Metyrosine, Intranasal Suramin and Visbiome/Viviomixx for Autism?

 

Our reader Natasa brought to my attention various things recently; this included the fact that intranasal delivery of Suramin for autism is being developed and the repurposing of an old drug called Metyrosine for autism.

I also noted a recent study that used a popular probiotic formerly called VSL#3, now called Visbiome/Viviomixx. This is interesting because it found that autistic people without GI dysfunction benefited.  The study had a high drop out rate and the improvement was not huge. Visbiome/Viviomixx is pricey for a probiotic, but not the price of two Ferraris like Metyrosine.

 

Suramin Nasal Spray -  PAX 102

Suramin is Dr Naviaux’s idea to treat autism and indeed several other conditions. Suramin is an existing drug approved outside the USA and made by Bayer.  Clearly Dr Naviaux’s new partner Paxmedica was not able to make a deal with Bayer, so they have to figure out themselves how to manufacture Suramin, which loses more time.  The good news is that they are working on intranasal delivery, the traditional way to delivery Suramin is by injection.

Research showed that the effect of Suramin is lost after a few weeks, so quite frequent injections would be needed.  Intranasal delivery has the advantage of avoiding injections and hopefully reduces the side effects of Suramin.

 

https://www.paxmedica.com/pipeline

 

  Metyrosine

  

 Metyrosine looks very interesting, until you see the price.

Metyrosine is yet another old generic drug, from 40 years ago, that can be used to lower blood pressure.  It inhibits the enzyme tyrosine hydroxylase and, therefore, catecholamine synthesis, which, as a consequence, depletes the levels of the catecholamines dopamine, adrenaline and noradrenaline in the body.

Metyrosine seems to have been forgotten about as a cheap hypertensive drug, but was repositioned as an ultra-expensive drug for a rare condition called Pheochromocytoma (PHEO).  PHEO is a rare tumor of the adrenal gland; these tumors are capable of producing and releasing massive amounts of catecholamines, metanephrines, or methoxytyramine, which result in the most common symptoms, high blood pressure, fast heart rate, and sweating.

Unfortunately, Metyrosine (brand name Demser) has become one of the world’s most expensive drugs, costing up to $30,000 a month.

Old posts on catecholamines:-

Secondary Monoamine Neurotransmitter Disorders in Autism – Treatment with 5-HTP and levodopa/carbidopa?

Catecholamines and Autism

Metyrosine for Autism

The proposed mechanism of action for the treatment of ASD is consistent with the assumption that an imbalance exists between catecholaminergic systems and the modulators of aminergic systems in the CNS and periphery.  Excess levels of nerve growth factor (NGF) and brain-derived NGF (BNGF), which are released into the catecholamine synaptic cleft, can cause branching and arborization of synaptic terminals, thus increasing the strength of catecholaminergic neurotransmission. Because growth factors are a component in these synapses, elevated levels of NGF and BNGF become chronic, along with elevated levels of dopamine and other catecholamines from these hypertrophic nerve terminals. The result may be a hypertrophy of the synaptic architecture, resulting in a persistent imbalance between aminergic systems and their offsets, which can lead to overstimulation of some CNS tracts and depletion of others. Consequently, increased dopamine activity within the CNS and the gut is associated with ASD, repetitive stereotyped behaviors, and defiant and anxiety disorders.  By reducing presynaptic catecholamine synthesis, storage, and release, Metyrosine/L1-79 may reduce the associated release of NGF and BNGF, rebalancing catecholaminergic mechanisms in the brain, gut, mesentery, and elsewhere. These effects are not mimicked by receptor-blocking agents that reduce postsynaptic depolarization without addressing the underlying hypertrophic dendritic architecture.  If this proposed mechanism of action in ASD is correct, reduced catecholamine synthesis, storage, and release should improve ASD symptoms. In the long term, reducing catecholamine release may enable the hypertrophic sympathetic nervous system to regress to a homeostatic configuration.

 

I suppose to get a unique patent, the developer has decided to use a different version of Metyrosine.

Their version, L1-79, is slightly different to Metyrosine

Metyrosine is the L-isomer of amethylparatyrosine.

L1-79 is a mixture of the L-isomer of amethylparatyrosine and the D-isomer amethylparatyrosine.

