Mutations in CACNA2D1 plus KDM6B -- Gabapentin and Calcium Folinate? Perhaps PQQ? Perhaps BHB?

 

A little research can sometimes be eye opening

I was recently sent genetic results from several parents and surprisingly some have multiple potentially highly causal genes. Some are mutations that are extremely rare and one was unique.

Today I am looking at one case with two genes highlighted in whole exome sequencing (WES), one is a calcium ion channel and the other is a gene extremely close to the one causing Kabuki syndrome.  Interestingly, two possible interventions did very quickly appear.

The report states:

UNCLEAR RESULT

Variants of uncertain significance (VUS) identified

Based on current evidence, the clinical relevance of the detected variants remains unclear.

Kabuki syndrome is caused by mutations in KMT2D or KDM6A.

KDM6A and today’s gene KDM6B both target trimethylation on lysine 27 of histone H3 (H3K27me3), a mark associated with gene silencing. By removing this mark, they activate gene expression. So, mutations in either gene will cause a cascade of effects on numerous other genes.

The old post below suggested the use of HDAC inhibitors to correct the mis expressed genes. In particular, BHB from the ketogenic diet was discussed.

Notably, histone deacetylase inhibition rescued structural and functional brain deficits in a mouse model of Kabuki syndrome.

 

Ketones and Autism Part 5 - BHB, Histone Acetylation Modification, BDNF Expression, PKA, PKB/Akt, Microglial Ramification, Depression and Kabuki Syndrome

           

The calcium channel involved today is not one we have previously looked at, but it is the target of the very well-known drug Gabapentin. This drug is used to treat epilepsy and neuropathic pain. The child does have abnormal EEG and seizures, plus autism, ADHD and absent speech.

Mutations of the KDM6B causing autism were first described only in 2019. In 2022 mutations in this gene were found in several patients with cerebral folate deficiency (CFD), one of the authors is our old friend Dr Ramaekers.

We know a lot about CFD, thanks to our reader Roger, Dr Frye, Dr Ramaekers, and now Agnieszka and Stephen. Over in the US one of the founders of an autism organisation told me her son was diagnosed in adulthood with CFD, when he finally had a spinal tap.

Interestingly, Agnieszka has pointed out a novel way to potentially increase folate in the brain using an OTC supplement called PQQ.

 

Protective effects of pyrroloquinoline quinone in brain folate deficiency

Results

Folate deficiency resulted in increased expression of inflammatory and oxidative stress markers in vitro and in vivo, with increased cellular ROS levels observed in mixed glial cells as well as a reduction of mitochondrial DNA (mtDNA) content observed in FD mixed glial cells. PQQ treatment was able to reverse these changes, while increasing RFC expression through activation of the PGC-1α/NRF-1 signaling pathway.

Conclusion

These results demonstrate the effects of brain folate deficiency, which may contribute to the neurological deficits commonly seen in disorders of CFD. PQQ may represent a novel treatment strategy for disorders associated with CFD, as it can increase folate uptake, while in parallel reversing many abnormalities that arise with brain folate deficiency.

 

PQQ is a relatively common OTC supplement that looks helpful in older people and those with mitochondrial dysfunctions (most older people, plus many with autism).  It can also improve sleep.  The common 20mg dose seems to be based on what was used in a clinical trial in Japanese adults. Japanese drugs are dosed to reflect the size of Japanese people. American women on average weigh 40% more than Japanese women.

PQQ is present in mother’s milk, so it is not some scary artificial compound.

CFD looks like another nexus point where may different genetic variants produce a downstream meeting point.  This means numerous different underlying autisms will share a common beneficial therapy. It will not be a cure, but it should improve the outcome.

The only way to access I/V calcium folinate looks to be via confirmation of very low levels in spinal fluid, so a spinal tap would be necessary.  This is not easy, as Agnieszka has found out.  For some people oral calcium folinate is not sufficiently potent to reverse CFD.

KDM6B

Mutations of the KDM6B gene causing autism were first described only in 2019. In 2022 mutations in this gene were found in several patients with cerebral folate deficiency (CFD).

 

Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features

Lysine-specific demethylase 6B KDM6B demethylates trimethylated lysine-27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders. We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings. Our findings will allow for further investigation in to the role of the KDM6B gene in human neurodevelopmental disorders.

