This blog is full of clinical trials
that use existing drugs that are repurposed to treat autism. One constant issue
is whether the trial drug is free from side effects. Generally speaking side effects
tend not to be a problem, but there always can be exceptions.
I was recently contacted by the
parents of a two year old with a single gene (monogenic) type of autism and
they want to treat their child to improve his outcome.This is the youngest case I have encountered.
With monogenic autisms you often have
clear indications from a very early age that something unusual is present. Once
you have a diagnosis you quickly discover what issues the child is going to
face. You therefore have a good idea of what will happen if you do nothing.
Some other two year olds have delayed speech and other signs of autism, but within a
couple of years develop normally – it was a case of delayed maturation.
I noted long ago that American autism
doctors tend to want to treat younger patients with supplements rather than
drugs.
The reality is that the sooner you
start to correct a severe biological dysfunction the better the outcome will
be. We even see that some treatments are only effective if given to toddlers.
This makes perfect sense although it may be uncomfortable to accept.
I was looking for supporting evidence
for very early intervention. I found a glowing report of the treatment of a 2
year old with Fragile X syndrome using Metformin. I am amazed Fragile X still
remains untreated in most cases.
On examination at age 2 years, typical
physical features of FXS were observed,
and baseline laboratory findings were normal (see Table Table1).1). He was started on metformin
at 25 mg of the liquid form that is 100 mg/ml at dinner, and his dose was
gradually increased to 200 mg twice a day (bid) over 1 year (see Table
Table1).1). After initiation of metformin, his sleep disturbance resolved, only
occasionally awakening once for roughly 30 min. Two weeks after initiation, he went from stacking 3–4
blocks to stacking a tower of 11 or more blocks; within a few more weeks, he
began building more complex structures comprised of different size blocks.
He showed marked improvement in self‐help and motor activities, including
toilet training, clearing the table and loading the dishwasher, brushing his
own teeth, dressing independently, and learning how to make toast. His preschool teachers, who were
unaware of metformin treatment, told his mother that “it's like something just
clicked or he just woke up. He's a whole different kid.”
Some drugs including bumetanide are
already safely given to babies.
Nonetheless, it is a brave step to
start treatment in a two year old. I did connect the parents to a reader of
this blog whose child has the same syndrome but is a few years older.
Today’s post was prompted by the news
that the child is already showing improvements from the first therapy, which is
a small dose of clemastine. In this syndrome there is a mutation in TCF4 and there
is impaired myelination and very likely activated microglia (the brain’s immune
cells). The near immediate beneficial effect cannot be on myelination, but it
could be resetting microglia to the resting state.
Other genes very recently raised have
been TRIT1 and PSMB9; neither of these are classed as autism genes, but
evidently can cause it. Mutations in TRIT1 cause a problem in the mitochondria
and PSMB9 mutations cause the immune system to misbehave.It looks like both can lead to an autism
diagnosis.
A common issue parents encounter is
that often the interest shown by researchers and clinicians stops at the point
of diagnosis. What really matters is what to do next. Only very rarely will
such “experts” suggest what to do next.
It looks like there nearly always are
therapeutic avenues to pursue after such a diagnosis. It should be noted that
even in single gene (monogenic) autisms there are varying levels of response to
the same therapy. We saw this a while back with the new FDA approved therapy
for Rett syndrome – it works for some, but not for others.
Treating self injurious behavior (SIB) in
idiopathic autism
I recently received feedback from
several parents who have had success in treating SIB based on ideas in this
blog.
Verapamil came up again as successful.
Pioglitazone, at a low dose of 7.5mg,
was the game changer for one child.
Ibuprofen worked in another case, but
this cannot be used long term. Celecoxib should be better tolerated and in
theory should be as effective. Time will tell.
More people are trying the add-on
therapy of a small dose of taurine.
Macroautophagy as a cause of impaired
cognition
Impaired autophagy came up recently in
two people’s genetic testing results. There is a lot in this blog about
autophagy and dementia/mild cognitive impairment.
Today we have a paper that links
impaired autophagy with impaired cognition.
Twenty years ago severe autism
generally also meant impaired cognition. Nowadays it does not; you can have
severe autism with normal cognition.
There are various different types of
autophagy but in general it is all about collecting bits of cellular garbage
that might clog things up. As we get older this intracellular garbage
collection process works less well and then diseases like Alzheimer’s follow
decades later.
Impaired autophagy may contribute to
impaired cognition at any age. Most research concerns dementia treatment, or
other conditions affecting older people like Huntington’s disease.
There is little focus on younger
populations, even though we know that children with Down syndrome are prone to
get early onset Alzheimer’s. Treating young people with Down syndrome to
improve autophagy might bring both short and long term benefits.
Autism spectrum disorder (ASD) represents a
complex of neurological and developmental disabilities characterized by
clinical and genetic heterogeneity. While the causes of ASD are still unknown, many ASD risk factors are found
to converge on intracellular quality control mechanisms that are essential for
cellular homeostasis, including the autophagy-lysosomal degradation pathway.
Studies have reported impaired autophagy in ASD human brain and ASD-like
synapse pathology and behaviors in mouse models of brain autophagy deficiency,
highlighting an essential role for defective autophagy in ASD pathogenesis. To
determine whether altered autophagy in the brain may also occur in peripheral
cells that might provide useful biomarkers, we assessed activities of autophagy
in lymphoblasts from ASD and control subjects. We find that lymphoblast
autophagy is compromised in a subset of ASD participants due to impaired
autophagy induction. Similar changes in autophagy are detected in postmortem
human brains from ASD individuals and in brain and peripheral blood mononuclear
cells from syndromic ASD mouse models. Remarkably, we find a strong correlation between impaired
autophagy and intellectual disability in ASD participants. By depleting
the key autophagy gene Atg7 from different brain cells, we provide further
evidence that autophagy deficiency causes cognitive impairment in mice. Together, our findings suggest
autophagy dysfunction as a convergent mechanism that can be detected in
peripheral blood cells from a subset of autistic individuals, and that
lymphoblast autophagy may serve as a biomarker to stratify ASD patients for the
development of targeted interventions.
There are different types of autophagy
and there are some overlaps.
·mTOR dependent (Fasting or Rapamycin)
·AMPK dependent (Spermidine)
·P53 dependent (no simple therapies)
·Calcium signalling dependent (Verapamil)
The OTC way to increase autophagy is
to use Spermidine, which is made from wheat germ or rice germ. Studies in
humans are rather mixed and I think the dose is likely far too low. Supplements
tend to contain about 1mg; I suspect you need much more to have an impact. You
can indeed grow your own wheat sprouts which are highly nutritious and a rich
source of spermidine. You can eat them raw or even in smoothies. 100 g of
sprouts contains 10-15mg of spermidine.
The most researched calcium channel
drug to induce autophagy is Verapamil, from my son’s original autism Polypill.