Metyrosine is already an approved agent, and the US Food and Drug Administration  guidance states that any stereoisomer of an approved agent can be considered to be the same agent, so the developer can treat their drug L1-79 as being an FDA approved drug (but not yet approved for autism as the use).

 

Effect of L1-79 on Core Symptoms of Autism Spectrum Disorder: A Case Series

Purpose:

This study examines the effects of the tyrosine hydroxylase inhibitor L1-79, a racemic formulation of a-methylparatyrosine, in patients with autism spectrum disorder (ASD) in a prospective case series. The L-isomer formulation of amethylparatyrosine, metyrosine, is approved for the management of patients with pheochromocytoma.

Methods:

Six male and 2 female patients aged 2.75 to 24 years with ASD were treated for 8 weeks at L1- 79 doses ranging from 90 to 400 mg thrice daily. Assessments at weekly intervals included the Aberrant Behavior Checklist eCommunity (ABC-C), Connor's Parent Rating Scale (CPRS), and Clinical Global Impressions (CGI) scale. The Autism Diagnostic Observation Schedule (ADOS) was administered at baseline and week 10. Findings: The ABC-C and CPRS scores improved between baseline and end of study for 7 of 8 participants; most participants' assessment scores decreased. At week 8, the CGI efficacy index was 05 for 6 of 8 participants, indicating modest improvement with at least partial resolution of symptoms and no medication adverse effects, and 09 for 2 participants, indicating minimal improvement and no change in status or care needs, without adverse effects. The mean ADOS scores improved by 31% for 4 of the 6 participants tested, with 1 patient experiencing a 47% improvement. Seven of the 8 participants previously taking psychotropic medications were stable without their legacy medications while receiving L1-79, and 1 patient resumed a single legacy medication at a lower dose. Three adverse events were reported; symptoms were mild and resolved without change in therapy.

Implications:

These results suggest L1-79 may be a tolerable and effective treatment for the core symptoms of ASD, which must be confirmed with double-blind studies.

 

The trial was very small, but if you look at the results, half of the participants were big-time responders.

If Metyrosine was still a cheap antihypertensive drug it would be very interesting.

Unfortunately, there is a clear trend to withdraw cheap generic drugs that can be repurposed and then bring them back as ultra expensive drugs for the new use.

Sadly, autism will need polytherapy, so you may need 5 drugs.  Nobody can afford 5 ultra-expensive drugs.

 

Viviomixx/ Visbiome for those without GI dysfunction 

Italians like probiotics and the study below is from Italy.  It uses the De Simone Formulation (DSF) which became well known as VSL#3, but following legal disputes is now marketed as Vivomixx in EU, Visbiome in USA.

The study does suggest that those without any GI dysfunction may benefit from this product. These people are in the “NGI group”, in the paper below.

We already know that some people with autism and GI dysfunction do benefit from this product, which is widely used by people with all kinds of GI dysfunction.  Clearly if you reduce GI dysfunction, behavior is likely to improve.

It is more potent than many probiotics.

Each packet contains 450 billions bacteria from eight probiotic strains:

·        Streptococcus thermophilus DSM24731

·        Bifidobacterium breve DSM24732

·        Bifidobacterium longum DSM24736

·        Bifidobacterium infantis DSM24737

·        Lactobacillus acidophilus DSM24735

·        Lactobacillus plantarum DSM24730

·        Lactobacillus paracasei DSM24733

·        Lactobacillus delbrueckii ssp. bulgaricus DSM24734

 

The beneficial effect was there, but not huge.

 

No differences between groups were detected on the primary outcome measure, the Total Autism Diagnostic Observation Schedule - Calibrated Severity Score (ADOS-CSS). An exploratory secondary analysis on subgroups of children with or without Gastrointestinal Symptoms (GI group, n= 30; NGI group, n=55) revealed in the NGI group treated with probiotics a significant decline in ADOS scores as compared to that in the placebo group, with a mean reduction of 0.81 in Total ADOS CSS and of 1.14 in Social-Affect ADOS CSS over six months. In the GI group treated with probiotics we found greater improvements in some GI symptoms, adaptive functioning, and sensory profiles than in the GI group treated with placebo. These results suggest potentially positive effects of probiotics on core autism symptoms in a subset of ASD children independent of the specific intermediation of the probiotic effect on GI symptoms. Further studies are warranted to replicate and extend these promising findings on a wider

 

Viviomixx/Visbiome is one of the expensive probiotics, but it is one of the serious ones. It looks like some people without GI issues are likely to benefit to some degree.  Is it worth the expense?  You would have to try it.

