People With Joint Hypermobility Are Much More Likely To Have Autism. Why?
Exploring The Connection Could Lead To Better Understanding For These Conditions and Other Related Conditions
I have spent most of my life disabled from four different conditions. While this has been personally devastating to me, that is not what this article is about. The story of my illnesses is much bigger than me. The same pattern of conditions repeats over and over again in people across the globe and we will not understand their origin unless we start to evaluate them as a pattern. This is the beginning of a story about connections and about why people like me are sick.
I have:
- Ehlers-Danlos syndrome — hypermobility subtype (hEDS)
- High-functioning autism
- Mast cell activation syndrome (MCAS)
- Myalgic Encephalomyelitis (also known as chronic fatigue syndrome or ME/CFS)
Hypermobility type Ehlers-Danlos Syndrome (hEDS) is a connective tissue disorder that makes my joints bendier than normal. I’ve had it since birth. I’ve had ME/CFS for over twenty years since I was a teenager. People with ME/CFS suffer from chronic exhaustion and exercise intolerance.
MCAS came on at precisely the same time as the ME/CFS. MCAS is caused by an overreactive type of immune cell called a mast. It causes strange reactions to foods, mold, heat, chemicals and other things and chronic inflammatory symptoms.
I am a woman and thought that I was merely autism-y or autism-ish until I was actually diagnosed with autism in my mid-thirties. Like most people, I had always thought that autism was for boys.
No one knows the cause of hypermobility type EDS, ME/CFS, high-functioning autism, or MCAS. People with these conditions do not get effective treatment. Many do not even get diagnosed. But a huge proportion of people with ME/CFS also have hypermobility type Ehlers-Danlos syndrome and MCAS. They form a distinct and pitifully researched cluster.
Even less recognized is how very often autism and hypermobility type EDS occur together in the same individuals.
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. Autism and hEDS co-occur in families.
Indeed, autism and hEDS occur much more often than expected in the same individuals. 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. We look fairly normal on the surface but if you dig a little bit deeper, many of us are kind of odd, possessed of a peculiar profile of talents and slight learning or social disabilities.
Hypermobility is rife on both sides of my family. I’m the second person with ME/CFS. Food allergies are a sign of mast cell activation disorder. None of my grandparents have food allergies. My parents have mild food allergies. On my mother’s side of the family, at least seven out of ten grandchildren have food allergies, including every last girl. Whatever is going on, it’s getting worse.
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. A phenotype is a collection of observable signs of someone’s genetic or environmental input, like blue eyes or a tendency towards anxiety.
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 I think 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. Plus a collection of people who are bright but inexplicably difficult to be around. 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.
I think the important thing about the broad autism phenotype is that it is in fact broad enough to incorporate a sizable chunk of humanity. At some point on the autistic spectrum, traits that we would consider notably odd gradually fade into traits we would consider merely quirky or even beneficial. At some undefined point, the autistic spectrum meets up with the neurotypical spectrum.
If the autistic spectrum is as broad as I think it is, the cause of it must be quite common. Something that is not present or absent, but present to varying degrees in a lot of people. The cause itself is present along a spectrum of severity.
A Broad Hypermobility Phenotype?
There are thirteen types of Ehlers-Danlos syndrome. All types involve joint hypermobility. hEDS stands out as having no known genetic cause. Other types of Ehlers-Danlos syndrome all have known, discrete genetic mutations that affect the synthesis of connective tissue. Connective tissue includes the skin, ligaments and tendons in the body.
I think we have not found a genetic mutation for hEDS because there is not one in the same way that there is not a single genetic mutation for most people who have autism. We don’t know why most autistic people are autistic. We think it is due to an array of genes, all of which are also shared in different combinations by non-autistic people, coupled with incompletely understood environmental factors.
What if hypermobility type EDS is the extreme end of a spectrum of hypermobility that is so frequent and varied in the population that most manifestations of it go unremarked upon? This would be analagous to how autism may be an extreme manifestation of psychological and cognitive traits that are relatively common in humans.
At work, I watch people’s hands. This is anecdata, but the people with double-jointed fingers are largely women who are extra bright, extra anxious, extra quirky and/or extra rigid. It is primarily women who exhibit hypermobility type EDS, which suggests that there is something about female connective tissue that is more susceptible to developing joint laxity than male connective tissue.
This casual type of hypermobility is not part of any formal testing for EDS and is so common it goes generally unnoticed. And yet most of the people I know with food allergies, are women who have markedly hypermobile hands with double-jointed fingers.
As with autism, there may be a broad spectrum phenotype associated with hypermobility, signs of which are ignored because they are so commonplace.
The co-occurrence of autism and hypermobility and their frequency in the population suggest an underlying cause that is quite common. The pattern does not fit a gene you either have or don’t have, it fits the pattern of some factor you can either have a little of or a great deal of.
Myofibroblasts & Connective Tissue
From here to the end of the article, I am going to put forth a hypothesis about some ways in which these conditions may be connected.
