Chronic Pain Partners is excited to share a significant breakthrough from the Norris Lab regarding hypermobile Ehlers-Danlos Syndrome (hEDS). After a long wait, the research, spearheaded by Dr. Cortney Gensemer, identifying a genetic variant associated with hEDS has been published, pinpointing mutations in the Kallikrein gene family.
The Kallikrein gene family, known for encoding enzymes that play crucial roles in various physiological processes, has now been linked to hEDS. These mutations are believed to disrupt normal connective tissue function, contributing to the symptoms of hEDS, such as joint hypermobility, chronic pain, and skin elasticity issues.
About Ehlers-Danlos Syndromes
The Ehlers-Danlos Syndromes are a group of hereditary connective tissue disorders characterized by symptoms like joint hypermobility, skin hyperextensibility, and tissue fragility. There are 13 recognized types of EDS, each with a distinct genetic cause except hEDS. Diagnosis typically involves a combination of clinical evaluation, family history, and genetic testing. However, diagnosis of hEDS so far was only possible via clinical examination based on a strict set of rules outlined by the 2017 New York classification.
Genes associated with hEDS
Historically, identifying the specific genetic mutations associated with hypermobile Ehlers-Danlos Syndrome (hEDS) has been challenging. Unlike the other subtypes of EDS, which have well-defined genetic markers, hEDS has been a mystery in terms of the genetic cause. Researchers, up to this day, feel strongly that there may be more than one gene associated with hEDS.
In the past, several genes were suspected to play a role in hEDS, including those related to collagen synthesis and processing due to the connective tissue abnormalities observed in patients. Some of these genes included Tenascin-X-B, a gene encoding the Tenascin-X protein, an extracellular matrix protein involved in connective tissue structure, which was another candidate. Heterozygous Mutations in TNXB have previously been linked to hEDS (not in the recent classification), while homozygous mutations are linked to classical-like EDS. Additionally, a recent publication by scientists at Tulane University proposed a possible new mechanism behind hypermobility: folate dependency. The researchers hypothesize that MTHFR mutations may lead to or contribute to a form of hypermobile EDS, and researchers from Poland released a preprint of research that found the MIA3 gene to cause some of the hEDS cases. There have been some more papers over the years hypothesizing one or another gene for a small number of hEDS cases.
Norris Lab Study Design
The study by the Norris Lab, which was released as a preprint with no peer-review process, involved extensive genetic analysis of individuals diagnosed with hEDS. Researchers started with one family with hEDS and identified a specific mutation in the Kallikrein gene family. Additionally, they searched for pathological mutations in hEDS patients via whole exome sequencing and found 65 patients out of the 197 with variants in the Kallikrein gene family. Knock-in mice, meaning genetically engineered mice in which that specific DNA sequence is inserted into the genome – in this case, the Kallikrein gene mutation – showed clinical signs of hEDS as well, proving those mutations causative for EDS.
This discovery is a monumental step forward for the hEDS community, offering a specific genetic marker for a subtype of Ehlers-Danlos Syndrome that had previously eluded genetic identification. The findings promise to enhance diagnostic accuracy and open new avenues for targeted therapies, providing much-needed validation for patients who have long struggled with misdiagnosis and misunderstood symptoms.
For more detailed information, you can access the complete study here.
Thank you for the aticle, just so no one gets confused, the study authors didn’t find 197 patients with variants like the above article states, rather it was 65 patients out of the 197 patient co-hort;; “WES was performed on 197 clinically diagnosed, unrelated hEDS patients and filtered for KLK variants with MAFs less than 0.01 (<1%) in gnomAD. A total of 76 variants were identified, with 48 being unique in the cohort and 65 patients having at least one rare variant in a KLK gene (32.8%) (Figure S4).”
Hi Julia, thanks for pointing this out. This was a mistake on our end and it has been fixed now. Best, Karina
Glad to hear that there may be a more definitive way to tell if someone has hEDS than the current criteria!
Hi Old Texan, yes, it’s definitely giving hope for many patients, but I want to re-iterate that this is only one gene of likely several that are involved in hEDS. So this may give the option of genetic testing to some people with hEDS but not all. Best, Karina
I suspect that I have hEDS but am getting bogged down in the process of trying to figure out how to have it diagnosed. This is incredibly exciting that there may be a definitive way to arrive at a diagnosis! The people that I know that have hEDS or suspect that they do have a horrible time getting diagnosed and have to deal with a lot of doubt, disbelief, and dismissal from family, friends, and medical professionals because hEDS is poorly understood. I hope this will come to some significant changes and relief for those suffering with hEDS. If there was less time spent trying to diagnose, more time can be spent managing treatment.
Hi Katy, yes, it’s definitely giving hope for many patients, but I want to re-iterate that this is only one gene of likely several that are involved in hEDS. So this may give the option of genetic testing to some people with hEDS but not all. Best, Karina
This is good news and I hope can lead to definitive testing and access to better care
I am very much feeling hopeful by continued research on hEDS. I am now 62 years old. Starting in 2013 I started requiring surgeries to joints affected by hEDS. First it was my left shoulder which has always been exceptionally loose, I had a SLAP tear and partial tears to several tendons. Almost exactly a year later I needed a second surgery for another SLAP tear in the same tear. This time they did an open shoulder surgery and tightened the capsule that holds the shoulder together. Here I am ten years later with even more tears and needing surgery once again.
In the meantime I had a SLAP tear in my right hip that was surgically repaired. I broke my wrist 1 1/2 years ago and tendons continue to rupture requiring tendon transfers. I am headed to my 5th surgery for yet another tendon transfer. I am preparing for a surgery in July to repair torn tendons in my hip, there is also a SLAP tear in that joint but since I have developed mild arthritis from bone on bone damage they can’t fix it until it gets to the point requiring a full hip replacement.
Had ortho Drs been educated on the reality of hEDS and its effect on the soft tissues in joints perhaps they wouldn’t wait so long to do repairs before they are very large and I am completely disabled by pain. The go to in ortho is an xray. If there’s nothing on the xray then your sent away for PT and pain injections. It takes years to get them to do an MRI.
I think an early diagnosis of hEDS would prevent needing serial surgeries later in life. By the time the send you to PT the damage is done and by then PT is only going to make the damage worse. If the PT is too painful to do then you’re labeled “noncompliant” and get treated badly.
I do think my multiple ortho surgeons and pain mgmt Dr are beginning to believe me when I told them all that the plethora of joint damage and dysfunction has been a lifetime of undiagnosed hEDS.
I am INCREDIBLY thankful research has continued to discover a way to definitively prove hEDS. However, I wish that the research would be printed in peer reviewed publications prompting others to replicate results and giving the studies legitimacy.
Hi Lesa, thanks for sharing part of your journey with us. And yes, we also hope this will lead to improved diagnostics and care in the long run. Best, Karina
Such exciting progress. Sorry if this has been addressed, but do you know if study participants will be notified if they are one of the 65 with the variants? Thanks for the update on the study!
Hi Sarah, you’d have to contact the study coordinators regarding this questions. We are only sharing the news. Best, Karina