We have seen case histories of people with autism, and severe GI issues, greatly improving with VSL#3/ Viviomixx/Visbiome.

 

Effects of Probiotic Supplementation on Gastrointestinal, Sensory and Core Symptoms in Autism Spectrum Disorders: A Randomized Controlled Trial

Participants were randomly assigned to probiotics (De Simone Formulation) (n=42) or placebo (n=43) for six months. Sixty-three (74%) children completed the trial. No differences between groups were detected on the primary outcome measure, the Total Autism Diagnostic Observation Schedule - Calibrated Severity Score (ADOS-CSS). An exploratory secondary analysis on subgroups of children with or without Gastrointestinal Symptoms (GI group, n= 30; NGI group, n=55) revealed in the NGI group treated with probiotics a significant decline in ADOS scores as compared to that in the placebo group, with a mean reduction of 0.81 in Total ADOS CSS and of 1.14 in Social-Affect ADOS CSS over six months. 

In the GI group treated with probiotics we found greater improvements in some GI symptoms, adaptive functioning, and sensory profiles than in the GI group treated with placebo. These results suggest potentially positive effects of probiotics on core autism symptoms in a subset of ASD children independent of the specific intermediation of the probiotic effect on GI symptoms. Further studies are warranted to replicate and extend these promising findings on a wider population with subsets of ASD patients which share targets of intervention on the microbiota-gut-brain axis.

 

A novel and promising finding of our study is the significant decline in ADOS CSS scores (both Total and Social-Affect scores) in the NGI group treated with probiotics as opposed to those obtained in the placebo group. This result, although deriving from a secondary analysis, is particularly important from a clinical point of view, especially in the light of the abovementioned psychometric properties of the used tool. In fact, a mean reduction of 0.81 in Total ADOS CSS and of 1.14 in Social-Affect ADOS CSS over six months constitutes a clinically significant decrease of ASD symptoms (34). Not all previous trials with probiotics examined their effect taking into consideration the presence/absence of GI symptoms (25). Our result suggests that ASD children with and without GI symptoms could represent two different populations and that probiotics interventions could potentially provide different effects, likely due to distinct microbiota targets. Previous studies have already suggested that differences in microbiome (45, 46) are independent from GI dysfunction, and Luna et al. (45) argued that larger and well-designed studies are still needed to determine whether microbial composition may stratify ASD children beyond the GI symptoms. Within this framework, a positive impact of probiotics on autism severity in children without pre-existing GI symptoms supports the complexity of the microbiota-gut-brain axis warranting further studies on this subgroup of ASD subjects.

 

 

In the subgroup of children with GI symptoms we found a positive effect of probiotics not only on GI symptoms, but also on adaptive functioning, developmental pathways, and multisensory processing, the latter now reported by the DSM-5 (1) among core symptoms of ASD.

Taken together, these different results on NGI and GI groups of children suggest that the effects of probiotic supplementation in ASD children may be due to distinct mechanisms. The well-known neurobiological heterogeneity of ASD implies that each medication is likely to benefit only a subset within the spectrum of affected children, as suggested by results of pharmacological trials in this population (49, 50). The described positive effect on both GI and NGI children paves the way for the identification of those ASD subjects who can respond to probiotic supplementation beyond the presence of GI symptoms, and even beyond GI inflammatory status. In fact, in the current study, the supplementation with DSF compared with placebo resulted in no significant effects on the levels of plasma and fecal inflammatory biomarkers. In a previous investigation, we have reported that the values of these biomarkers were in the normal range already at baseline (51); thus, we do not confirm the two previous studies (52, 53) reporting some positive effects of probiotics on biomarkers of inflammation, and we could hypothesize that the effect of probiotics on adaptative functioning is not mediated by a reduction in systemic or intestinal inflammation.

 

Efficacy: Secondary Exploratory Analyses on GI and NGI Parallel Arms

One of the original aims of this study was to evaluate the effects of probiotics on ASD core symptoms, GI symptoms, and plasma and fecal inflammatory biomarkers in ASD children with and without GI symptoms. For this purpose the randomization was made independently in the GI and NGI groups, to obtain four parallel arms. At the end of recruitment, the sample size of each arm did not reach the target already determined for the whole sample; the GI group, already less numerous, was also affected by a bigger drop-out rate than the NGI one. Therefore, secondary exploratory analyses among subgroups were performed. The four parallel arms were well balanced for the total number of hours of rehabilitative treatments (GI placebo: 175± 91, GI Probiotic 156 ± 68, NGI placebo 134± 84, NGI probiotic 137 ± 129 p>0.05 for all the comparisons).