 

Layman’s guide to the KDM6B gene

https://www.simonssearchlight.org/research/what-we-study/kdm6b/

 

12% of people with CFD studied in the paper below had mutations in KDM6B. So clearly all people with a mutation in this gene should be tested for CFD vis a spinal tap.

 

KDM6B Variants May Contribute to the Pathophysiology of Human Cerebral Folate Deficiency

Cerebral folate deficiency syndrome (CFD) was defined as any neurological condition that was associated with low concentrations of 5-methyltetrahydrofolate in the cerebrospinal fluid. Previous clinical studies have suggested that mutations in the folate receptor alpha FOLR1 gene contribute to CFD. In this study, we identified six genetic variants in histone lysine demethylase 6B (KDM6B) in 48 CFD cases. We demonstrated that these KDM6B variants decreased FOLR1 protein expression by manipulating epigenetic markers regulating chromatin organization and gene expression. In addition, FOLR1 autoantibodies were identified in CFD patients’ serum. To the best of our knowledge, this is the first study to report that KDM6B may be a novel CFD candidate gene in humans.

The way to confirm CFD, with certainty, is via a spinal tap.  This can then open the door to intravenous therapy with calcium folinate.

There is a blood test which then would lead to oral calcium folinate therapy.  This is now very common in children with autism in the US. It improves speech.

www.fratnow.com

The problem is that some people need the more potent intravenous therapy and without a spinal tap there is not enough proof to get the therapy.

 

CACNA2D1

The CACNA2D1 gene encodes voltage-dependent calcium channel subunit alpha-2/delta-1. 

Different types of mutation will have different effects and varying degrees of severity.

Some mutations in this gene are associated with a condition called “Developmental and Epileptic Encephalopathy 110”.

Developmental and epileptic encephalopathy-110 (DEE110) is an autosomal recessive disorder characterized by profound global developmental delay and hypotonia apparent in infancy followed by onset of seizures in the first months or years of life. Affected individuals achieve almost no developmental milestones and show impaired intellectual development, poor or absent speech, inability to walk or grasp objects, peripheral spasticity, and poor eye contact. Brain imaging shows hypoplastic corpus callosum and cortical atrophy.

CACNA2D1 is also a novel Brugada Syndrome susceptibility gene.

Brugada syndrome may be a major cause of sudden cardiac death in men under 40. People with Brugada syndrome on average die between the ages of 26 to 56 years, with an average age of 40 years. If treated appropriately, patients can have a normal lifespan.

A pediatric cardiologist should be consulted.

Fortunately the Alpha-2/delta proteins are believed to be the molecular target of the gabapentinoids gabapentin and pregabalin, which are used to treat epilepsy and neuropathic pain.

This means that an obvious path to investigate is whether the drug gabapentin has a positive effect. Mutations could produce either gain of function of loss of function.

Gabapentin binds to a the α2δ subunit. This binding does not directly block or open the channel, but it influences its overall activity.

The exact mechanism of action is still not fully understood, but it is believed that gabapentin:

·       Reduces the release of certain neurotransmitters involved in pain signaling, such as glutamate and substance P.

·       Alters the trafficking and function of the calcium channels themselves.

·       Therefore, gabapentin's action is more complex than simply "blocking" or "opening" channels. 

Gabapentin is not guaranteed to help in this case, but certainly might do.

Conclusion

The take home is really that if you invest thousands of dollars/euros/pounds in genetic testing, it is well worth your time spending some time on the internet looking up any flagged genes.

People expect too much from the geneticist writing the report.

Double check these things yourself.  Take your findings to an open-minded neurologist, who reads the research literature.

Be aware that the same mutation can be present in one or even both parents, with no noticeable negative effect, but be disease causing in their child. Genetics is often about the probability of something happening, rather the certainty. 

Look at partially-effective or sometimes-effective interventions in the research. For example, one reader is looking at mutations in NF1 plus a gene affecting epigenetics. He might want to try Lovastatin.  NF1 causes an increase in RAS, which is a pro-growth signal, this leads to RASopathies which can cause intellectual disability (ID). Lovastatin reduces RAS and it was trialled to reduce ID in NF1 - the results were mixed. It probably matters at what age you start trying to reduce RAS.

