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.
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 ZMYND11. She 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.