6. Hyperacusis
Hyperacusis developed a little after immunization at almost 2 1/2 years old.
Hyperacusis is the increased sensitivity to sound and a low tolerance for environmental noise. Definitions of hyperacusis can vary significantly; it can refer to normal noises being perceived as: loud, annoying, painful, fear-inducing, or a combination of those, and is often categorized into four subtypes: loudness, pain, annoyance, and fear.
At this point I think the ANK3 (paternal), SMARCA4 (maternal), and congenital pyloric stenosis (grandfather maternal) is screaming that we have a person who is susceptible to immunization adverse events.
I begin by looking for insight about postnatal development of the inner ear. But, this will steer me toward some conclusion about an autism lung difference that has held my curiosity for a very long time.
My own daughter's earliest childhood represents an experience where vestibular development remained wonderfully in tact, as evidenced by an early walking milestone. Yet, hyperacusis-like hyper-acute hearing ensued in her toddler stage. What might the concerns be within postnatal development for one such as her?
There were no outward morphologic signs with regard to her ear's appearance. That indicates embryogenesis was not affected.
Concerns would certainly encompass auditory mechanisms of the inner ear. A curiosity would involve, but not be limited to, hair cells and innervation development. How might auditory development be interrupted in a child with uncompromised vestibular development?
During embryonic development growth factors trigger the morphogenesis cascade. Inner ear signaling systems are said to be representative of morphogenesis processes of other epithelial tissues that undergo change. Experts say that correlations can be made between the developing inner ear and organs such as the lung.
Shh [sonic hedgehog] has a role in promoting otic fates; it restricts Wnt regulation signaling. That balance actually distinguishes the vestibular from the auditory cell types. Hh [hedgehog] is involved in innervation patterns for the inner ear. It drives posterior, but not ventral, otic fates. Wnt is required for patterning and differentiation of both the vestibulum and chochlea. The inner ear is a direct target of Wnt. A little about Wnt:
Recent studies have demonstrated a strong correlation and at times causative relationships between deregulated Wnt signaling and human diseases. Thus the investigation of Wnt signaling remains an important goal for dually understanding both the basic mechanism of embryonic development and human diseases.(1)
AND
[M]utations in Wnt signaling components including Frizzled and Dishevelled were found to randomize the orientation of epithelial structures including cuticle hairs and sensory bristles. Cells in the epithelia are known to possess a defined apical-basolateral polarity but in addition they are also polarized along the plane of the epithelial layer. This rigid organization governs the orientation of structures including orientation of hair follicles, sensory bristles and hexagonal array of the ommatidia in the eye.(1)
Embryogenesis' epithelium-intrinsic developmentally-regulated mechanisms govern neuron and hair cell production. Inhibition at developmental branch points direct unique variations within every stage.
It is said that Wnt proteins are unlikely to diffuse over long distances, even without FGF (fibroblast growth factor) localizing and limiting Wnt effects. FGF/WNT cross-talk mechanisms control a variety of biological processes and such signaling has just begun to be defined.
Researchers are busy learning how to use WNT:
It should be understood that Wnt expression can lead to induction of genes encoding other secreted factors... Whether cells respond to particular Wnt will depend on the receptors expressed, but there is little known about Wnt-receptor specificity. Most cells respond to Wnt signaling by an increase in beta-catenin... one can activate Wnt using overexpression constructs or beta-catenin...(3)
AND
The wnt-2 mRNA was also detected in human fetal lung fibroblast cell lines, where the mRNA levels were dramatically regulated by growth state as well as growth factor stimulation. In situ hybridization showed that, in fetal rat lung, wnt-2 mRNA expression is restricted to the mesenchyme... Based on the known properties of other wnt proteins, our data lead us to propose that wnt-2 may play a role in lung development by mediating intercellular interaction(s) between mesenchyme and epithelium.(3) [Human fetal lung fibroblasts cell lines include MRC-5 and WI38...and more by now]
On mRNA integration, and single gene disorder:
Protein synthesis takes place in two major processes. First, the DNA is transcribed into the mRNA in the nucleus followed by cytoplasmic mRNA translation into the protein.
Alteration in a single gene (i.e., a single-gene disorder) caused by a mutation in the gene’s DNA sequences leads to dysfunction of the gene. As a result, the protein the gene codes for is either altered or missing, which can result in serious complications in the human body.
