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.