My takeaway continues to be to look for convergent mechanisms, like impaired autophagy, myelination, microglial activation etc that commonly occur in severe autism, of any origin. You then try and treat these likely dysfunctions rather than getting overly focused on individual genes.
Having read
the literature, it looked to me that anyone over 50 years old is likely to benefit
from a little extra Taurine, but it certainly was not clear whether it would
make my 21 year old’s autism better or worse. I went ahead and ordered some to
investigate.
In theory
one of the many effects of Taurine is negative. Taurine does affect the KCC2 transporter
that takes chloride out of neurons the “wrong” way. The other effects include
on calcium homeostasis, which we know is disturbed in most autism.
N = 2 Trial
Subject
#1 (Peter)
I took 2g a
day for a month and noticed no effect at all, other than some mild GI
irritation.
In adults
the long-term effects are numerous and varied throughout the body. Even the
cells that remodel your bones (osteoblasts and osteoclasts) have special
taurine transporters, whose sole role is to let taurine inside – taurine makes the
osteoblasts work harder, while encouraging osteoclasts to take a break. The net
effect should be stronger bones. As you get
older your natural levels of taurine fall substantially. There are taurine-rich
foods you can eat and if you engage in strenuous exercise your liver starts making
more taurine.
Subject
#2 (Monty)
There is a
clear contradiction when it comes to Taurine and sleep. Many energy drinks
contain Taurine to keep you alert, but in theory Taurine should be calming and
many people take it add bedtime to improve sleep.
Monty, aged
21 with ASD, likes getting up early and going to bed early.
Adding 2g a
day of Taurine at breakfast shifted his circadian rhythms, so that he now goes
to bed at a time typical for a 21 year old, but still wants to get up at 7am. Monty even fell asleep on the sofa watching TV late one night, something big brother often does. Indeed, Monty received a nod of approval when big brother discovered him in the early hours.
The most
beneficial change has been on his spring and summertime aggression. This has
been controlled for years using an L-type calcium channel blocker. This does
not resolve the allergy at all, but it “switches off” the consequential
anxiety/aggression. With the addition of allergy therapies and the
immunomodulation of Pioglitazone (in peak allergy season) the problem behaviors
are controlled.
It appears
that Taurine has a similar anti-anxiety/aggression effect. Maybe its effect
on calcium channels and broader calcium homeostasis is the reason why. Anyway,
it works – simple, cheap, OTC and effective.It has no effect on allergy, in case you are wondering.
Conclusion
Taurine can
be bought as a bulk powder for very little money. It is not like those numerous
expensive supplements that would cost you several hundred dollars/euros/pounds
a year.
If you have your
own “healthspan polytherapy”, to ward off high blood pressure, high cholesterol,
type 2 diabetes, dementia, arthritis, osteoporosis etc, consider spending a few
pennies more and add a scoop of taurine.
The people who
write to me and tell me how Verapamil has transformed life at home, by banishing
aggression and self-injurious behaviors, should seriously consider a trial of
Taurine.
I was contacted by a reader in
Italy whose child with autism may respond to bumetanide, but has a sulfonamide
allergy and got a skin reaction (hives). She had to stop giving the drug, but wanted to know how she could re-start bumetanide.
Other readers have pointed out
how they dare not try bumetanide because they know their child has a
sulfonamide allergy. I think our longtime reader Tanya is one example.
Key
Point to Note
Most people discover their
sulfonamide after being giving an antibiotic in early childhood.
It is now well established that
many (but not all) people with an allergy to sulfonamide antibiotics can safely
take a sulfonamide diuretic like Bumetanide or Diamox/Acetazolamide. This is presented
in case studies later in this post.
Sulfonamide
Drugs
Many common drugs are
“sulfonamides”. Their chemical structure includes a sulfonyl (–SO2)
group attached to an amine group (–NH2). They include common antibiotics, like erythromycin,
many diuretics (bumetanide, furosemide, acetazolamide (Diamox), some
anticonvulsants (zonisamide) and some anti-inflammatory drugs (sulfasalazine).
Sulfonamide
Allergy
Many parents discover early in their
child’s life that their child has a sulfonamide allergy. Sometimes this is abbreviated
to a “sulfa allergy.”
The symptoms of a
sulfonamide allergy can vary but may include:
Skin reactions (rash,
hives, or itching)
Fever
Swelling
Respiratory issues (shortness
of breath)
Anaphylaxis (in severe
cases)
Usually the symptoms are minor, but once
diagnosed the parents usually take note never to give their child any
sulfonamide drug.
If you have the
allergy must you avoid all sulfonamide drugs?
The standard assumption has been that
if you have a sulfonamide allergy you cannot take Bumetanide or Acetazolamide
(Diamox).
Upon further investigation in the
research, this may not always be true.
What happens when
there is no alternative drug?
When treating ion channel/transporter
dysfunctions there may not be a non-sulfonamide alternative.
Acetazolamide (Diamox) is
documented in the literature as a case in point. Bumetanide has not yet made it
to the literature.
Furosemide fortunately has been
researched and a safe desensitization protocol exists. Furosemide is a very
similar drug to bumetanide.
Desensitization strategies
I did recently write about enzyme potentiated
desensitization, which is an old, mostly overlooked, technique to overcome
allergic reactions. I was interested in pollen allergy.
The best-known kinds of desensitization
are allergy shots and more recently overcoming nut allergies, which gets media
attention.
The
study also found that the youngest children and those who started the trial
with lower levels of peanut-specific antibodies were most likely to achieve
remission.
“The
landmark results of the trial suggest a window of opportunity in early
childhood to induce remission of peanut allergy through oral immunotherapy,”
says NIAID Director Dr. Anthony Fauci. “It is our hope that these study
findings will inform the development of treatment modalities that reduce the
burden of peanut allergy in children.”
I did wonder that if it works for nuts
then why not bumetanide.
It turns out that I am not the first
to consider desensitization to a drug allergy. The best known method is rapid drug
desensitization (RDD), usually intravenous, which opens a window to be able to start
taking a drug you are allergic to. Once you stop taking the drug, you then
again become allergic to it.
The other
approach is more like dealing with nut allergies, it is called slow drug
desensitization (SDD) and involves taking a tiny initial dose and then slowly
increasing it over weeks and months.
Drug desensitization
is normally done in hospital as part of some therapy when you absolutely must
have a drug that you are allergic to.
The paper below
contains information on a very large number of common drugs where drug desensitization
has been successfully carried out.
