It is nice to have a city named after you and Monty finally visited “his” city, Montevideo in Uruguay.
I suppose my city would be St Petersburg, which I have visited several times.
A really impressive
city in Latin America is Buenos Aires; it has a very large central area with
beautiful architecture. It enjoyed several decades of great wealth, the “golden
age,” when the city was laid out. In 1930 there was a military coup and the
party was over. It has been boom and bust ever since.
We visited
what they call the Southern Cone of Latin America, which is made up of
Argentina, Chile and Uruguay. We went from Buenos Aires all the way down to
Tierra del Fuego.
Santiago,
the capital of Chile, looks to be booming. It has a small historic centre and
everything else is new.
Montevideo was
more what I expected, except for the graffiti everywhere which makes it look
less safe than it likely is. Uruguay has many beautiful beaches, but until you
get away from the vast River Plate estuary (Río de la Plata = river of silt)
and to the Atlantic ocean the water is a dirty brown colour. Monty would not go in the water.
Southern
Chile and Argentina have some stunning scenery with volcanoes, mountains and
glaciers. It looks great, but it is no
longer the cheap backpacker destination it once was.
.gif)
Back to
the Autism Research
The highlight from the recent research comes from The RIKEN institute in Japan. It does go some way to explaining why so many people with autism appear to have nothing in their genetic results to explain their condition.
Normally,
when you have your state of the art whole genome screening (WGS) the geneticist
who interprets the results is looking for mutations in one of the many hundreds
of known “autism genes” and nowadays, hopefully, in the non-coding areas next to them.
Whole exome screening (WES) just looks at the 2% of the genome that has the
instructions for how to make each of your 22,000 genes. The other 98% includes
things like promoters that increase activity of a specific gene.
Many people
with autism appear to show no mutations that are relevant.
The Japanese
have figured out one of the reasons why this is the case. There are other reasons.
Our genetic
material is not stored on something like a long role of paper, which is like a
two-dimensional object. It is a three-dimensional twisted object all folded up. As a result, the DNA physically closest
to each autism gene may not be the part expected. The Japanese use the term “topologically
associating domain” (TAD) to define which zones of DNA are actually interacting
with each other.
They found
that de novo mutations in promoters heightened the risk of ASD only when the
promoters were located in TADs that contained ASD-related genes. Because they
are nearby and in the same TAD, these de novo mutations can affect the
expression of ASD-related genes.
This means
that geneticists now need to go back to school and learn about the TAD of each
autism gene. Or else just replace the geneticist with an AI generated report.
Mutation butterfly effect: Study reveals how
single change triggers autism gene network
Researchers in the RIKEN Center for Brain Science (CBS) examined the genetics of autism spectrum disorder (ASD) by analyzing mutations in the genomes of individuals and their families. They discovered that a special kind of genetic mutation works differently from typical mutations in how it contributes to the condition. In essence, because of the three-dimensional structure of the genome, mutations are able to affect neighboring genes that are linked to ASD, thus explaining why ASD can occur even without direct mutations to ASD-related genes. This study appeared in the scientific journal Cell Genomics on January 26.
The researchers analyzed an extensive dataset
of over 5,000 families, making this one of the world's largest genome-wide
studies of ASD to date. They focused on TADs-;three-dimensional structures in
the genome that allow interactions between different nearby genes and their
regulatory elements. They found that de novo mutations in promoters heightened
the risk of ASD only when the promoters were located in TADs that contained
ASD-related genes. Because they are nearby and in the same TAD, these de novo mutations
can affect the expression of ASD-related genes. In this way, the new study
explains why mutations can increase the risk of ASD even when they aren't
located in protein-coding regions or in the promotors that directly control the
expression of ASD-related genes.
"Our most important discovery was that de novo
mutations in promoter regions of TADs containing known ASD genes are associated
with ASD risk, and this is likely mediated through interactions in the
three-dimensional structure of the genome."
