviour is within half an hour, but I would only try once to see if it works. The beneficial effect on GI issues is for the opposite problem, Irritable Bowel Syndrome with diarrhoea/diarrhea. I do not think verapamil is likely to be helpful in your case.

      Ritalin is a stimulant used to treat ADHD. I doubt ADHD is his real problem.

      Your son does not know how to play, or communicate, so he acts up. That is only natural.

      If you can improve his cognition/learning with bumetanide, or low-dose clonazepam, perhaps Atorvastatin then you need to teach him how to play and better communicate.

      It takes a great deal of time to teach such children. It is all 1:1 sitting at their level, facing them. You can do it yourself or get people in to help you. Methods include Floortime, ABA etc.

      Delete
    2. Thanks so much Peter for your comprehensive reply.It is most helpful.

      The clonazepam I got is 2mg should that be dissolved into 100ml of water or I should split the pill into four making 0.5mg into 100ml of water.Thanks I will go with your advice .

      I will start with the low dose clonazepam and see what happens and try and adjust to get the right dosage.

      Yes I will work on improving cognition and learning but the problem is he can't sit till he runs all over the place though he knows quite a bit when you say show me , but the problem is he can't say it out.

      I will also try and see if we can get someone to help with this too as you suggested .I try a lot to teach him but he has younger ones demanding attention too but we will push on.

      Many thanks for your help again.I really appreciate it
      Apinke

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    3. Apinke, it is best to use the 0.5mg in 100ml of water. You will then need 3ml once a day.

      The tablet does not dissolve properly, you just get a suspension. This is why you need to shake/mix very well, before you measure out the 3ml. The frappe mixer works well because it fits inside the bottle.

      Some OTC kids medicines come in 100 ml glass bottles with a syringe. This is what I use. Glass bottles are better than plastic.

      There are online apps that work well with non-verbal kids and allow you to see how much they know. You just need a touch screen.

      The first step to educating a child with autism is getting them to sit still at a table. The instructor sits the other side and then the learning begins. You can use a reward/reinforcer to get him to come and sit at the table, and engage in a simple task, like stacking lego bricks, to match an example you made. At the start you have him come and sit for 1 minute, next day 2 minutes and eventually he sits still for 30 minutes. You gradually reduce the rewards. Rewards can be edible or even a cartoon break. You find what he wants to work for.

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  14. Thank you so much Peter .The 3ml is that at once or spread 1ml at three times a day .I will look for a glass bottle as I already set a plastic bottle aside already .I will also get the frappe mixer .

    We have a table and chair but I usually to force him to sit .I will look for reinforcers that he likes and start with the lego.Many thanks for your help .

    ReplyDelete
    Replies
    1. Thanks I have reread again it’s 3ml once a day .Many thanks

      Delete
  15. Hello Peter! I’m just starting to browse through your blog. You mentions genes of interest, however, doesn’t the impact depend largely on the exact variant/mutation? My son has inherited variants in two of the channel genes (parents are NT) and these are classified as uncertain significance. How does one find out if this falls under the differentially expressed category? Any better way than to trial treatment?

    ReplyDelete
    Replies
    1. If you know the exact genes and the exact mutation you can read the research to see if the exact effect is known. You want to know about gene expression in your son's brain, that is not easy.

      I think trialing treatment for just 2 genes is actually a very good option.

      Delete
    2. Thanks! I have been looking at acetazolamide and I see that you mention doing a trial of this. do you see this as a addition to or a replacement for Bumetanide when it works? (Sorry if this has been answered, I haven't read through your posts extensively yet).

      Delete
    3. SD, in people who tolerate acetazolamide well, it may well complement Bumetanide. As well as its own functions, which do help some people, acetazolamide (an OAT3 inhibitor) slows down the excretion of bumetanide from the body, so making bumetanide more potent.

      Delete
    4. Hi Peter,

      Quick question--what kind of potassium bromide do you use? The prescription form only available in Germany? KBr seems to be 100% absolutely verboten in the US, so I'm not even going to mention it to our doctor. Strangely enough you can buy it for pets with epilepsy w/o prescription.

      Thanks
      MKate

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    5. MKate, my experience is with the German version.

      KBr was the original drug used for human epilepsy, so there is nothing scary about it. At high doses it causes bromo-acne and this is why they stopped using it in adults, but in some types of epilepsy it is the only effective treatment, eg Dravet Syndrome.

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  16. Hi Peter,

    We just got the genetic test result from GeneDx xtended autism panel for my son, Vik (age 5, mild/moderate ASD).

    There was only one gene variant: CACNA1G (Uncertain Clinical Significance)

    "p.(Glu2220Lys) (GAG>AAG): c.6658 G>A in exon 38 of the CACNA1G gene (NM_018896.4)
    The proband's father is heterozygous for the p.(E2220K) variant in the CACNA1G gene. The proband's mother does not harbor the p.(E2220K) variant in the CACNA1G gene."

    Full report here: https://drive.google.com/file/d/1Nfp-Y5n23f-IWC2py7bfSOFCc9iMHbJG/view?usp=sharing

    In one of your other posts, you had mentioned that this gene is involved in Cav3.1 channel. I tried looking up on genecards but I will need a lot of time to make sense of the information.

    Any initial thoughts? Should I reach out to someone like Dr.Boles?
    My son's main complaints as of today are sensory seeking (jumping, screaming) and racing thoughts/memories.

    This might be unrelated, but I used to be pretty good at math and I started having grey hair when I was around 14.

    Anvesh

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    Replies
    1. Anvesh, there are 42 listed substances affecting the calcium channel Cav3.1, which is encoded by your gene CACNA1G. Many of the substances are cheap generic drugs.

      If you are in California, it would make sense to go and see Dr Boles and discuss this.

      Being good at maths and premature greying do seem to be associated with autism in later generations.

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  17. Thanks Peter,

    I will see if there is a way to get in touch with Dr.Boles.

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