Drug desensitization is the temporary induction of tolerance
to a sensitized drug by administering slow increments of the drug, starting
from a very small amount to a full therapeutic dose. It can be used as a
therapeutic strategy for patients with drug hypersensitivity when no comparable
alternatives are available. Desensitization has been recommended for
immunoglobulin E (IgE)-mediated immediate hypersensitivity; however, its
indications have recently been expanded to include non-IgE-mediated, non-immunological,
or delayed T cell-mediated reactions. Currently, the mechanism of desensitization is not fully
understood. However, the attenuation of various intracellular signals in
target cells is an area of active research, such as high-affinity IgE receptor
(FcɛRI) internalization, anti-drug IgG4 blocking antibody, altered signaling
pathways in mast cells and basophils, and reduced Ca2+ influx.
Agents commonly requiring desensitization include antineoplastic agents,
antibiotics, antituberculous agents, and aspirin/nonsteroidal anti-inflammatory
drugs. Various desensitization protocols (rapid or slow, multi-bag or one-bag,
with different target doses) have been proposed for each drug. An appropriate
protocol should be selected with the appropriate concentration, dosage, dosing
interval, and route of administration. In addition, the protocol should be
adjusted with consideration of the severity of the initial reaction, the
characteristics of the drug itself, as well as the frequency, pattern, and
degree of breakthrough reactions.
Two categories of desensitization protocols are currently
available: RDD and slow drug desensitization (SDD). RDD is recommended for
immediate reactions, both allergic and nonallergic. The most widely used RDD
protocol is doubling the dosage every 15 minutes until the therapeutic dose is
achieved. SDD is recommended for type IV delayed hypersensitivity reactions
with T cell involvement, and can be performed both orally and intravenously.
There is as yet no consensus on SDD protocols, including the initial dose, dose
increments between steps, and dosing interval. Further clinical experience and
research are required to establish the role and efficacy of desensitization for
delayed reactions.
H1 blockers, H2
blockers, and glucocorticoids can be used as premedication. Aspirin and
montelukast block the end products of the arachidonic acid cascade and decrease
the incidence and severity of BTRs. NSAIDs can help to control the symptoms of
cytokine release syndrome. Glucocorticoids alone are not recommended because they cannot prevent
the initial degranulation of mast cells.
The desensitization process is known to be antigen-specific,
as the level of drug-specific immunoglobulin E (IgE) decreases but the levels
of other allergen-specific IgE remain consistent throughout the treatment
period. However, the cellular and molecular mechanisms underlying drug
desensitization are not yet fully understood.
Aspirin/NSAID desensitization is considered for patients with
cardiovascular or musculoskeletal diseases who require aspirin or NSAID
administration for prolonged periods.
The temporary
tolerance to aspirin/NSAIDs lasts 48 to 72 hours after desensitization.
Therefore, hypersensitivity reactions can recur 2 to 5 days after
discontinuation if the therapeutic dose is not continued.
DHR to β-lactams, such as penicillin or cephalosporin, is
more common than that to non-β-lactams. Desensitization can be performed for
both immediate and delayed hypersensitivity reactions. The protocol should be
selected based on patient characteristics, hospital capacity, and physician
preferences. It is generally started with 1/1,000 of the therapeutic dose and
then increased by 2 to 3-fold every 15 minutes to 5 hours. Oral administration
is preferred due to its ease, safety, and effectiveness. Desensitization to
penicillin and cephalosporins has been well established. Successful desensitization has
also been reported for other β-lactams, such as carbapenem and monobactam, and
non-β-lactams, such as vancomycin, clindamycin, metronidazole, macrolides,
aminoglycosides, tetracycline, and ciprofloxacin.
Successful
desensitization to other antimicrobials has also been reported for antifungals, such as amphotericin B,
fluconazole, itraconazole, voriconazole, and micafungin, and for antivirals,
such as acyclovir, valganciclovir, ribavirin, and nevirapine.
Furosemide desensitization
There is no literature specific to bumetanide but there
is on the very similar drug furosemide.
Furosemide is a commonly used loop diuretic that contains a
sulfonamide group. Although there are rare reports of hypersensitivity to
furosemide, severe reactions, including anaphylaxis, have been reported.
Ethacrynic acid, the only loop diuretic without a sulfonamide moiety, is no
longer available in oral formulation, thus posing a dilemma in the outpatient
treatment of patients with furosemide allergy.
Published protocols for furosemide desensitization include
rapid intravenous administration and oral protocols lasting 3 to 10 days.3–5
The oral protocols were performed in patients with non–type I hypersensitivity
reactions. We present a rapid, oral protocol for desensitization in a patient
with presumed type 1 furosemide allergy manifesting as urticaria.
Desensitization to sulfonamide-containing antibiotics has
been extensively used, but desensitization to furosemide is uncommon. The oral
protocols previously described took 3 to 10 days and were performed in patients
with non–type I hypersensitivity reactions, one with pancytopenia and the other
with pancreatitis. The patient with a type I hypersensitivity reaction
underwent an intravenous desensitization protocol. Rapid oral desensitization to a loop diuretic has
not been previously described. The potential advantages of oral desensitization
are that it is probably safer than intravenous desensitization, it may be more
cost-effective in terms of monitoring and staff requirements, and it may be
possible to perform in an outpatient setting. We propose our protocol as
a novel approach to furosemide desensitization therapy for patients with
non–life threatening reactions to furosemide. Further progress in the diagnosis
and treatment of hypersensitivity to sulfonamide drugs will require
identification of the major antigenic determinant and standardization of skin
testing and specific IgE testing.
I think we
should say good work to Dr Naureen Alim, then at Baylor College of Medicine
Houston, Texas.
If anyone wants
to desensitize to a bumetanide allergy I think she is the one to contact for
advice. She is easy to find via Google.
Allergy to furosemide is a rare phenomenon.
Desensitization to this sulfa-containing drug has not been frequently
performed. We describe a patient with severe congestive heart failure and type
I allergy to furosemide. Because of the severity of her condition, we decided
to use a rapid intravenous desensitization protocol. Following the
desensitization, the patient was treated with intravenous and oral furosemide
with a dramatic improvement in her clinical state. We suggest that rapid
desensitization may be a safe and effective way of introducing furosemide to
allergic patients for whom loop diuretics are urgently indicated.
In the case
of Acetazolamide, here is one published desensitization method:
Acetazolamide
is a carbonic anhydrase inhibitor that is frequently used in the management of
idiopathic intracranial hypertension. Acetazolamide is a sulfonamide agent;
specifically, it is a non sulfonylarylamine, which lacks the amine moiety found
at the N4 position that is seen in sulfa antibiotics.
Sulfonamide
antibiotics contain a substituted ring at the N1 position that is thought to be
the driving factor in immediate hypersensitivity reactions.
Although sulfa allergies are commonly reported, there is no evidence to
suggest cross-reactivity between sulfonamide antibiotics and sulfonamide
nonantibiotics. However, patients can report a history of allergy to both
categories of drugs. We
present a rapid desensitization protocol to acetazolamide in a patient with
history of immediate hypersensitivity reactions to both a sulfonamide
antibiotic and acetazolamide.