Atsushi Takata at RIKEN CBS
Whole-genome sequencing (WGS) studies of autism spectrum disorder (ASD) have demonstrated the roles of rare promoter de novo variants (DNVs). However, most promoter DNVs in ASD are not located immediately upstream of known ASD genes. In this study analyzing WGS data of 5,044 ASD probands, 4,095 unaffected siblings, and their parents, we show that promoter DNVs within topologically associating domains (TADs) containing ASD genes are significantly and specifically associated with ASD. An analysis considering TADs as functional units identified specific TADs enriched for promoter DNVs in ASD and indicated that common variants in these regions also confer ASD heritability. Experimental validation using human induced pluripotent stem cells (iPSCs) showed that likely deleterious promoter DNVs in ASD can influence multiple genes within the same TAD, resulting in overall dysregulation of ASD-associated genes. These results highlight the importance of TADs and gene-regulatory mechanisms in better understanding the genetic architecture of ASD.
Bumetanide
I did come
across a Chinese study with an eye-catching title:-
Highlights
- Bumetanide showed significant and large effects on the overall core symptoms of ASD.
- Bumetanide’s efficacy on ASD is influenced by subjects’ age, dosage form, duration.
- Results of RCTs on bumetanide in ASD are moderated by study designs, measurement tools
A
systematic search was conducted on PubMed, EMBASE, MEDLINE, PsyclNFO, Web of
Science, Clinical Trials.gov, and references in reviews from the earliest
available date to September 2023. Randomized controlled trials (RCTs) were
identified that evaluated the efficacy of bumetanide in improving overall core
symptoms (OCS) of ASD. Therefore, nine studies with 1036 participants were
included in the study.
Results
Bumetanide
showed significant effects on OCS of ASD (WMD = － 1.91, p = 0.006), particularly in
sub-domains including relation to inanimate objects, adaption to environment
changes, auditory response, near sensory responses, anxiety and hyperactivity.
Moderating analysis indicated that a significant effect size of bumetanide on
OCS of ASD was observed in specific subgroup, including 3–6 years old (WMD = －1.08,
p = 0.008), the tablet (WMD = －2.80, p = 0.003), 3-month intervention (WMD = －2.54,
p = 0.003), and the single-center studies (WMD = －2.80, p = 0.003).
Conclusions
Bumetanide
has a large and significant impact on the OCS of ASD. Given the limited number
and quality of included RCTs, future research should prioritize conducting
large-scale trials focusing on sub-parameters or specific clinical features to
comprehensively evaluate the efficacy of bumetanide in subpopulations of
children with ASD.
Meanwhile, Professor Ben Ari has written another paper on why the phase 3 trial failed and has also published a book.
Introduction:
Extensive experimental observations suggest that the
regulation of ion fluxes and, notably, chloride are impacted in autism spectrum
disorders (ASD) and other neurodevelopmental disorders. The specific NKCC1
cotransporter inhibitor Bumetanide has been shown to attenuate
electrophysiological and behavioral features of ASD in experimental models.
Both pilot and phase 2 double-blind randomized independent trials have
validated these effects with thousands of children treated successfully. Both
brain imaging and eye tracking observations also validate these observations.
However, final large phase 3 trials failed, with no significant differences
between placebo and treated children.
Methods:
Here, I discuss the possible reasons for these failures and
discuss the exclusive reliance on complex patent cooperation Treaty (PCT)
regulations. Indeed, available data suggest that bumetanide responders could be
identified by relying notably on EEG measures, suggesting that biological
sub-populations of patients might benefit from the treatment.
Results:
These observations raise important debates on whether
treating only a % of children with ASD is acceptable.
Discussion:
It is likely that in many disorders, the heterogeneity of the
pathological event precludes a single general treatment for all, suggesting
that trials centered on selective populations of responders might be essential
for large clinical trials to succeed.