In the NGI group we found a significant decrease both in the primary outcome measure, Total ADOS-CSS scores (which decreased from 6.72 to 5.91 in the probiotic group and increased from 6.96 to 7.17 in the placebo group; mean change probiotic vs placebo, - 0.81 vs + 0.21 [95%CI, -0.76 to +0.20]; P = 0.026), and in Social-Affect ADOS-CSS (mean change probiotic vs placebo -1.14 vs -0.04 [95%CI, -1.01 to +0.06]; P = 0.027).

In the GI group, statistically significant effects were found in GI symptoms (Total GSI, Total 6-GSI, stool smell and flatulence mean scores), and in adaptive functioning (Receptive Skills, Domestic Skills and Coping Skills VABS-II subscales) for which probiotic therapy was associated with greater improvements than placebo (Table 3). In addition, in the GI group a significantly higher proportion of children in the probiotic group than in placebo group showed a normalization of Sensory Profile scores in the Multisensory Processing subscale (p= 0.013): the scores improved in 87% vs 28%, respectively, and got worse in 0% vs 42%, respectively (Tables S4, S5).

 

 

 

Several limitations must be noted. Firstly, the large dropout rates, although satisfactory considering the duration of the study, may have affected the trial’s ability to reliably detect significant differences between the two main treatment groups. This seems to have affected particularly the subjects within the GI group, in which almost half of participants dropped out, mostly in the placebo group (as reported in Figure 1). We could speculate that parents of these children had more expectations about the efficacy of the probiotic supplementation on GI symptoms than parents of children within the NGI group. For this reason, they could be disappointed when the treatment (or placebo) was not fully effective on GI symptoms of their children, dropping out of the trial without waiting for its possibile positive effects on core and developmental symptoms. Consequently, children who dropped out were substantially comparable to children who completed the trial in all clinical variables, with the exception of higher levels of GI symptoms. This discrepancy between the two groups could impact the study’s ability to detect other possible significant differences in the whole spectrum of GI symptoms. A second limit is that the use of the ADOS-CSS evaluation as an outcome measure in clinical trials has been recently disputed (43), mostly because it lacks sensitivity to detect changes in short time periods.

 

 

In conclusion, a six-month probiotic supplementation did not result in statistically significant changes in autism symptoms in the whole sample of ASD preschoolers. Nevertheless, for the first time at our knowledge, we have observed in children without GI symptoms treated with probiotics significant modification of core ASD symptoms measured by the ADOS-CSS scores (specifically Social-Affect domain) that are unrelated to the specific intermediation of the probiotic effect on GI symptoms. As far as children with GI symptoms, the six-month supplementation with DSF showed significant effects, when compared to placebo, in improving not only GI symptoms but also multisensory processing and adaptive functioning.

All these findings could pave the way for further studies on larger subgroups of ASD with the aim of improving precision medicine in ASD.

 

  

Conclusion

I am a big fan of affordable drug therapy.

There are some extremely clever one-off therapies that cost more than $1 million.  That seems OK, you give it to a baby who then may go on to have a normal life, but someone has to pay.

 

A $2.1 Million Drug for a Deadly Childhood Disease Is Approved by FDA

A potential cure for a lethal childhood disorder -- the first of its kind in the U.S. -- is hitting the market at a cost of $2.1 million, paving the way for more therapies that bring dramatic benefits for patients, along with challenges for health-care systems.

The U.S. Food and Drug Administration on Friday approved Novartis AG’s Zolgensma, a gene therapy targeting children under two years old who have a severe illness called spinal muscular atrophy. The Swiss drugmaker said it’s offering novel payment options, including spreading out the costs over time, refunds for patients whose treatment fails and discounts for insurers that provide swift coverage. 

What looks really unacceptable is repurposing a cheap existing approved drug and then charging a King’s ransom for it.

It is very expensive, and hugely risky, to develop a new drug, much less so to repurpose an old one.

Repurposing a cheap drug does cost money and somebody has to pay for this, and also the risk of it not being successful.