We formulated a 12-step intravenous protocol
that was performed in the intensive care unit setting (Table 1). Informed
consent was provided by the patient, and she tolerated the procedure well
without any adverse reactions. The desensitization procedure took 395 minutes
or approximately 6.5 hours. She was monitored overnight in the hospital and was
observed the following morning after taking 500 mg of acetazolamide orally to
ensure tolerance. She was thereafter able to continue her recommended dose of acetazolamide
without any issues to date.
Allergy to a sulfonamide
antibiotic does not always mean you will be allergic to the non-antibiotic sulfonamide
drugs.
The 3 patients had been considered for carbonic anhydrase
inhibitor treatment but a pharmacist had refused to fill a prescription for
acetazolamide for 1 patient and the other 2 patients were denied treatment
because of the allergy history. All 3 patients were prescribed acetazolamide
and had no adverse reaction. Two patients improved substantially and are
continuing treatment. A review of the pharmacology literature suggests that
cross-reactivity between antibiotic and nonantibiotic carbonic anhydrase inhibitors
is unlikely. Moreover, a review of case reports does not suggest
cross-reactivity. Previous reports in the ophthalmology literature also
indicate that acetazolamide can be administered to patients with a history of
antibiotic sulfonamide allergic reaction.
Conclusions
These 3 cases confirm
that the carbonic anhydrase inhibitor acetazolamide can be given to patients
with a history of allergic skin rash with antibiotic sulfonamide.
Acetazolamide has been used for the treatment of episodic
ataxia type 2, with benefit in 50% to 75% of patients. In episodic ataxia
type 1, acetazolamide was also effective in decreasing attack frequency. Acetazolamide
is also effective in the periodic paralyses. Carbonic anhydrase inhibitors
have been used to prevent altitude sickness, to lower intraocular pressure in
open-angle glaucoma, and to treat refractory absence, myoclonic, and catamenial
epilepsy as part of multidrug regimens. Acetazolamide has recently been used
for hemiplegic migraine and idiopathic intracranial hypertension.
The lack of available clinical or pharmacological evidence to
support cross-reactivity between sulfonamide antibiotics and acetazolamide
lends supports to the use of acetazolamide to treat patients with episodic
ataxia and periodic paralysis. Of
our 3 sulfonamide-allergic patients, 2 improved in symptoms after
treatment with acetazolamide and none of the 3 had a hypersensitivity reaction. We conclude that a sulfonamide
allergy should not be a contraindication to treatment with acetazolamide in
patients with neurologic channelopathies.
Allergies and adverse reactions to sulfonamide
medications are quite common. Two distinct categories of drugs are classified
as sulfonamides: antibiotics and nonantibiotics. The two groups differ in their
chemical structure, use, and the rate at which adverse reactions occur.
Cross-reactivity between the two groups has been implied in the past, but is
suspect. Acetazolamide, from the nonantibiotic group, is routinely used in the
prevention and treatment of high altitude issues and may not need to be avoided
in individuals with a history of sulfonamide allergy. This review addresses the
differences between the groups and the propensity for intergroup and intragroup
adverse reactions based on the available literature. We also examine the
different clinical presentations of allergy and adverse reactions, from simple
cutaneous reactions with no sequelae through Stevens-Johnson syndrome and
anaphylaxis, with risk for significant morbidity and mortality. We offer a
systematic approach to determine whether acetazolamide is a safe option for
those with a history of allergy to sulfonamides.
Sulfonamide-containing
antibiotics are the second most frequent cause of allergic drug reactions,
after the b-lactams (penicillins and cephalosporins). In one large study, the
incidence of reactions to trimethoprim–sulfamethoxazole (TMPSMX) was 3% of patients
exposed, compared with 5% for amoxicillin. The incidence of reactions to nonantibiotic sulfonamides
is not well established; it is clearly less than with antibiotics.
There
are several approaches to the use of sulfonamide drugs (specifically
acetazolamide) in patients with past reactions to this class of medications.
The choice of strategy depends on the type and severity of the previous
reaction, as well as the class of drug (antibiotic versus non antibiotic) and
the risk–benefit profile for the patient. However, regardless of the approach,
the risks of subsequent reactions cannot be completely eliminated, and a
thorough discussion between the medical provider and the patient should include
this point so that an informed decision regarding the use of acetazolamide can
be made. The safest approach for the patient with any prior reaction to a sulfa
drug, multiple drug allergies, or penicillin allergy would be to avoid all
drugs in the sulfonamide group, including acetazolamide.
Avoidance
of the entire sulfonamide drug group is warranted for individuals whose
previous reaction included a serious and/or life-threatening condition such as
anaphylaxis, SJS, and TEN. Any form of reexposure to the precipitating drug or
a sulfonamide in the same group is strictly contraindicated. Published evidence
has shown that SJS/TEN can recur with even minor reexposures and may be more
severe in the second episode. Even though SJS/TEN reactions are so far not
associated with nonantibiotic sulfonamides, because of the severity and
life-threatening nature of these reactions, a safe practice is to avoid all
sulfonamides in patients with past SJS or TEN from sulfonamide containing
medications.
This
paper was published in a journal on high altitude medicine. That is why the
suggested alternatives are staged ascents of the mountain and oxygen.
Conclusion
The first
key point is that you can have an allergy to sulfonamide antibiotics and have
absolutely no negative reaction to sulfonamide drugs like bumetanide and
acetazolamide (Diamox).
If you do
have a mild allergic reaction to a sulfonamide drug, there are desensitization strategies
that are proven to work in many people.
It looks
like rapid oral desensitization to bumetanide and acetazolamide is likely possible,
based on what has been shown possible with furosemide and a wide variety of
other drugs.
Clearly the
level of sensitivity and hence the nature of the allergic reaction can vary
massively from person to person, this is why rapid desensitization usually takes
place in hospital.
If you opt
for the slower process, much less is known, because it is not generally used.
If you did it in hospital it would require a very long stay and so would be
hugely expensive.
It is
suggested that slow drug desensitization (SDD) should be much more long lasting
and hopefully might become permanent – as is the hope for nut allergy treatment.
When posed
the initial question by our reader wanting to use bumetanide, I was thinking
along the lines of slow drug desensitization (SDD), because this is how you
would treat a pollen allergy. If rapid oral desensitization will work for taking
bumetanide once a day that would be great. To maintain the protection from
allergy it might be safer to take a small second daily dose.
Here is a
quick overview of desensitization options for sulfonamide allergy:
Rapid Desensitization
(RDD):
Faster process (hours)
Temporary tolerance
achieved
May be repeated if
needed
Slow Desensitization
(SDD):
Slower process (days,
weeks, or months)
Might offer a greater
chance of longer-lasting
Still requires close
monitoring
Important
Considerations:
Always consult your
doctor: They
can assess your allergy severity, treatment options, and the suitability
of desensitization if necessary.
