Why Do the Subtypes of EDS Have Different Symptoms?

f they all impact connective tissue, why are they so different? And why do some people with the same subtype still have different symptoms?

The Ehlers-Danlos Syndromes (EDS) encompass a group of connective tissue disorders that vary widely in their symptoms and severity. If they all impact connective tissue, why are they so different? And why do some people with the same subtype still have different symptoms? There are 14 different subtypes of the Ehlers-Danlos syndromes caused by mutations in more than 20 different genes. While most subtypes have general features involving some degree of joint hypermobility and tissue fragility, they can vary in their presentation. Let’s talk about why!

1. Genetic Heterogeneity: Many Genes Responsible for EDS Subtypes Are Different

There is genetic heterogeneity in EDS, meaning that different subtypes of EDS are linked to mutations in different genes. These genes are crucial as they encode proteins that play a vital role in the structure and function of connective tissues.

Each of these genes has a unique role in connective tissue maintenance and function, which explains the different symptoms observed across EDS subtypes.

2. Gene Expression: The Tissues That Genes Are Expressed In Can Correlate to Symptoms

Even though all your cells contain the same DNA, different genes are expressed by different cell types in various tissues. This pattern of gene expression across different tissues helps explain the varied symptoms observed in EDS.

For example, kyphoscoliotic EDS (kEDS) can be caused by mutations in the PLOD1 gene. In the image, you can see higher gene expression (dark purple) in the spine of the PLOD1 embryo, which correlates with the spinal defects that occur in kEDS. Similarly, C1S, is highly expressed in developing craniofacial structures and may help explain some of the phenotypes related to periodontal EDS (pEDS). However, expression alone does not drive symptoms experienced by patients with different types of EDS. There are a lot of other factors that contribute to disease presentation.

Gensemer C., et al. Hypermobile Ehlers-Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes. Dev Dyn. 2021;250(3):318-344. doi:10.1002/dvdy.220

3. The Type of Mutation Matters: The Same Gene Can Cause Different Types of EDS!

Why can individuals with different mutations in the same gene have different types of EDS? This phenomenon occurs with other genetic conditions too. The specific details of the mutation—such as whether it's a frameshift, insertion/deletion (indel), or splice-site mutation—and its location within the protein structure significantly impact its pathogenic potential.

Types of Mutations:

• Frameshift Mutations: Can disrupt the entire protein’s function, often leading to severe manifestations.

• Indel or Splice-Site Mutations: Might only affect specific parts of a protein or alter its expression, possibly in certain tissues only.

• Missense Mutations: Depending on the location, could impact a critical aspect of the protein needed for its function.

• Start loss, Start gain, stop loss, stop gain: these mutations can impact the start or stop site of protein production, often changing the structure and/or size of a protein

Example: Mutations in the COL1A1 gene are associated with different types of EDS. A pathogenic splice-site variant in COL1A1 can lead to Arthrochalasia EDS (aEDS), characterized by joint hypermobility and skin issues, while a pathogenic missense mutation in the same gene can lead to Classical EDS (cEDS) with vascular fragility.

Similarly, in other conditions some genes are associated with many different diseases! It is not as simple as one gene, one health condition.

On top of all of this, some types of EDS require two pathogenic mutations (recessive) while others require only one (dominant). With recessive types of EDS, it is possible to have one copy of a mutation and only be a carrier without symptoms.

This intricate interplay between the specific type of mutation (genotype) and the resulting symptoms (phenotype) highlights the complexity of EDS. It underscores the importance of comprehensive genetic analyses in clinical diagnosis and management.

4. Beyond Genetics: Environmental, Hormonal, and Epigenetic Factors

Even with the same genetic mutation, symptom presentation can vary widely among individuals due to non-genetic factors.

Environmental Influences:

• Lifestyle factors such as physical activity, joint stress, sleep, and nutrition can influence the severity and progression of EDS symptoms. For instance, excessive joint use can exacerbate symptoms in hypermobile EDS (hEDS), and high-impact sports may worsen symptoms for some patients.

Epigenetic Modifications:

• These are changes in gene expression without altering the DNA sequence itself. Environmental factors such as stress, diet, and exposure to toxins can trigger epigenetic changes, potentially influencing the severity and onset of symptoms.

Hormonal Changes:

• Hormonal fluctuations during puberty, pregnancy, or menopause can impact EDS symptoms, often exacerbating joint instability or skin elasticity issues. Hormones like estrogen and progesterone can affect connective tissue, making symptoms more pronounced at different life stages.

In some diseases, there can be additional mutations in other genes other than the pathogenic one for the disease, that can modulate severity.

There are certainly other factors that can influence EDS that we don’t fully understand yet. Research is ongoing to uncover the full extent of how these factors interact with genetic predispositions to shape the diverse clinical presentations seen in EDS.