All the autism start-ups think they are entering a $2 billion a year market, but they neglect the fact that people with severe autism will likely need polytherapy.  They think people will pay $50,000 a year for a drug, but what if you really need 3 or 4 of these clever drugs?

Take Knut’s idea to repurpose Ponstan.  This NSAID is sold OTC in many countries for a few dollars.  Is it realistic to charge $50,000 for a slightly modified autism version?  In the case of Ponstan, this would be a preventative therapy for just a few years.

Metyrosine was probably another three dollar drug, before it stopped being used.  Now a one month supply costs $30,000.

 

Synchrony 2020 and Back to School with Covid

 

I am giving a presentation in November at an online autism conference called Synchrony 2020. It is organized by a group of parents of children with autism.  You can read all about it here: 

 

https://synchronysymposium.com/

 

If you want to attend this virtual conference there is a coupon code for readers of this blog: -

EPIPHANY

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

Our doctor reader Agnieszka gave a presentation at this event last year.

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

The proceeds go towards the Brain Foundation’s funding of autism research. 

The Brain Foundation

Our mission is to support translational research that will lead to the development of FDA-approved treatments and an improved standard of care for co-morbidities in individuals with autism spectrum disorder. 

I suppose my mission is to take the fast track, by repurposing existing approved drugs and skip the part requiring $30 million and 15 years to get FDA approval, specific to autism, for each drug.

As you would expect, most of the presenters are medical doctors or medical researchers. 

I did point out to the organizers that many of these people are not going to like what I do.  They spend decades researching autism and here comes Peter, not a doctor, developing therapies by repurposing existing drugs. 

There will be nothing controversial in my presentation, I am just talking about the effects of long-term Bumetanide therapy.

Doctors who have a child with autism do see things differently. I had a British pediatrician come up to me at an event and just about the first thing he said was “I want to do for my daughter, what you have done for your son”.  Good luck to him.

I did my bit to help the conference organisers by asking Dr Ben-Ari to present about Bumetanide.

Dr Ben-Ari does read this blog and I know he does not entirely approve of my methods.  If I did not have a child with autism, I would also not approve of my methods. Necessity is the mother of invention.

A classic example of medical dithering appeared in a recent meta-analysis of the research into the use of NAC in autism.

The review concludes that NAC is safe to use and does reduce some key symptoms of autism, but then adds the caveat “However, further evidence should be sought before a general recommendation.”

So, NAC is cheap, safe and effective, but don’t use it. 

Effectiveness of N-acetylcysteine in autism spectrum disorders: A meta-analysis of randomized controlled trials

Conclusion: We concluded that N-acetylcysteine is safe and tolerable, reduces hyperactivity and irritability and enhances social awareness in children with autism spectrum disorder. However, further evidence should be sought before a general recommendation. 

Incidentally, the FDA do not seem to like NAC being sold as a supplement in the US.  NAC is very popular and it is included in hundreds of OTC products, so banning it would not go unnoticed.  They are not concerned on safety grounds. Some drug producers seem to want it to be exclusively an expensive prescription drug. 

I think the Brain Foundation has noble goals and good luck to them.

I suspect Dr Ben-Ari’s what will be 15-year push to get Bumetanide adopted as an approved autism therapy will have the most transformative impact. Good luck to him too. 

 

Back to School with Covid 

After several months break, Monty started back at school on September 1^st.  The only significant difference from before is that everyone is wearing a mask. School is 5 days a week from 8.30am to 3.30pm, as before.

Nobody likes wearing a mask, but it is just something you currently have to do.  Monty, like most people with autism, can cope just fine wearing a mask.  Some people need to practise, others do not.  Without a mask there would be no school.

Online learning at home actually worked very well, with lessons via Zoom.  We are not new to the idea of home schooling; Monty’s 1:1 assistants have been teaching him at home since he was 4 years old.  Our current assistant was happy to come during the lockdown period.

It is much more fun to actually go to school.

Monty, now aged 17, attends a mainstream international school that follows the English curriculum.  He has no IEP (Individual Education Plan), so he does the same work and has the same tests as everyone else. Because I held him back 2 years at the age of 9, his classmates are 15-year olds.

He is remarkably well included, particularly by the girls.  In kindergarten and junior school there often is a little girl who takes a special interest in the cute little boy with classic autism, but this can fade away as the girl heads to puberty and the cute little boy becomes adult-sized, with not so cute classic autism.