Desensitization is not
without risks: It
requires careful monitoring.
I for one
found this an interesting investigation and with promise for parents of those
with severe autism who have been unable to trial Bumetanide due to a
sulfonamide allergy.
Hopefully our reader Dr Antonucci will follow up
on this and make a bumetanide desensitization protocol for those people with autism and a
sulfonamide allergy. Maybe he has already done it. It looks very achievable.
Today’s post
should be of wide interest because it concerns the potential benefit from the
OTC supplement taurine. There is a section at the end answering a query about
mutations in the KAT6A gene.
Taurine is
an amino acid and it is found in abundance in both mother’s milk and formula
milk.It has long been used as a supplement by some
people with autism. It is finally going to be the subject of a clinical trial in
autism and not surprisingly that will be in China - nowadays home to much
autism research.
Taurine is
also a key ingredient in energy drinks like Red Bull.
In a study
of children with autism a third had low levels of taurine. Since taurine has
anti-oxidant activity, children with ASD with low taurine concentrations were
then examined for abnormal mitochondrial function. That study suggests that taurine
may be a valid biomarker in a subgroup of ASD.
Taurine has
several potential benefits to those with autism and it is already used to treat
a wide variety of other conditions, some of which are relevant to autism. One
example is its use in Japan to improve mitochondrial function in a conditional
called MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and
stroke-like episodes).
The effects
that are suggested to relate to some types of autism include:-
·Activating GABAA
receptors, in the short term
·Down regulating
GABAA receptors, after long term use
·Reduce NMDA mediated activation of calcium
channels
·Protective effect on mitochondria and
upregulating Complex 1
·Improving
the quality of the gut microbiota
If you have
a pet you may know that taurine is widely given to cats and dogs. All cat food
has taurine added and some breeds of dog need supplementation.
Taurine is
crucial for several bodily functions in pets, including:
Heart Health: Taurine helps regulate heart rhythm and improves heart
muscle function. It can help prevent a type of heart disease called dilated
cardiomyopathy (DCM) in both cats and dogs.
Vision: Taurine plays a role in maintaining healthy vision and can prevent
retinal degeneration, a serious eye disease.
Immune System Function: Taurine may help boost the immune system and fight off
infections.
From China
we have the following recent study showing a benefit in the BTBR model of
autism:
Effective treatment of patients
with autism spectrum disorder (ASD) is still absent so far. Taurine exhibits
therapeutic effects towards the autism-like behaviour in ASD model animals.
Here, we determined the mechanism of taurine effect on hippocampal neurogenesis
in genetically inbred BTBR T+tf/J (BTBR)
mice, a proposed model of ASD. In this ASD mouse model, we explored the effect
of oral taurine supplementation on ASD-like behaviours in an open field test,
elevated plus maze, marble burying test, self-grooming test, and three-chamber
test. The mice were divided into four groups of normal controls (WT) and models
(BTBR), who did or did not receive 6-week taurine supplementation in water (WT,
WT+ Taurine, BTBR, and BTBR+Taurine). Neurogenesis-related effects were
determined by Ki67 immunofluorescence staining. Western blot analysis was
performed to detect the expression of phosphatase and tensin homologue deleted
from chromosome 10 (PTEN)/mTOR/AKT pathway-associated proteins. Our results showed that taurine
improved the autism-like behaviour, increased the proliferation of
hippocampal cells, promoted PTEN expression, and reduced phosphorylation of
mTOR and AKT in hippocampal tissue of the BTBR mice. In conclusion, taurine
reduced the autism-like behaviour in partially inherited autism model mice,
which may be associated with improving the defective neural precursor cell
proliferation and enhancing the PTEN-associated pathway in hippocampal tissue.
A trial in
humans with autism is scheduled in Guizhou, China. In this trial they seem to
believe the benefit may come from modification to the gut microbiota.
In the treatment of autism spectrum disorders (ASD),
medication is only an adjunct, and the main treatment modalities are education
and behavioral therapy. People with autism incur huge medical and educational
costs, which puts a great financial burden on families. Taurine is one of the
abundant amino acids in tissues and organs, and plays a variety of
physiological and pharmacological functions in nervous, cardiovascular, renal,
endocrine and immune systems. A large number of studies have shown that taurine
can improve cognitive function impairment under various physiological or
pathological conditions through a variety of mechanisms, taurine can increase
the abundance of beneficial bacteria in the intestine, inhibit the growth of
harmful bacteria, and have a positive effect on intestinal homeostasis. This
study intends to analyze the effect of taurine supplementation on ASD, and
explore the possible mechanism by detecting intestinal symptoms, intestinal
flora, markers of oxidative stress and clinical symptoms of ASD.
Taurine granules mixed with corn starch and white sugar, 0.4g
in 1 bag, taken orally. One time dosage: 1 bag each time for 1-2 years old, 3
times a day, 1.5 bags each time for 3-5 years old, 3 times a day, 2 bags each
time for 6-8 years old, 3 times a day, 2.5-3 bags each time for 9-13 years old,
3 to 4 bags each time for children and adults over 14 years old, 3 times a day.
The use of taurine is strictly in accordance with the specifications of Chinese
Pharmacopoeia.
Taurine is a key functional amino acid with many functions in
the nervous system. The effects of taurine on cognitive function have aroused
increasing attention. First, the fluctuations of taurine and its transporters
are associated with cognitive impairments in physiology and pathology. This may
help diagnose and treat cognitive impairment though mechanisms are not fully
uncovered in existing studies. Then, taurine supplements in cognitive impairment of different physiologies,
pathologies and toxicologies have been demonstrated to significantly improve
and restore cognition in most cases. However, elevated taurine level in
cerebrospinal fluid (CSF) by exogenous administration causes cognition
retardations only in physiologically sensitive period between the perinatal to
early postnatal period. In this review, taurine levels are summarized in
different types of cognitive impairments. Subsequently, the effects of taurine
supplements on cognitions in physiology, different pathologies and toxication
of cognitive impairments (e.g. aging, Alzheimer' disease, streptozotocin
(STZ)-induced brain damage, ischemia model, mental disorder, genetic diseases
and cognitive injuries of pharmaceuticals and toxins) are analyzed. These data suggest that taurine
can improve cognition function through multiple potential mechanisms (e.g.
restoring functions of taurine transporters and γ-aminobutyric acid (GABA) A
receptors subunit; mitigating neuroinflammation; up-regulating Nrf2 expression
and antioxidant capacities; activating Akt/CREB/PGC1α pathway, and further
enhancing mitochondria biogenesis, synaptic function and reducing oxidative
stress; increasing neurogenesis and synaptic function by pERK; activating PKA
pathway). However, more mechanisms still need explorations.