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 hypermobility type EDS. The implication of the separate HSD and hypermobility type EDS diagnoses is that they are two different conditions.
These researchers looked at skin tissue, which the researchers understand to be generally representative of connective tissue in the body. In both hEDS and HDS patients, you find an unusually high amount of a connective tissue cell type called a myofibroblast. They did not find this cell in high quantities in other types of EDS, types cause by genetic defects in the synthesis of collagen.
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, or looseness, features prominently in hEDS. It is why our joints are hypermobile. 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.
Remodeling connective tissue is a little like remodeling your house: you break down a wall and build new walls. Myofibroblasts are cells with a pronounced capacity to both break down and to build connective tissue, which is why they are present in the remodeling phase of healing. They break down tissue that has been injured so that it can be removed and they lay down fresh new connective tissue.
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 process that is related both to chronic inflammation and to chronic attempts at healing. This is a process that, in the case of hEDS patients, may have been ongoing since early life or even before birth.
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. In my late thirties, I look nearly twenty years young than I am.
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.”
Incidentally, autistic 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. The people that Tania Marshall is talking about are women and girls with high functioning autism, a type of autism that nearly always falls into the category of having no known cause.
Perhaps we can think of the connective tissue, such as the skin and ligaments in hEDS as abnormal yet abundant, the subject of much breaking down, yet much building up.
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 the 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 cell danger response begins with an inflammatory phase that is initiated by infection, tissue damage or other signs of cellular danger and is meant to clear away damaged parts or pathogens and then trigger a healing response and a return to health. It’s a totally normal process in the body that happens every time you have a minor injury or get a cold.
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 and attempts to heal do not stop.
Dr. Naviaux, in keeping with this theory, conducted a small trial with autistic boys using a drug called suramin to block the continuation of the cell danger response. Parents reported remarkable gains in language and social capabilities in their sons shortly after the administration of the drug and the benefits lasted for weeks. I encourage you to read the parents’ statements here. They are fascinating.
Interestingly, Dr. Naviaux has found a similar cell danger response process occurring in myalgic encephalomyelitis/chronic fatigue syndrome as well, suggesting that the cell danger response might be a commonality across more than one of my conditions.
Could the cell danger response also relate to hypermobility EDS? Is hED what people can look like when the cell danger response has been occurring across the entire body since early life?
The process of ligament repair begins with inflammation that recruits agents that repair the damaged tissue and ends in healing. In short, what happens in damaged ligaments that heal is a cell danger response that has resolved. Ligament healing concludes when myofibroblasts commit cellular suicide and are cleared away. In connective tissue, does a persistent cell danger response look like the persistence of the healing cell: the myofibroblast? Is ligament tissue in hEDS stuck in the middle of the cell danger response in the same way that autistic people are stuck in the cell danger response?
Mast Cells
Mast cells are primitive immune cells that carry around a veritable Swiss army knife of chemicals that they release when stimulated. This is why MCAS makes people so sick. Mast cells release a huge variety of inflammatory molecules. They are deeply involved in the process of healing as well as in the cell danger response.
Mast cells have been linked to autistic symptoms. My mast cell reaction without a doubt trigger autistic symptoms in me.
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.
Mast cell activity, therefore, may very well cause hypermobility type EDS. It is suspicious that mast cell activation disorder seems nearly ubiquitous among hEDS patients.
Unfettered myofibroblast activity will shoot past the normal remodeling process in healing tissue and promote a process called fibrosis. Fibrosis is the production of excess amounts of connective tissue material that is disorganized in structure. The connective tissue in hEDS patients 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.
Conclusion
Medicine has a long history of success in discovering the causes and treatments for various illnesses. A crucial approach has been to separate people into those who do and those who do not have a given illness. You either have the H5N1 influenza virus or you do not. You have autoantibodies that cause rheumatoid arthritis or you do not. You have cancer or you do not. Defining who has the illness allows researchers to discover the cause of the illness and its treatment as efficiently as possible.
This approach has fallen flat with autism, hEDS, MCAS and ME/CFS. We are still arguing over who does and who does not have these and we are missing the big picture.
In order to understand these conditions as quickly as possible and develop treatments for those that desperately need them, we must understand why these conditions are connected. Increasing research into ME/CFS and hEDS could help increase our knowledge of autism. Conversely, we should be considering how research findings in autism could shed light on ME/CFS, MCAS and hEDS.
Postscript: Neurodiversity
I know that many people have autism and are proud of it and like themselves just how they are. Many people do not think about autism as an illness. I support anyone who does not wish to have treatment for their autism and acknowledge that autism often comes with many unique gifts. My personal belief is that the gifts are hardwired and many of the difficult things about autism like anxiety and difficulty understanding other people are not hardwired. I believe that when autism is treated we won’t fundamentally change anyone’s identity. We will simply relieve suffering and allow autistic people to make more complete use of their gifts.
