Ehlers-Danlos Syndrome and Autism
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A 2018 study found that a certain type of connective tissue cell called a myofibroblast was found in high quantities in the skin of people with hypermobility type EDS (hEDS), but not in other types of EDS. This cell is induced by inflammation and also by mast cells and has certain properties that could give rise to joint laxity. hEDS is also linked to a markedly increased risk of autism. Read on for links between these two conditions.
Autism & hEDS
The geneticist who diagnosed me with hypermobility type Ehlers-Danlos Syndrome (hEDS) happened to help collect DNA for genetic research. He supplied DNA samples for research into the origin of hEDS but also saw many autistic pediatric patients and collected samples from them for separate research into autism. He casually mentioned that many of his autistic pediatric patients had parents with hypermobile joints and many adults he diagnosed with hEDS had children with autism.
Indeed, a 2016 study published by Swedish and American researchers estimated that people with hEDS had 7.4 times the risk of being autistic.
In my family, we have many people who function well in many respects and are successful with their work, but who also have autistic traits. Hypermobility is rife on both sides of my family.
The Broad Autism Phenotype
The broad autism phenotype or BAP encompasses the idea that people, especially family members of autistic people, may themselves have milder autistic traits. This mild version of autism is also known as an intermediate phenotype.
In one study, parents of autistic children were assessed for six personality traits: aloof, anxious, hypersensitive, overly conscientious, rigid, and untactful. These are good questions to consider, but in my view, the broad autistic phenotype is broader than this. I think that somewhat close to this junction are the most of the people you know who are especially quirky, talented, creative or bright or anxious. Forty-year olds who dye their hair blue. People with an abiding interest in esoteric hobbies. Collectors of rocks, stamps, plants or other objects. Scientists who retain a childlike curiosity in their subject into old age.
There isn’t, in my view, a dividing point between who is part of the autistic phenotype and who is not. I think that the transition between clearly autistic and clearly not autistic is quite smooth, with no precipitous drop offs and quite broad, encompassing a large chunk of humanity. I think that some aspects of the broad autism phenotype are traits that we consider distinctively, wonderfully human.
A Broad Hypermobility Phenotype?
Something similar might be true for hEDS. hEDS may be the extreme end of a spectrum of hypermobilty that is so frequent and varied in the population that most manifestations of it go unremarked upon.
At work, I watch people’s hands. This is anecdote, but the people with hypermobile hands are largely women who are extra bright, extra anxious, extra quirky and/or extra rigid.
Suppose that hypermobility is in fact a spectrum condition. It is found frequently alongside autism, another spectrum condition. Autism is frequently idiopathic, meaning we don’t know the cause. I suspect that this true especially of people with high functioning autism. People like me.
hEDS is currently also idiopathic. Unlike other subtypes of EDS, we have never found a discrete genetic mutation directly affecting the synthesis of collagen or other connective tissue components. Because autism and hEDS co-occur so often, I think it’s reasonable to explore the idea that the same uknown thing potentially causes both and that this thing is perhaps quite common.
I think that this underlying process is in no way unusual. What is unusual is having a great deal of it going on, especially from before birth.
Myofibroblasts & Connective Tissue
An interesting study was published in 2018 about connective tissue in hEDS and in hypermobility spectrum disorders (HSD). HSD is the designation given to people who have hypermobility, but do not meet the current, stricter criteria for hEDS. The implication of the HDS diagnosis is that you have something categorically different than hEDS.
These researchers found that in skin tissue of both hEDS and HDS patients, you find an unusually high amount of a connective tissue cell type called a myofibroblast.
Myofibroblasts are a type of cell that is created to heal wounds. Inflammation stimulates the production of myofibroblasts.
The authors of the study that found the excess myofibroblasts in hEDS and HSD patients conclude that hEDS and HSD “are likely not distinct entities, but rather part of a phenotypic continuum characterized by a common altered tissue homeostasis and a chronic inflammatory condition.” In other words, hEDS and HSD are the same thing, just with different levels of severity, and the cause for both conditions is inflammation.
Ligament laxity features prominently in hEDS. Given that we have not found a gene that alters collagen production in hEDS, the cause of the laxity is mysterious.
Myofibroblasts are characteristic of a phase of healing in wounded ligaments called remodeling. The remodeling phase is known for ligament laxity because the tissue in the remodeling phase is not normal ligament tissue. At a microscopic level, it has a different structure and different physical properties than ligaments that had never been injured and undergone a healing process.