Although ER stress
assumes an important role in the cytoprotective actions of taurine in the
central nervous system (CNS), another important mechanism affecting the CNS is
the neuromodulatory activity of taurine. Toxicity in the CNS commonly occurs
when an imbalance develops between excitatory and inhibitory neurotransmitters.
GABA is one of the dominant inhibitory neurotransmitters, therefore, reductions
in either the CNS levels of GABA or the activity of the GABA receptors can
favor neuronal hyperexcitability. Taurine serves as a weak agonist of the GABAA, glycine and
NMDA receptors Therefore, taurine can partially substitute for GABA by
causing inhibition of neuronal excitability. However, the regulation of the
GABAA receptor by taurine is complex. While acute taurine administration activates the
GABAA receptor, chronic taurine feeding promotes the
downregulation of the GABAA receptorand the upregulation of glutamate
decarboxylase, the rate-limiting step in GABA biosynthesis. Therefore, complex
interactions within the GABAeric system, as well as in the glycine and NMDA
receptors, largely define the actions of taurine in the CNS.
Taurine
is one of the most abundant free amino acids especially in excitable tissues,
with wide physiological actions. Chronic supplementation of taurine in drinking water to mice increases
brain excitability mainly through alterations in the inhibitory GABAergic
system. These changes include elevated expression level of glutamic acid
decarboxylase (GAD) and increased levels of GABA. Additionally we reported that GABAA receptors were down
regulated with chronic administration of taurine. Here, we investigated
pharmacologically the functional significance of decreased / or change in
subunit composition of the GABAA receptors by determining the threshold for
picrotoxin-induced seizures. Picrotoxin, an antagonist of GABAA receptors that
blocks the channels while in the open state, binds within the pore of the
channel between the β2 and β3 subunits. These are the same subunits to which
GABA and presumably taurine binds.
Methods
Two-month-old
male FVB/NJ mice were subcutaneously injected with picrotoxin (5 mg kg-1) and
observed for a) latency until seizures began, b) duration of seizures, and c)
frequency of seizures. For taurine treatment, mice were either fed taurine in
drinking water (0.05%) or injected (43 mg/kg) 15 min prior to picrotoxin
injection.
Results
We
found that taurine-fed mice are resistant to picrotoxin-induced seizures when
compared to age-matched controls, as measured by increased latency to seizure,
decreased occurrence of seizures and reduced mortality rate. In the
picrotoxin-treated animals, latency and duration were significantly shorter
than in taurine-treated animas. Injection of taurine 15 min before picrotoxin
significantly delayed seizure onset, as did chronic administration of taurine
in the diet. Further, taurine treatment significantly increased survival rates
compared to the picrotoxin-treated mice.
Conclusions
We
suggest that the elevated threshold for picrotoxin-induced seizures in
taurine-fed mice is due to the reduced binding sites available for picrotoxin
binding due to the reduced expression of the beta subunits of the GABAA
receptor. The delayed effects of picrotoxin after acute taurine injection may
indicate that the two molecules are competing for the same binding site on the
GABAA receptor. Thus, taurine-fed
mice have a functional alteration in the GABAergic system. These include:
increased GAD expression, increased GABA levels, and changes in subunit
composition of the GABAA receptors. Such a finding is relevant in conditions
where agonists of GABAA receptors, such as anesthetics, are administered.
Taurine
as used in Japan to treat MELAS (mitochondrial myopathy, encephalopathy, lactic
acidosis and stroke-like episodes)
This medicine improves mitochondrial dysfunction related to cell
energy production etc., and suppresses stroke-like episodes.
It is usually used for prevention of stroke-like episodes of MELAS
(mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like
episodes).
·Your dosing schedule prescribed by your doctor
is (( to be written by a
healthcare professional))
·In general, take as following dose according to your weight, 3 times a day
after meals. If you weigh less than 15 kg, take 1.02 g (1 g of the active
ingredient) at a time. If your weight ranges 15 kg to less than 25 kg, take
2.04 g (2 g) at a time. If your weight ranges 25 kg to less than 40 kg, take
3.06 g (3 g) at a time. If you weigh 40 kg and more, take 4.08 g (4 g) at a
time. Strictly follow the instructions.
·If you miss a dose, take the missed a dose as soon as possible. However,
if it is almost time for the next dose, skip the missed a dose and continue
your regular dosing schedule. You should never take two doses at one time.
·If you accidentally take more than your prescribed dose, consult with
your doctor or pharmacist.
·Do not stop taking this medicine unless your doctor instructs you to do
so.
Contemporary research has found that people
with autism spectrum disorder (ASD) exhibit aberrant immunological function,
with a shift toward increased cytokine production and unusual cell function.
Microglia and astroglia were found to be significantly activated in
immuno-cytochemical studies, and cytokine analysis revealed that the macrophage
chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), tumor necrosis factor
α (TNF-α), and transforming growth factor β-1 (TGFB-1), all generated in the
neuroglia, constituted the most predominant cytokines in the brain. Taurine
(2-aminoethanesulfonic acid) is a promising therapeutic molecule able to
increase the activity of antioxidant enzymes and ATPase, which may be
protective against aluminum-induced neurotoxicity. It can also stimulate
neurogenesis, synaptogenesis, and reprogramming of proinflammatory M1
macrophage polarization by decreasing mitophagy (mitochondrial autophagy) and
raising the expression of the markers of the anti-inflammatory and pro-healing
M2 macrophages, such as macrophage mannose receptor (MMR, CD206) and
interleukin 10 (IL-10), while lowering the expression of the M1 inflammatory
factor genes. Taurine also induces autophagy, which is a mechanism that is
impaired in microglia cells and is critically associated with the
pathophysiology of ASD. We hypothesize here that taurine could reprogram the
metabolism of M1 macrophages that are overstimulated in the nervous system of
people suffering from ASD, thereby decreasing the neuroinflammatory process
characterized by autophagy impairment (due to excessive microglia activation),
neuronal death, and improving cognitive functions. Therefore, we suggest that
taurine can serve as an important lead for the development of novel drugs for
ASD treatment.
Autism spectrum disorders (ASD) are a complex
sequelae of neurodevelopmental disorders which manifest in the form of
communication and social deficits. Currently, only two agents, namely
risperidone and aripiprazole have been approved for the treatment of ASD, and
there is a dearth of more drugs for the disorder. The exact pathophysiology of
autism is not understood clearly, but research has implicated multiple pathways
at different points in the neuronal circuitry, suggesting their role in ASD.
Among these, the role played by neuroinflammatory cascades like the NF-KB and
Nrf2 pathways, and the excitotoxic glutamatergic system, are said to have a
bearing on the development of ASD. Similarly, the GPR40 receptor, present in
both the gut and the blood brain barrier, has also been said to be involved in
the disorder. Consequently, molecules which can act by interacting with one or
multiple of these targets might have a potential in the therapy of the
disorder, and for this reason, this study was designed to assess the binding
affinity of taurine, a naturally-occurring amino acid, with these target
molecules. The same was scored against these targets using in-silico docking
studies, with Risperidone and Aripiprazole being used as standard comparators.
