Differential Diagnosis and Treatment in Autism – Verapamil & Curcumin for Williams Syndrome?

 

The face of Williams syndrome kids. Source: Figure 2.  GeneReviews® - NCBI Bookshelf

Continuing from the last post, today we look again at differential diagnosis and treatment, which I prefer to just call personalized medicine.

This is the subject of a conference for parents in the UK, that I agreed to draw to the attention of readers.

 

Click on the picture above to read about the upcoming event in London.

 

 

Williams syndrome

Williams syndrome: MedlinePlus Genetics (click for info)

Williams syndrome occurs when someone is missing a small piece of chromosome 7, resulting in them lacking 25 to 27 genes. Most people with Williams syndrome have not inherited the condition from a parent.

Williams syndrome can delay a child’s milestones including:

·         Learning (mild to moderate intellectual challenges)

·         Saying their first words and talking

·         Sitting and walking

Socializing is unusual – there is excessive empathy. A child will be outgoing and very friendly, but has difficulty identifying strangers. There may be attention problems, phobias, or anxiety.

Williams is another syndrome with distinct facial features that can help with diagnosis.

·         Large ears

·         Full cheeks

·         Small jaw

·         Wide mouth

·         Small teeth

·         Upturned nose

Williams syndrome is still viewed as untreatable.

In this blog we always start from the basis that all severe autism is potentially treatable.  Often some of the downstream effects of genetic mutations overlap with other types of autism and some of these effects actually are treatable.

There is a great deal in this blog about targeting both calcium channels and potassium channels to treat autism. Verapamil and Ponstan are the two drugs I have written most about.

Curcumin is an OTC therapy for autism that has been widely covered in this blog and people do regularly write to me to tell me that it is beneficial.  Just last week a reader told me that both Ponstan and Curcumin are beneficial in his specific case.

I was intrigued to read the paper from Spain below where the researchers found the combination of Verapamil + Curcumin to improve behaviors in Williams syndrome.  The mechanism was found to be by regulation of MAPK pathway and microglia overexpression.

 

Verapamil + Curcumin to treat the behavioral issues in Williams syndrome

One key takeaway is that in the model of Williams syndrome you need both verapamil (VER) and curcumin (CUR). Either intervention on its own provided no benefit – you need the combination (VERCUR). 

Co-Treatment With Verapamil and Curcumin Attenuates the Behavioral Alterations Observed in Williams–Beuren Syndrome Mice by Regulation of MAPK Pathway and Microglia Overexpression

Williams–Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by a distinctive cognitive phenotype for which there are currently no effective treatments. We investigated the progression of behavioral deficits present in WBS complete deletion (CD) mice, after chronic treatment with curcumin, verapamil, and a combination of both. These compounds have been proven to have beneficial effects over different cognitive aspects of various murine models and, thus, may have neuroprotective effects in WBS. Treatment was administered orally dissolved in drinking water. A set of behavioral tests demonstrated the efficiency of combinatorial treatment. Some histological and molecular analyses were performed to analyze the effects of treatment and its underlying mechanism. CD mice showed an increased density of activated microglia in the motor cortex and CA1 hippocampal region, which was prevented by co-treatment. Behavioral improvement correlated with the molecular recovery of several affected pathways regarding MAPK signaling, in tight relation to the control of synaptic transmission, and inflammation. Therefore, the results show that co-treatment prevented behavioral deficits by recovering altered gene expression in the cortex of CD mice and reducing activated microglia. These findings unravel the mechanisms underlying the beneficial effects of this novel treatment on behavioral deficits observed in CD mice and suggest that the combination of curcumin and verapamil could be a potential candidate to treat the cognitive impairments in WBS patients.

Accumulated evidence has described that curcumin, the major constituent of turmeric (Curcuma longa), exerts a variety of pharmacological effects due to its antioxidant, anti-inflammatory, and neuroprotective properties. Recent studies have reported positive effects of curcumin over different cognitive aspects such as anxiety-like behaviors, memory deficits, and motor impairments of different murine models Many studies have described that its effects on the behavioral phenotype of mice models are mediated by upregulation of BDNF (brain-derived neurotrophic factor) expression BDNF has been described as a crucial molecule for neural development and plasticity processes and its mechanism of action is highly dependent on a proper maintenance of intracellular ionic homeostasis Moreover, it has also been described to prevent neuroinflammation by modulating pathways related to NRF2 and MAPK signaling.

Verapamil is a widely used medication, and its mechanism of action involves mainly the blocking of voltage-dependent calcium channels, but it has also been proven to directly bind and block voltage-gated potassium channels  and to inhibit drug efflux pump proteins like P-glycoprotein. Although it has been mainly studied for cardiovascular applications, it has also been associated with positive effects on anxiety and memory processing in murine models.

Given the properties of both compounds, we decided to explore the effects of each compound and a combinatorial treatment on the behavioral phenotype of CD mice. The results show that only the combined treatment with curcumin and verapamil improved the deficits. This improvement can be correlated with the normalization of the MAPK and inflammasome signaling pathways and with the concomitant reduction of activated microglia. 

·   The Increased Microglia Activation in Motor Cortex and Hippocampus Presented by CD Mice Is Prevented by VERCUR Co-Treatment

·    Combinatorial Treatment Prevents Hypersociability of CD Mice

·    Only VERCUR Co-Treatment Improves Motor Coordination in CD Mice

·    VERCUR Co-Treatment Prevents Gene Expression Changes in Cortex of CD Animals

·    Neuroanatomical Features of CD Mice Do Not Change After VERCUR Co-Treatment

In conclusion, we suggest that the hemizygous loss of WBSCR in the cerebral cortex of CD mice has a direct effect on the neuroinflammatory state of the brain, as well as on the expression of some genes related to synaptic signaling or extracellular matrix structure, which are crucial for a proper neural function. This may at least be partly responsible for the behavioral phenotype observed in CD animals. A treatment combining verapamil and curcumin is able to address different molecular targets and rescue some of those pathways, being a promising therapeutic approach for the cognitive phenotype of WBS patients.

  

Conclusion 

Today’s study was in a mouse model of William’s syndrome; clearly it would be more informative if the researchers had tried it on humans.  It does though raise the question as to what other treatments from idiopathic autism might be effective in this supposedly untreatable genetic condition.

The other perspective of course is to wonder what other types of autism might benefit from Verapamil plus curcumin (VERCUR). It was interesting to note that in the model neither Verapamil nor curcumin was effective by itself, they needed the combined therapy (VERCUR).

If you read the experiences that have been shared over the years in this blog you can see that some parents spend a lot of money on genetic testing, hoping to improve their child’s outcome.  It is only very rarely that you see any great success resulting.

The alternative approach is understand the commonly shared biological features of autism and try and treat those, to see whether the individual shows a benefit.  Where there is a positive response, it is a “keeper,” if there is no response, or a negative response, the therapy is dropped.  Essentially it is a process of trial and error.  Not as fancy as genetic testing, but it works.

Clearly if your child has Williams syndrome you would be well advised to look up the function of each of the 26 missing genes, to see if there are any obvious steps to take. One good tool to use is www.genecards.org.  

Old posts that refer to cucumin:

Epiphany: Curcumin (epiphanyasd.com)

 

Old posts that refer to verapamil

Epiphany: Verapamil (epiphanyasd.com)