Over the last few years, it has become apparent that single-gene disorders are far more numerous than previously assumed, and more than 1800 single-gene disorders have been identified. Moreover, single-gene disorders are associated with severe, early-onset conditions necessitating lifelong care.(4)
WNT is implicated in autism pathology: "The canonical Wnt pathway is involved in cell proliferation, differentiation and migration, especially during nervous system development." Even further, "Mounting data and evidence suggests that the Wnt pathway, a key regulator in the proliferation, differentiation, apoptosis, and embryonic development of the central nervous system, is involved in the pathogenesis of autism."(5)
What is more curious? The fact that "Deregulation of Wnt signaling might be a frequent pathomechanism leading to regressive brain illness... (6)
Not enough is known about "nonconformist" Wnt signaling:
Despite advances in the biomedical characterizations of Wnt proteins, many mysteries remain unsolved. In contrast to other developmental signaling molecules, such as fibroblast growth factors (FGF), transcriptional growth factors (TGFB), and Sonic Hedge Hog (Shh), Wnt proteins have not conformed to many standard methods of protein production, such as bacterial overexpression, and analysis-such as ligand-receptor binding assays. The reasons for their recalcitrant nature are likely a consequence of the complex set of postranslational modifications and poorly characterized processing enzymes.(7)
Researchers know how to produce a secondary embryogenesis axis. Over-expressing beta-catenin led to a duplication of a complete secondary axis. (8)
Spemann and Mangold found that cells from transplanted tissue "talked" with recipient cells to induce change in their behavior. Called induction, cells or tissue communicate with neighboring cells or tissues to alter development.(9)
"The phenomenon of embryonic induction was discovered in amphibians by Spemann (1918). He grafted a piece of the dorsal lip of blastopore of an early amphibian gastrula into the flank of another similar embryo at the same stage of development, and demonstrated formation of a secondary embryonic axis."(10)
Host vs graft:
Subsequently, Spemann and Mangold (1924) modified the experiment so that they were able to decide which of the tissues of this axis were formed from the host and which from the graft. This was done by taking the graft and the host from two separate amphibian species which differed from one another in their intracellular pigmentation. It was then possible to see which were host tissues and which were of the graft. They found that most of the neural tissues were formed from the host and that in general, there was a collaboration of host and graft tissues to form a unified axis. It became apparent that the graft had influenced the host tissues around it to form an embryo.(10)
Tissue transplant can result in an induction process, but also a instructive and/or permissive mutated collaboration passed from graft to host. Instructive interaction finds an inducing cell initiating gene expression to a responding cell, specifying differentiation.
Lung mesenchyme grafted on a portion of tracheal epithelium, denuded from its own mesenchyme, branches in a similar pattern as the distal lung.(10)
[As a reminder, I am considering the aforementioned correlations between ear (hyperacusis) and lung (autism lung doublets) development within epithelium-intrinsic factors. That brought me to considerations of Wnt proteins which are expressed in fetal lung fibroblasts. Wnt expression seems to be errant in an autism affected subset. If lung-mutated double branching can form in autism affected, there may be mutations that are hard to confirm for ear maturation in childhood. Epithelium intrinsic factors would likely be involved.]...
This is continued here for ear / lung considerations.
1. Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis. 2008;4(2):68‐75. doi:10.4161/org.4.2.5851
2. Levay-Young BK, Navre M. Growth and developmental regulation of wnt-2 (irp) gene in mesenchymal cells of fetal lung. Am J Physiol. 1992 Jun;262(6 Pt 1):L672-83.
3. Tatjana Michel, Hans-Peter Wendel, Stefanie Krajewski. Next-Generation Therapeutics: mRNA as a Novel Therapeutic Option for Single-Gene Disorders. May 18th 2016: DOI: 10.5772/62243
4. Zhang Y, Yuan X, Wang Z, Li R. The canonical Wnt signaling pathway in autism. CNS Neurol Disord Drug Targets. 2014;13(5):765-70
5. Berwick DC, Harvey K.J. Mol Cell Biol. The regulation and deregulation of Wnt signaling by PARK genes in health and disease. 2014 Feb;6(1):3-12. doi: 10.1093/jmcb/mjt037. Epub 2013 Oct 9
6. Willert K, Nusse R. Wnt proteins. Cold Spring Harb Perspect Biol. 2012 Sep 1;4(9):a007864. doi: 10.1101/cshperspect.a007864
7. Kelly GM, Erezyilmaz DF, Moon RT. Induction of a secondary embryonic axis in zebrafish occurs following the overexpression of beta-catenin. Mech Dev. 1995 Oct;53(2):261-73
8. Khan Academy. Frog development examples. Body axes. Gastrula stage. Available at: https://www.khanacademy.org/science/biology/developmental-biology/signaling-and-transcription-factors-in-development/a/frog-development-examples. Accessibility verified 4/28/20
9. Shodhganga. Chapter 2. https://shodhganga.inflibnet.ac.in/bitstream/10603/60498/6/06_chapter%202.pdf. Accessibility verified 4/28/20
10. Volckaert T, De Langhe SP. Wnt and FGF mediated epithelial-mesenchymal crosstalk during lung development. Dev Dyn. 2015;244(3):342‐366. doi:10.1002/dvdy.24234