Encouraging docking scores were obtained for taurine across all the selected
targets, indicating promising target interaction. But the affinity for targets
actually varied in the order NRF-KEAP > NF-κB > NMDA > Calcium channel
> GPR 40. Given the potential implication of these
targets in the pathogenesis of ASD, the drug might show promising results in
the therapy of the disorder if subjected to further evaluations.
Taurine is a sulfur-containing amino acid which
is not incorporated into protein. However, taurine has various critical
physiological functions including development of the eye and brain,
reproduction, osmoregulation, and immune functions including anti-inflammatory
as well as anti-oxidant activity. The causes of autistic spectrum disorder
(ASD) are not clear but a high heritability implicates an important role for
genetic factors. Reports also implicate oxidative stress and inflammation in
the etiology of ASD. Thus, taurine, a well-known antioxidant and regulator of
inflammation, was investigated here using the sera from both girls and boys
with ASD as well as their siblings and parents. Previous reports regarding
taurine serum concentrations in ASD from various laboratories have been
controversial. To address the potential role of taurine in ASD, we collected
sera from 66 children with ASD (males: 45; females: 21, age 1.5-11.5 years,
average age 5.2 ± 1.6) as well as their unaffected siblings (brothers: 24;
sisters: 32, age 1.5-17 years, average age 7.0 ± 2.0) as controls of the
children with ASD along with parents (fathers: 49; mothers: 54, age 28-45
years). The sera from normal adult controls (males: 47; females: 51, age 28-48
years) were used as controls for the parents. Taurine concentrations in all
sera samples were measured using high performance liquid chromatography (HPLC)
using a phenylisothiocyanate labeling technique. Taurine concentrations from
female and male children with ASD were 123.8 ± 15.2 and 145.8 ± 8.1 μM,
respectively, and those from their unaffected brothers and sisters were 142.6 ±
10.4 and 150.8 ± 8.4 μM, respectively. There was no significant difference in
taurine concentration between autistic children and their unaffected siblings.
Taurine concentrations in children with ASD were also not significantly
different from their parents (mothers: 139.6 ± 7.7 μM, fathers: 147.4 ± 7.5
μM). No significant difference was observed between adult controls and parents
of ASD children (control females: 164.8 ± 4.8 μM, control males: 163.0 ± 7.0
μM). However, 21 out of 66
children with ASD had low taurine concentrations (<106 μM). Since
taurine has anti-oxidant activity, children with ASD with low taurine
concentrations will be examined for abnormal mitochondrial function. Our data
imply that taurine may be a valid biomarker in a subgroup of ASD.
Taurine is a naturally occurring
sulfur-containing amino acid that is found abundantly in excitatory tissues,
such as the heart, brain, retina and skeletal muscles. Taurine was first
isolated in the 1800s, but not much was known about this molecule until the
1990s. In 1985, taurine was first approved as the treatment among heart failure
patients in Japan. Accumulating
studies have shown that taurine supplementation also protects against
pathologies associated with mitochondrial defects, such as aging, mitochondrial
diseases, metabolic syndrome, cancer, cardiovascular diseases and neurological
disorders. In this review, we will provide a general overview on the
mitochondria biology and the consequence of mitochondrial defects in
pathologies. Then, we will discuss the antioxidant action of taurine,
particularly in relation to the maintenance of mitochondria function. We will
also describe several reported studies on the current use of taurine
supplementation in several mitochondria-associated pathologies in humans.
Taurine
is known not as a radical scavenger. Several potential mechanisms by which
taurine exerts its antioxidant activity in maintaining mitochondria health
include: taurine conjugates with uridine on mitochondrial tRNA to form a
5-taurinomethyluridine for proper synthesis of mitochondrial proteins
(mechanism 1), which regulates the stability and functionality of respiratory
chain complexes; taurine reduces superoxide generation by enhancing the
activity of intracellular antioxidants (mechanism 2); taurine prevents calcium
overload and prevents reduction in energy production and the collapse of
mitochondrial membrane potential (mechanism 3); taurine directly scavenges HOCl
to form N-chlorotaurine in inhibiting a pro-inflammatory response (mechanism
4); and taurine inhibits mitochondria-mediated apoptosis by preventing caspase
activation or by restoring the Bax/Bcl-2 ratio and preventing Bax translocation
to the mitochondria to promote apoptosis (mechanism 5).
Taurine
Forms a Complex with Mitochondrial tRNA
Taurine
Reduces Superoxide Generation in the Mitochondria
Taurine therapy, therefore, could potentially
improve mitochondrial health, particularly in mitochondria-targeted
pathologies, such as cardiovascular diseases, metabolic diseases, mitochondrial
diseases and neurological disorders. Whether the protective mechanism on
mitochondria primarily relies on the taurine modification of mitochondrial tRNA
requires further investigation.
Taurine
and the gut microbiota
We now regularly in the
research see that you can make changes in the gut microbiota to treat medical
conditions. I think the most interesting was the discovery that the ketogenic
diet, used for a century to treat epilepsy, actually works via the high fat
diet changing the bacteria that live in your gut; it has nothing at all to do
with ketones. UCLA are developing a bacteria product that will mimic the effect
of this diet.
We should not be surprised
to see that one mode of action put forward for Taurine is changes it makes in
the gut microbiota.It is this very
mechanism that the Chinese researchers think is relevant to its benefit in
autism.
The paper below is not
about autism, but it is about Taurine’s effect on the gut microbiota.
Taurine,
an abundant free amino acid, plays multiple roles in the body, including bile
acid conjugation, osmoregulation, oxidative stress, and inflammation
prevention. Although the relationship between taurine and the gut has been
briefly described, the effects of taurine on the reconstitution of intestinal
flora homeostasis under conditions of gut dysbiosis and underlying mechanisms
remain unclear. This study examined the effects of taurine on the intestinal
flora and homeostasis of healthy mice and mice with dysbiosis caused by
antibiotic treatment and pathogenic bacterial infections. The results showed that taurine
supplementation could significantly regulate intestinal microflora, alter fecal
bile acid composition, reverse the decrease in Lactobacillus abundance, boost
intestinal immunity in response to antibiotic exposure, resist colonization by
Citrobacter rodentium, and enhance the diversity of flora during infection.
Our results indicate that taurine has the potential to shape the gut microbiota
of mice and positively affect the restoration of intestinal homeostasis. Thus,
taurine can be utilized as a targeted regulator to re-establish a normal
microenvironment and to treat or prevent gut dysbiosis.
Conclusion
Your body
can synthesize taurine from other amino acids, particularly cysteine, with the
help of vitamin B6. In most cases, this internal production is enough to meet
your daily needs for basic bodily functions.