I heard an endearing anecdote from Monty’s Assistant.  Two of the girls in class have been reading on the internet about boarding/residential schools. They found a school they liked the look of in Holland and asked our Assistant “would Monty’s parents allow him to come with us?  Look, it says they have 24-hour provision for those with special needs”.  I doubt they will actually be changing schools, but it was nice they kept Monty in mind. 

As I mentioned in previous posts, it does help to have a younger Assistant, if you want to promote social interactions with teenage classmates. Our Assistant has a sister the same age as Monty’s peers.

I did ask our Assistant why she thinks people are so nice to Monty; there are other people at school who are ignored by their peers and are pretty miserable. “Oh, he’s so cute, he says funny things in class and acts differently, look how he sits nicely and he’s the only one that eats properly; he also knows what is on the lunch menu and people come and ask him”, was the first response.  There must be more to do with it than that.   

There is a girl with spots who everyone ignores, do they really ignore her because of her spots?

As regular readers may recall, there is an interesting therapy for Aspie girls with spots.  Spironolactone, which lowers male hormones, will reduce acne in girls, but will also affect ROR alpha which determines the expression of many autism genes. So, both acne and autism might improve. Then add a squirt of oxytocin, or an oxytocin inducing gut bacteria and watch what happens.

I did see an interesting paper about children with autism who are flourishing at home with remote learning during covid.  The paper is about high functioning children (HFA in the text below), but some children with Classic autism also prefer life at home.

 

Debate: Remote learning during COVID‐19 for children with high functioning autism spectrum disorder 

Over the past 6 months, many children with HFA have told us they enjoy learning from home for a variety of reasons. They do not need to worry about whom to sit with at lunch, or be annoyed by the frequent changing classes, or have to tolerate the aversiveness of the school bell ringing, or the smell of the cafeteria. They report feeling liberated by not having to try so hard to fit in with the neurotypical world while trying to thrive academically. The anxiety, demoralization, and depression that have plagued them when in school have dissipated. Ironically, then, COVID‐19 has allowed many children like Stephan, who are oftentimes silently suffering, to flourish at home in ways that they could not do while in the regular classroom setting. We speculate that by eliminating the demands of the elusive, ‘hidden curriculum’, such children now expend their emotional and cognitive resources on the formal curriculum, which has resulted in improved grades and improved mental health. The following example illustrates this point … 

I advocate teaching the "hidden curriculum" to pre-teen Aspies, so they do not have a miserable time in high school and later in life, perhaps becoming an autism self-advocate. I would also use the buddy system to pair them with a slightly older outgoing neurotypical girl.

It looks like many of the parents of children with severe autism are ones that really do not like remote learning during Covid.  In some cases, they do not try to engage in remote learning.  If they were already teaching their child pre-Covid, it would not have been so difficult.

In some countries public schooling provides a seamless service year-round picking up the child from home and bringing him/her home at the end of day, setting both parents free.  You then become totally dependent on this level of service.  We never had that kind of support, so had to create our own independent approach.

 

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 Na_v1.7 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. Na_v1.7.

Other sodium channels involved in pain signalling are Na_v1.3, Na_v1.8, and Na_v1.9.

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 Na_v1.4 voltage-gated sodium channel is encoded by the SCN4A gene. Mutations in the gene are associated with hypokalemic periodic paralysis, hyperkalemic periodic paralysis, paramyotonia 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 Na_v1.3 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 (Na_V1.3) 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 Na_V1.3. Pathogenic Na_V1.3 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 (Na_V1.1) 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 Na_v1.2 sodium ion channel is encoded by the SCN2A gene.

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

  

SCN1A

 The Na_v1.1 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 syndrome, autism, attention deficit-hyperactivity disorder (ADHD), bipolar disorder, major 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 Ca_v2.1 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 Ca_v1.2.   Ca_v1.2 is a subunit of the L-type voltage-dependent calcium channel.

 

CACNA1S

The CACNA1S gene encodes Ca_v1.1 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 paralysis, thyrotoxic 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 Ca_v1.3.

Ca_v1.3 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 Ca_v1.3 Ca²⁺ channels contribute to the death of dopaminergic neurones in patients with Parkinson's disease

Inhibition of L-type channels, in particular Ca_v1.3 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 Cav_2.3 , 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 Ca_v1.4.

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.