Treating Autism with Bumetanide
https://www.cambridgescholars.com/product/978-1-5275-1890-2/
In spite of its high incidence, extensive media coverage and major clinical burden to families, there is not a single approved European or American drug treatment of Autism Spectrum Disorders (ASDs). The dominant genetic and psychiatric approaches to treat ASDs have various limitations, suggesting that a novel global approach to understand and treat ASDs is warranted. Based on the authors’ converged expertise on brain development, ASD treatment and brain imaging, this book provides a fresh view of the disorder which is validated by experimental imaging and large clinical trials, culminating in the first large phase 3 final pediatric trial (on 400 children in EU countries and the US) using a repositioning of a drug used for decades to treat hypertension and edema. The convergence of experimental and clinical data on this disorder is unprecedented, confirming the potential of the drug to be the first pediatric treatment of ASDs.
After explaining the mechanisms underlying ASDs, we describe
specific cases of children who, after treatment, considerably improved their
sociability and reduced their agitation. The book also discusses the skepticism
that the authors met from the tenants of pure genetics and psychiatry, and why
the abyssal poverty of information on developmental disorders has hampered
progress in understanding and treating ASD.
Bumetanide dosage is key – “wonderful effects from increasing from 0.5mg to 1mg”
One recuring
feature I have noticed from bumetanide use in the United States is the low
dosage often used, as if these doctors want to show the drug is ineffective.
A reader
recently contacted me about his young son who responded to the low dose of
0.5mg, but his autism doctor would not increase the dose. The parent took matters into his own hands
and increased the dose and then wrote to tell me about the “wonderful effects.”
Diuresis
has stopped, but restarts at a lower dose
In a
minority of cases bumetanide causes no diuresis. The question is whether it can
have any effect in the brain if it causes no diuresis. Has the drug been
absorbed at all?
One reader
contacted me to tell me that her son, who has responded well to bumetanide for
several years, stopped experiencing any diuresis. Then she told me that when
she reduces the dose the diuresis returns.
There are
many possible explanations, but perhaps those people who find bumetanide causes
no diuresis should try a lower dose and see what happens.
Vasopressin/Desmopressin
Much of the
research into the hormone vasopressin comes from Stanford. They have published
a string of papers over the years. I think they are definitely on to something, but they are taking their time and may never commercialize the result.
The very
recent one is:
For some reason there is no abstract.
Thanks to our reader Seth, I have now added the link below that takes you directly to Stanford's website, which holds the full text version of the paper.
https://med.stanford.edu/content/dam/sm/parkerlab/documents/da035ad7-7c80-41bd-a9a6-ee03a8bcc58d.pdf
The same group
previously published a paper showing that people with ASD have a reduced level
of vasopressin in their spinal fluid. As you can see in the chart below the
level of oxytocin was normal.
There have also been successful trials using intranasal vasopressin in humans.
Cerebrospinal fluid vasopressin and symptom severity in
children with autism
Vasopressin
and oxytocin are closely related hormones and possibly some interactions are
not yet fully understood.
Both these
hormones can be given via a nasal spray.
The Bumetanide-Vasopressin
interaction
Under normal
circumstances you would never combine vasopressin with a diuretic.
Vasopressin
stops you peeing and that it is why it is given to some children who wet their
bed at night.
Bumetanide
is a fast-acting diuretic that causes you to pee a lot.
So if you
gave a diuretic to an elderly overweight person to reduce their blood pressure,
it would be mad to also prescribe vasopressin.
The drugs are therefore contraindicated.
In autism we
do not actually want the diuretic effects of bumetanide. We just want its
effects on the brain.
The social
and emotional beneficial effects of vasopressin have already been established by the existing Stanford research.
The combined
effects of bumetanide + intranasal vasopressin might then be a win-win. Less
autism and without the diuresis.
I was
contacted long ago by a father whose daughter was prescribed Desmopressin, a
synthetic analog of vasopressin that is an approved drug, and her autism markedly
improved.
The Stanford
research in humans uses a nasal spray that they have compounded specially rather
than the commercially available Desmopressin.