“Autism treatments proposed by clinical studies and human genetics are complementary” & the NSAID Ponstan as a Novel Autism Therapy

Today’s post was not my idea at all, it was the author of one of the papers who has drawn my attention to the subject.

Genetic studies are complicated and are not the sort of thing I would have chosen to read, let alone write about, before starting this blog. 

The optimal time to initiate pharmacological 

intervention in Autism?

However, much of the complex subject matter has now already been covered, step by step, in earlier posts. Regular readers should not feel put off.

It is perhaps easier to think about ion channel dysfunctions, or channelopathies.  Some of the key genetic dysfunctions produce these channelopathies.  There are many posts in this blog about channelopathies, partly because many therapies already exist to treat them.

Then we have the complex signaling pathways which are often the subject of cancer research, but we have seen that certain ones like RAS and PTEN are key to conditions like some autism and some MR/ID.

So it is not a big leap therefore to consider the findings of a statistical reassessment of the existing genome-wide association studies (GWAS).  As is often the case in medical science, it is the acronyms/abbreviations, like GWAS, that make it look more complex than it really is.

If you only ever read one paper about the genetics of autism, I suggest you make it this one.

Fortunately, the conclusion from the genetic study really fits nicely with the clinical studies reviewed on this blog and even my own first-hand experience of investigating and treating my n=1 case of autism.

Knut, the Biometrician

It was Knut who left a brief comment on this blog and, after a little digging, I was very surprised how much a statistician/biometrician could figure out about autism, from re-analyzing the existing genome-wide association studies (GWAS).

I think the Simons Foundation could save themselves a decade or two by giving him a call.

The Research

For those wanting the science-lite version, there is a short article reviewing the research in lay terms:-

Biostatistics provides clues to understanding autism: an interview with Dr Knut M. Wittkowski

“Hence, modulation of ion channels in children at the age of about 12 months, when the first symptoms of autism can be detected, may prevent progression to the more severe end of the spectrum.” .

The actual research paper is here:-

You may find it heavy going and I have highlighted some key parts.

A novel computational biostatistics approach implies impaired dephosphorylationof growth factor receptors as associated with severity of autism

  

“Despite evidence for a likely involvement of de novo and environmental or epigenetic risk factors, including maternal antibodies or stress during pregnancy  and paternal age, we contend that coding variations contribute substantially to the heritability of ASD and can be successfully detected and assembled into connected pathways with GWAS—if the experimental design, the primary outcome, the statistical methods used, and the decision rules applied were better targeted toward the particulars of non-randomized studies of common diseases.”

The data comes from the Autism Genome Project (AGP), and there are two sets of data AGPI and AGPPII.

The third data set is for Childhood Absence Epilepsy (CAE)

What I would call Classic Autism, others call severe autism or autistic disorder; Knut calls it Strict Definition Autism (SDA).  HFA is high functioning autism, much of which is Asperger’s Syndrome.

“Study design We aimed at risk factors specific to strict definition autism (SDA) by comparing case subpopulations meeting the definition of SDA and milder cases with ASD (excluding SDA), for which we here use the term ‘highfunctioning autism’ (HFA). To reduce variance, we included only subjects of European ancestry genotyped on the more frequently used platform in either stage. In AGP II, we also excluded female cases because of confounding between chip platform and disease severity. The total number of subjects included (m: male/f: female) was 547/98 (SDA) and 358/68 (HFA) in AGP I and 375 (SDA) and 201 (HFA) in AGP II.

Overall, the results (see Supplementary Figure 1 for a Manhattan plot) are highly consistent with previously proposed aspects of the etiology of ASD. The clusters of genes implicated in both of the independent stages (Figure 2a/b) consistently overlap with our published CAE results (Figure 2c), confirming the involvement of ion channels (top right) and signaling downstream of RAS (bottom left), with two noticeable additional gene clusters in ASD. Both stages implicate several genes involved in deactivation of growth factor (GF) receptors (Figure 2a/b, top left) as ASD-specific risk factors and chloride (Cl − ) signaling, either through Ca2+ activated Cl− channels

Click to enlarge the figure 

A new term is PTPR (protein tyrosine phosphatases receptor), just to confuse us it is also called RPTP.