Perhaps the key to understanding connective tissue abnormalities in hEDS is to consider that rather than being synthesized incorrectly because of a faulty gene, what we are seeing is connective tissue that has undergone a very prolonged abnormal healing process, a process that, in the case of hEDS patients, has been ongoing since early life or even before birth.
Myofibroblasts are cells with a pronounced capacity to both break down and to build connective tissue, which is why they are so useful for the remodeling phase. Perhaps we can think of the connective tissue, like skin and ligaments, in hEDS as abnormal yet abundant, the subject of much breaking down, yet much building up.
A curious thing about people with hEDS and people with autism is that we have a tendency to look much younger than we are. This is a feature you will find discussed on internet forums and remarked upon by experts. People have joked that I might be a vampire.
A paper presented at the 2006 annual meeting for the American Society of Human Genetics noted that, in people with EDS, “Patients with a clinical history consistent with the hypermobile form were found to have a youthful appearance, a non-quantifiable finding.”
It is fairly common knowledge in hEDS communities that we look young. Austistic people are also rumored to look young. Tania Marshall, who writes about girls and women with autism, lists “looks younger than her years” as a component of a profile for female autistic people.
I bruise like a peach and get tendonitis easily, but my skin is exceptionally youthful. When I was twenty, I looked fifteen. When I was thirty, I looked eighteen. I got the first barest hint of fine wrinkles at about thirty-five. My skin is thick and rubbery, not prone to wrinkling or sagging.
A material called extracellular matrix is the defining component of connective tissue. Extracellular matrix is the structural material that gives connective tissue its particular properties: weak, strong, stiff or stretchy. Collagen is a key protein in the extracellular matrix. Myofibroblasts break down and also synthesize collagen and other extracellular matrix proteins. What if people with hEDS have been manufacturing collagen and other extracellular matrix components in abnormally large amounts since before we were born?
Out ligaments might not just be stretchy: they could actually be too long because our connective tissue synthesis was always a bit in excess of normal. My skin might appear not to age because the collagen has always been manufactured in slightly more than normal amounts.
The Cell Danger Response, Autism & hEDS
I want to make a few possible connections with autism. Dr. Robert Naviaux at University of California, San Diego has found that autistic people seem to have a chronic inflammatory process called the Cell Danger Response (CDR) occurring. The inflammatory process of the CDR is a normal response that is initiated by infection or tissue damage and is meant to clear away damaged parts and then trigger a healing response and a return to health. However, for reasons that aren’t entirely clear, people with autism get stuck in the middle of this process: healing does not occur and the bodywide inflammatory process does not stop.
Could what is happening in the connective tissue of people with hEDS be consistent with an unresolving CDR? Ligament healing concludes when myofibroblasts undergo apoptosis, a sort of cellular suicide, and are removed. Is the persistence of myofibroblasts what an unresolving cell danger response looks like in connective tissue?
Dr. Naviaux also researches myalgic encephalomyelitis (ME), also called chronic fatigue syndrome (CFS), and has discovered an unresolving CDR process in this illness as well. hEDS is extremely common in people with ME/CFS. I have hEDS, ME/CFS and autism.
A condition called mast cell activation syndrome (MCAS) is nearly ubiquitous in hEDS and is extremely common in ME/CFS. There is also evidence that mast cell activation syndrome may be related to autism. I have MCAS. It is a disorder in which a primitive immune cell called a mast cell activates too easily and too often, triggering symptoms associated with inflammation.
Two components of mast cells, tryptase and TGF-β1 are extremely effective in causing the creation of myofibroblasts. High levels of mast cells are a common finding in areas with high levels of myofibroblasts and suppressing mast cell activation prevents the production of myofibroblasts.
Unfettered myofibroblast activity will shoot past the normal remodeling process in healing tissue and promotes a process called fibrosis. Fibrosis is the production of excess amounts of extracellular matrix material that is disorganized in structure. I have often wondered if my youthful looking skin is actually a sign of mild, ongoing fibrosis.
Fibrosis is most commonly associated with scarring, but what might fibrosis look like taking place at modest levels across the entire body since before birth? It might like loose, abnormal ligaments and skin with abnormally high rates of collagen synthesis. Youthful-looking skin and hypermobile joints.
Alpha tryptasemia, a genetic condition associated with high circulating levels of tryptase has been shown to cause a condition in many people that includes joint hypermobility and resembles the multisystem constellation of maladies commonly seen in hEDS. I wonder if the hypermobilty aspect of alpha tryptasemia is caused by a tryptase-triggered proliferation of myofibroblasts in connective tissue.