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Sunday 21 June 2015

Bumetanide “reverses” MR/ID in Down Syndrome




You probably know what Down Syndrome looks like, but you probably never expected the above life expectancy data.  It used to be the case that kids with this disorder were institutionalized after birth.



In an earlier post I suggested that some types of Mental Retardation (MR)/Intellectual Disability (ID) should be treatable.  I was thinking about RASopathies, dendritic spine morphology and the GABA E/I (Excitatory/Inhibitory) imbalance found in autism.  I even suggested to the autism researchers working on the bumetanide approval process that the simplest measure of effectiveness would be to measure IQ before and after treatment.

Recent research has shown that in Down Syndrome GABA is also excitatory.  GABA should be inhibitory, otherwise the brain cannot function properly and there will be a large risk of seizures.  In many people with autism GABA is excitatory; this reduces their cognitive function and leads to almost 80% having unusual epileptiform activity (like “pre-epilepsy”) and about 35% going on to developing seizures.

In the Down Syndrome mouse model the researchers found that Bumetanide improved cognitive function, via the shifting of GABA from excitatory to inhibitory.

Our findings demonstrate that GABA is excitatory in adult DS mice and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS.


I thought that was great news.  Perhaps other types of MR/ID are also the result of GABA E/I imbalance, they too would be treatable with Bumetanide.

The question remains, does anyone care enough to bother about these people?  Take a look at the life expectancy chart at the top of this post.  Things have got much better, but there is a long way to go.


Down Syndrome

Most people have heard about Down Syndrome (DS) and I certainly knew more about what DS looked like than what autism looked like.

People with DS look different, are short, and 99% have some degree of MR/ID.  About 10% also have autism and half will develop epilepsy.

Down syndrome is caused by having three copies of the genes on chromosome 21, rather than the usual two.  The extra genetic material present in DS results in overexpression of a portion of the 310 genes located on chromosome 21. This overexpression has been estimated at around 50%.

Some adults with DS lose the ability to use speech when they are about 30 years old.

Until 1970 children with DS used to live for just 10 years, whereas today most survive into their 50s.

About 92% of pregnancies in Europe with a diagnosis of Down Syndrome are terminated. In the United States, termination rates are around 67%.  When non-pregnant people are asked if they would have a termination if their fetus tested positive only 23–33% said yes.





Down syndrome (DS) is the most frequent genetic cause of intellectual disability, and altered GABAergic transmission through Cl-permeable GABAA receptors (GABAARs) contributes considerably to learning and memory deficits in DS mouse models. However, the efficacy of GABAergic transmission has never been directly assessed in DS. Here GABAAR signaling was found to be excitatory rather than inhibitory, and the reversal potential for GABAAR-driven Cl currents (ECl) was shifted toward more positive potentials in the hippocampi of adult DS mice. Accordingly, hippocampal expression of the cation Cl cotransporter NKCC1 was increased in both trisomic mice and individuals with DS. Notably, NKCC1 inhibition by the FDA-approved drug bumetanide restored ECl, synaptic plasticity and hippocampus-dependent memory in adult DS mice. Our findings demonstrate that GABA is excitatory in adult DS mice and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS.



Conclusion

It would appear that excitatory GABA may be more common than anyone thought.  I wonder how many other people with MR/ID might be affected and be potential beneficiaries of this very inexpensive therapy.

I did ask one of my doctor relatives if she has any patients with DS; I said that there may be a treatment for their MR/ID.  She is not going to prescribe her patients anything off-label, so unless Ben-Ari decides he wants to help people with DS, as well as ASD, people will DS will remain untreated.  I will ask him.

Also, given the large amount of money going into the genetics of autism, perhaps it would be worth looking at those 310 genes located on chromosome 21 to see if the overexpression of one may trigger speech loss in people with regressive autism and/or might be present from birth in people with classic autism.  One of them must trigger the speech loss in that sub-group of adults with DS.




7 comments:

  1. Peter, do you have any view on the likely date for the results of the bumetanide clinical trial (in ASD)?

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    1. I understand that they have started the process, but may not yet have the funds to complete the phase 3 trial. It costs 5 to 8 million euros. So it will likely take longer than if money was unlimited.

      Given all this I hope they will finish the approval process by the end of 2016 and or worst case 2017.

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  2. Peter, tomorrow i will make my son a ionogram, becuase my neurologist asked, but before i go to see him i would like to know how to interpret it, for example if his moving and sensory disorders can have an explanation. Would you interpret it if something is wrong? I should write to you the values. valentina

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    1. Valentina, good luck with the neurologist. I do not have any experience of ionograms.

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    2. Thankyou!,I was sure that you knew all about channelopathies, i am sure, never mind, i am also sure that when get the results, i ll start to guess!!!.

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  3. Hello,
    I'd love to trial Bumetanide on my son, but don't hold out much hope that I'll get prescription. Here in the US doctors are reluctant to go off label. Sorry if my question is simplistic, but is there any reason that a similar effect couldn't be achieved with a very low sodium diet and lots of water? If Bumetanide's mechanism of action is lowering serum chloride then couldn't low salt/high water (supplementing potassium to avoid electrolyte imbalance)do the same thing? I have no medical or scientific background so apologies for my noobie question.

    For your reference, my son (7yo ASD, ADHD, DCD, probably Dyslexic) has responded very well to NAC and broccoli sprouts, he sounds similar to your son, no SIB yet and no asthma but similar none the less- I am encouraged to trial all the drugs in your polypill but feel stymied by my inability to find a doctor that is willing to go off the beaten path. I could seek out a DAN type doctor but they don't seem very scientific in their approach and the charge so much.

    Anyway Thanks so much for sharing this blog with everyone. I'd love to hear your thoughts on any other potential "natural" or OTC equivalents to other pharmaceutical in your polypill-- I know that is a tall order and I know that supplements are unpredictable, but if we lived in a world where supplements could be relied on completely can you think of any non-prescription options that would approximate the MOA of your polypill pharmaceuticals?

    Yours in Autism Parenting,

    Andi

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    Replies
    1. Andi, a low sodium diet would be different. Bumetanide is lowering chloride inside cells, so it is raising it outside cells, it not just lowering the level in your blood.

      Some people in the US get bumetanide prescribed from a DAN doctor and some are buying it in Mexico, some online and some by going there.

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