Receptor Protein Tyrosine Phosphatases in Nervous System Development

 

For example, the receptor protein tyrosine phosphatases gamma (PTPRG) and zeta (PTPRZ) are expressed primarily in the nervous system and mediate cell adhesion and signaling events during development.

In an earlier post I highlighted the numerous dysfunctions in growth factors (GF) in autism.  Knut is highlighting here the effect of PTPR on growth factors.  Later it is suggested that this cascade of GF dysfunctions could be halted, pharmacologically if it was identified very early.  But, as Courchesne from UC San Diego noted, by the time people have been identified as having autism, around three years old, the accelerated brain growth has already run its course.

You would need to intervene around one year old.

Broad evidence for involvement of PTPRs One of the most striking observations is the involvement of at least five PTPRs in ASD (Figure 2, 10 o’clock position). PTPRs (Table 1e) regulate GF signaling through reversible protein tyrosine dephosphorylation.72 PTPRT (90th/20th, 8.57) was implicated in ASD by a deletion73 (Table S2 AU018704) and a somatic mutation

It was my post pondering the reasons for the positive effect of potassium supplementation that drew Knut’s attention to this blog.  Now we move on to Knut’s ideas on potassium and chloride channels.

K+ and Cl− ion channels as drug targets

Aside from PTPRs (Figure 2, 10 o’clock) as a risk factor for protracted GF signaling, our results suggest a second functional cluster of genes, involved in Cl− transport and signaling, as specific to ASD (Table 1f). In AGP I, the CaCCs ANO4 and ANO7 scored 1st and 70th, respectively. In AGP II, the lysosome membrane H+ /Cl- exchange transporter CLCN7 scored 21st, followed by CAMK2A, which regulates ion channels, including anoctamins82 (55th), and LRRC7 (densin-180), which regulates CAMK2A83 (Figure 2a/b, 2 o’clock). The role of the anoctamins in pathophysiology is not well understood, except that CaCC activity in some neurons is predicted to be excitatory84 and to have a role in neuropathic pain or nerve regeneration. More recently, CaCCs have also been suggested as involved in ‘neurite (re)growth’. Finally, we compared the HFA and SDA cases as separate groups against all parental controls in the larger AGP I population. Overall, the level of significance is lower and the enrichment is less pronounced, especially for the SDA cases (Supplementary Figure 9), as expected when cases and some controls are related. For the HFA cases (Figure 4, and Supplementary Figure 8), however, a second anoctamin, ANO2, located on the other arm of chromosome 12, competes with ANO4 (Figure 1, left), for the most significant gene among the result. Hence, drugs targeting anoctamins might have broader benefits for the treatment of ASD than in preventing progression to more severe forms of autism. ANO2 and ANO6 are associated with panic disorder and major depressive disorder, respectively. ANO3, ANO4, ANO8 and ANO10, but not ANO1, are also expressed in neuronal tissue.86 As ‘druggable channels’, anoctamins ‘may be ideal pharmacological targets to control physiological function or to correct defects in diseases’.  Few drugs, however, target individual anoctamins or even exclusively CaCCs. Cl− channel blockers such as fenamates, for instance, may decrease neuronal excitability primarily by activating Ca2+-dependent outward rectifying K+ channels.

Here is a follow-up paper with consideration of the possible next steps.

Early Pharmacological Intervention in Autism: Wide-Locus GWAS Leading to Novel Treatment Options

Gene gene environment behavior development interaction at the core of autism:

Here, we combine a recent wide-locus approach with novel decision strategies fine-tuned to GWAS. With these methodological advances, mechanistically related clusters of genes and novel treatment options, including prevention of more severe forms of ASD, can now be suggested from studies of a few hundred narrowly defined cases only.

(Nonsyndromic) autism starts with largely unknown prenatal events (♂: age, ♀: virus/stress ...)

• Mutations in growth factor regulators (PTPRs) lead to neuronal overgrowth (brain sizes).

• Mutations in K+/Cl− channels cause Ca2+ mediated over excitation of neurons (“intense world”).

• Stressful environments (urbanization) contribute to epistatic interaction (increasing prevalence).

• This GGE interaction causes “migraine-like” experiences during the “stranger anxiety” period where children learn verbal/social skills, leading to behavioral maladaptation (“tune-out”).

