Is it safe to treat autism in very young children? Plus, the impact of impaired autophagy on cognition and treating SIB

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.”

Source: Metformin treatment in young children with fragile X syndrome

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. 

Here is the recent paper on this subject. 

Impaired macroautophagy confers substantial risk for intellectual disability in children with autism spectrum disorders

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.