Infants and
some adults may need taurine added to their diet.
Based on the
small study in humans, about a third of children with autism have low levels of
taurine in their blood.
Is extra
taurine going to provide a benefit to the other two thirds?
Taurine looks
easy to trial. It is normally taken three times a day after a meal. Each dose
would be 0.4g to 4g depending on weight and what the purpose was. The 2 year
olds in the Chinese autism trial will be taking 0.4g three times a day.
Japanese adults with mitochondrial disease (MELAS) are taking 4g three times a
day.
One can oF Red Bull contains 1g of taurine. Most supplements contain 0.5 to 1g. This is a
similar dose to what is given to pet cats and dogs. Just like Red Bull contains B vitamins, so do the taurine products for cats and dogs.
Some of the
effects will be immediate, while others will take time to show effect. For
example there can potentially be an increase in mitochondrial biogenesis. I
expect any changes in gut bacteria would also take a long time to get established.
The effect
via GABA on increasing brain excitability is an interesting one for people
taking bumetanide for autism, where the GABA developmental switch did not take
place. Based on the research you could argue that it will be beneficial or
indeed harmful.
What I can
say is that in Monty, aged 20 with ASD and taking bumetanide for 12 years, he
responded very well on the rare occasions he drank Red Bull.
-------
Vitamin
B5 and L carnitine for KATA6A Syndrome
I was asked
about KATA6A syndrome recently.This
syndrome is researched by Dr Kelley, the same doctor who coined the term Autism
secondary to mitochondrial dysfunction (AMD).
KAT6A
Research and Treatment An Update by Richard I Kelley , MD, PHD
Some kids
with KATA6A, like Peter below, respond very well to Dr Kelley’s mito cocktail.
Here’s my experience with the mitochondrial cocktail:
– At 4 weeks after the start of the cocktail, Peter became
potty-trained during the day without any training. He pulled his pull up off,
refused to put it back on.
-At 2 months, Peter started riding his bike with no training
wheels and playing soccer. He became able to kick the ball and run after it
till he scores.
-At 2.5 months, he started skiing independently. I used to
try to teach how to ski since he was 3yo. I used to spend hours and hours
picking him up off the snow with no result. I tried different kind of
reinforcers (food,..) with no result. After the cocktail, he just went down the
hill by himself, He can ski independently now and knows how to make turns.
-At 2-3 months, I started noticing an increased strength in
playing ice hockey and street hockey with a better understanding of the game.
His typing ability improved too, he used to have severe apraxia while typing
(type the letter next to the letter he wants to type…).
-At 3-4 months, Peter’s fingers on the piano became stronger,
he became able to play harder songs with less training and less frustration. I
also noticed an increase in “common sense” like for example putting his
backpack in the car instead of throwing it on the floor next to the car and
riding the car without his backpack. Another example, when we go to the public
library, he knows by himself that he has to go to the children section, and
walks independently without showing him directions to the play area inside the
children section. In the past, he used to grab books the time he enters the
library, throw a tantrum on the floor. The most important milestone is that
Peter started to say few words that I can understand.
-At 11 months, Peter became potty-trained at night. His
speech is slowly getting clearer. His fine and gross motor skills are still
getting better.
Some readers
of this blog have been in touch with Dr Kelley and he does give very thorough replies.
Generally
speaking, the therapies for mitochondrial diseases/dysfunctions seem to be
about avoiding it getting worse, rather than making dramatic improvements. In
the case of Peter (above) the effects do look dramatic. There are many other ideas
in the research that do not seem to have been translated into therapy.
A study from
two years ago does suggest that vitamin B5 and L carnitine should be trialed.
Mutations in several genes involved in the
epigenetic regulation of gene expression have been considered risk alterations
to different intellectual disability (ID) syndromes associated with features of
autism spectrum disorder (ASD). Among them are the pathogenic variants of the
lysine-acetyltransferase 6A (KAT6A) gene, which causes KAT6A syndrome. The KAT6A enzyme participates in
a wide range of critical cellular functions, such as chromatin remodeling, gene
expression, protein synthesis, cell metabolism, and replication. In this
manuscript, we examined the pathophysiological alterations in fibroblasts
derived from three patients harboring KAT6A mutations. We addressed survival in
a stress medium, histone acetylation, protein expression patterns, and
transcriptome analysis, as well as cell bioenergetics. In addition, we evaluated the therapeutic
effectiveness of epigenetic modulators and mitochondrial boosting agents, such
as pantothenate and L-carnitine, in correcting the mutant phenotype.
Pantothenate and L-carnitine treatment increased histone acetylation and
partially corrected protein and transcriptomic expression patterns in mutant
KAT6A cells. Furthermore, the cell bioenergetics of mutant cells was
significantly improved. Our
results suggest that pantothenate and L-carnitine can significantly improve the
mutant phenotype in cellular models of KAT6A syndrome.
Next, we analyzed the expression changes of
specific genes in treated and untreated conditions. We found that the
expression levels of downregulated genes in the mutant KAT6A fibroblasts, such
as KAT6A, SIRT1, SIRT3, NAMPT1, Mt-ND6, NDUFA9, PANK2, mtACP, PDH (E1 subunit α2), KGDH (E2 subunit), SOD1, SOD2,
and GPX4 were
significantly restored after pantothenate and L-carnitine treatment. The
proteins encoded by these genes are involved in acetylation-deacetylation
pathways, CoA metabolism, mitochondria, and antioxidant enzymes, all of which
are critical for intracellular processes in embryonic and childhood
development.
KAT6A acts
as a master regulator by fine-tuning gene expression through chromatin
modifications, so we should expect it to have wide ranging effects. All the
closest interactions are will other genes that modify gene expression.
KAT6A mutations are indeed linked to
microcephaly, a condition characterized by a smaller than average head circumference.
Most autism is associated with
hyperactive pro-growth signalling pathways; only a minority is associated with the opposite and this would fit with
microcephaly, which is typical in KAT6A.
Microcephaly is a very common feature
of Rett syndrome.
Among the features of KAT6A syndrome
there will be overlaps with other syndromes.
Dr Kelley analyses amino acids looking
for mitochondrial dysfunction. He has found this present in KAT6A, but this is
only one treatable feature of the syndrome.
Targeting growth signaling pathways
might well be worth pursuing. You would be looking a what works in other people
with smaller heads.
I wrote quite a lot about IGF-1
previously in this blog.
It would be highly plausible that
these related therapies might be of benefit. The easy one to try is cGPMax,
because it is sold OTC. IGF-1 itself might be beneficial, you would have to
find a helpful endocrinologist to trial it.
All the therapies of idiopathic autism
could be trialed.
If the child has a paradoxical
reaction to any benzodiazepine drug, then you know that bumetanide is likely to
be beneficial.
Since mitochondrial function is
impaired in KAT6A, taurine is another thing to trial.