• The lack of verbal/social stimuli causes “patches of disorganization” (Stoner 2014, NEJM) as a form of developmental maladaptation when underutilized brain areas are permanently “pruned”. The PTPRs point to a short window of opportunity (WoO) for pharmacological intervention:

• Treatment has to begin as early as possible, while neurons are still growing (12 months of age. Broad support for the proposed unifying etiology and the 2nd year of life as the WoO:

• Regression (“loss of language”) seen in some children >12 mos of age.

• “Patches of disorganization” in >2 yr old brains.

• Romanian orphans developed “quasi-autism” when placed into foster care at >24 mos of age. 

• Hearing impairment leading to intellectual disability when diagnosed >24 mos of age.

 A rational drug target: treating either of two epistatic risk factors suffices:

• Blocking growth factors (Gleevac, ...) is unacceptable in children merely at risk of ASD.

• Ion channel modulators have been used in small children for arthritis and seizures.

Here is a response to Knut’s first paper from a professor at the UCLA medical school who suggests the combination of the specific NSAID and bumetanide. 

The professor would better understand the mechanism of action of bumetanide in autism if he read Ben Ari’s research more thoroughly, or even this blog.

  

Autism treatments proposed byclinical studies and human genetics are complementary

  

The article by Wittkowski et al.¹ reports results of human genetic studies that suggest that a nonsteroidal anti-inflammatory drug (NSAID) given for a few months from the time of the first symptoms might help some children who are at risk of developing more severe forms of atrial septal defect.

While the authors mention the recent article by Lemonnier et al.,² which reported that a clinical study of the diuretic Bumetanide was partially effective in children with milder forms of autism, they seem to have overlooked that these two treatments may well be complementary, leading to sequential interventions, each targeting specific risks related to well-defined stages in the development of brain and social interactions.

Since abnormal brain development in autistic disorder goes through different stages from infancy to childhood, targeting different developmental stages with different treatment interventions may well be necessary to foster continued normalization of brain growth.

Bumetanide is known to block inward chloride transporters, yet the relation of this mechanism to the etiology of autism is unknown. Wittkowski et al. identified mutations in calcium-activated (outward) chloride channels as associated with autistic disorder, suggesting loss-of-function mutations in anoctamins as one of the risk factors for autism. This provides a testable hypothesis for the mechanism by which Bumetanide alleviates symptoms of autism. For example, mouse models could test whether Bumetanide ameliorates a stress-induced phenotype caused by a knockout/down in ANO2 and/or ANO4.

A second cluster of genes identified receptor protein tyrosine phosphatases, which downregulate growth factors. These findings support the notion that successful treatment should start as early as possible,³ while neuronal development still takes place.

The rationale for combining these two treatments rests on the fact that Bumetanide is contraindicated in infancy because it is known to interfere with neuronal development when used long term. In contrast, the NSAID proposed in the second study has been given for decades to children with juvenile idiopathic arthritis from 6 months of age on, with no adverse effects on brain development. It is known to modulate chloride channels (see above) as well as potassium channels.⁴

In conclusion, I wish to extend their hypothesis based on the synergy of the two treatment approaches: (1) early treatment with NSAID can reduce early maladaptive behaviors that cause abnormal pruning of neurons in the cortical areas; (2) these children could subsequently benefit from Bumetanide, which would compensate for the primary ion channel defect, but could not reverse the secondary effect of abnormal pruning.

This hypothesis allows for a novel two-way interaction between behavior and molecular events. Traditionally, one assumes that molecular events determine behavior. The new hypothesis, based on human genetics, also allows for symptoms (such as the absence of social interactions, delayed speech onset and language development) during certain sensitive periods to change molecular events (pruning of neurons in areas required for normal development).

Therapeutic implications from the genetic analysis

Some of the therapies that Knut is proposing, based on the genetic analysis, have already been reviewed in this blog.  Some have not.  A few therapeutic ideas in this blog actually target genes Knut has identified, but not highlighted a therapy.

I will just review the drugs and genes that the above study highlights.

Benzodiazepines

Low dose clonazepam fits in this category.  We have the work of Professor Catterall to support its use.  At higher doses, benzodiazepines have different effects but use is associated with various troubling side effects.

Bumetanide

Bumetanide is at the core of my suggested therapy for classic autism or what Knut calls SDA (strict definition autism).  We have Ben-Ari to thank for this

Fenamates (ANO 2/4/7 & KCNMA1)

Here Knut is trying to target the ion channels expressed by the genes ANO 2/4/7 & KCNMA1. 

·        ANO 2/4/7 are calcium activated chloride channels. (CACCs)

·        KCNMA1 is a calcium activated potassium channel.  KCNMA1 encodes the ion channel K_Ca1.1, otherwise known as BK (big potassium).  This was the subject of post that I never got round to publishing.

  

Fenamates are an important group of clinically used non-steroidal anti-inflammatory drugs (NSAIDs), but they have other effects beyond being anti-inflammatory.  They act as CaCC inhibitors and also stimulate BKCa channel activity.

  

Fenamates stimulate BKCachannel osteoblast-like MG-63 cells activity in the human.

 “The fenamates can stimulate BKCa channel activity in a manner that seems to be independent of the action of these drugs on the prostaglandin pathway”

Molecular and functional significance of Ca2+-activated Cl− channels in pulmonary arterial smooth muscle

“Of this “first generation” of CaCC inhibitors, NFA (a fenamate called niflumic acid)  is the most potent blocker of these channels and the compound most frequently used to investigate the physiological role of CaCCs”

Choice of Fenamate

There are several fenamate-type NSAIDs, but one is a very well used generic drug, Mefenamic acid known as Ponstan, Ponalar, Ponstyl, Ponstel and other generic names.  It is even available as a syrup for children.

 It is not available in all countries.

Gabapentin

Gabapentin is used primarily to treat seizures and neuropathic pain. It is also commonly prescribed for many off-label uses, such as treatment of anxiety disorders, insomnia, and bipolar disorder.

Some people with autism are prescribed Gabapentin.  Some people suffer side effects and others do not.

If you have a dysfunction of voltage operated calcium channels, Gabapentin should help.

Memantine

This is all about modifying NMDA receptors.  Memantine is but one method.

http://epiphanyasd.blogspot.rs/2015/06/altered-homeostasis-in-autism-cl-k-ca2.html

Minocycline

Minocycline is an antibiotic with several little known extra properties.  In autism, we looked at its ability to reduce microglial activation and so improve autism.  A clinical trial showed that it did not help autism.

Minocycline also affects MMP-9.  MMP-9 is an enzyme found to be associated with numerous pathological processes, including cancer, immunologic and cardiovascular diseases.

High MMP-9 activity levels in fragile X syndrome are lowered by minocycline.

 “ The results of this study suggest that, in humans, activity levels of MMP-9 are lowered by minocycline and that, in some cases, changes in MMP-9 activity are positively associated with improvement based on clinical measures.”

So if you are treating a case of Fragile-X, or partial "Fragile-X-like" autism, better take note.

Rapamycin

Rapamycin and mTOR was the subject of the following post:

mTOR – Indirect inhibition, the Holy Grail for Life Extension and Perhaps Some Autism

Both too much and too little mTOR can occur in autism.

Conclusion

My conclusion is probably different to yours.

For me, it seems that all the pieces really are fitting together and so this blog on the cause and treatment of classic autism will eventually cover the current scientific knowledge, in its entirety.  No complex areas are off limits, because in the end they are not as complex as they seem, when you lift the veil of jargon and acronyms.

From the all-important therapeutic perspective, new insights from today’s post are:-

·        Those with a dysfunction of voltage operated calcium channels might want to give Gabapentin (Neurontin) a try.

·        The fenamate-type NSAID mefenamic acid,  widely known as Ponstan, really should be tested, either at home, or in a clinical trial.

This statistical analysis is based on “all autism”, so any one person would be highly unlikely to have all the mentioned dysfunctions.  These are the most common genetic dysfunctions and many can both hypo and hyper, as in the case of NMDA dysfunctions and indeed mTOR. 

In Knut’s chart, I would add a green line pointing to RAS and PTEN with the word Atorvastatin.  Baclofen would point to the growth factors.  Verapamil would point in multiple places.

The motto of University of Tübingen, where Knut originally comes from, is Attempto !  The Latin for "I dare".

This might be a useful motto for readers of this blog, and also a good tittle for a book on treating autism.