Newly Found vEDS Mutation Causes Severe Joint, Muscle Involvement

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A new mutation in the most common gene causing vascular Ehlers–Danlos syndrome (vEDS) — COL3A1 — was found to lead to severe involvement of the joints and muscles, a case study reported.

The findings provide insight into mutations causing the disease and expand clinicians’ understanding of “the phenotypic spectrum of vEDS,” according to the researchers.

“The reaching of a definite diagnosis is very important for patients, particularly those with atypical clinical presentations, to avoid inappropriate therapies and to establish a correct follow-up,” the team wrote, noting this patient showed “predominant and severe musculoskeletal involvement.”

“Our findings provide insight into genetic variants and clinical expression [activity] of vEDS, broadening the clinical scenario of the syndrome,” they wrote.

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The case study, “A novel mutation in COL3A1 associates to vascular Ehlers–Danlos syndrome with predominant musculoskeletal involvement,” by a team of researchers in Italy, was published in the journal Molecular Genetics & Genomic Medicine.

The symptoms of vEDS are caused by defects in collagen, a protein in the connective tissue that supports and holds the body’s tissues and organs together. Most people with vEDS carry mutations in COL3A1, the gene encoding part of type 3 collagen.

Considered the most severe type of Ehlers–Danlos syndrome, vEDS is characterized by thin and translucent skin that bruises easily, and fragile blood vessels, muscles, and internal organs. However, its clinical presentation varies widely.

Therefore, “the diagnosis of vEDS may be challenging,” the researchers wrote, noting it often may involve more than one diagnostic method.

Now, the team reported the case of a 35-year-old man with a new disease-causing mutation in COL3A1. The man had a 10-year history of knee sprains, thigh muscle rupture, shoulder weakness, and generalized muscle pain. He was taller and more slender than his parents, and had gone through a growth spurt at the age of 16, gaining 22 cm (about 8.7 inches) in height in one year, from 160 cm to 182 cm (5.25 feet to just under 6 feet tall).

At his admission to the hospital, a physical exam revealed pectus excavatum or a deformity of the chest wall, flat feet, and stretch marks on the hips and thighs.

After deeming Marfan syndrome (another disorder of connective tissue) unlikely and ruling out pituitary adenoma — a benign tumor of the pituitary gland that could have caused the growth spurt — doctors looked more closely at the heart and blood vessels.

An electrocardiogram, a test that records the electrical signals from the heart to see how well it is working, revealed a decrease in the heart’s ability to conduct electrical signals, while an echocardiogram — which uses sound waves to create a moving image of the heart — revealed mitral regurgitation, or a backward flow of blood in the heart.

Shortly after admission, the man started experiencing episodes of paroxysmal hypertension, or sudden increases in blood pressure. Blood pressure dropped at night — following a so-called dipper pattern that could not be controlled using antihypertensive medication.

Although the man had no family history of connective tissue disorders, the doctors suspected a disease related to collagen that also involved the heart.

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Genetic testing for a panel of genes associated with inherited heart diseases revealed a new mutation in COL3A1, known as c.3478 A to G, in which A stands for adenine and G for guanine, both building blocks of DNA. This mutation had never been reported and its clinical relevance was unclear.

To know more, the researchers took a sample of the man’s skin and tested its fibroblasts — the most common type of cell of connective tissue. Collagen is composed of three helix-shaped chains bundled around each other. Notably, the patient’s fibroblasts produced less of one of its chains than did control fibroblasts, supporting the role of the newly found mutation as likely disease-causing.

“Our findings broaden the phenotypic spectrum [range of manifestations] of vEDS, reporting a patient with predominant musculoskeletal and very mild cardiac involvement,” the researchers wrote.

The team said that having a definite diagnosis is important for ensuring that patients — especially ones, as in this case, with rare or new mutations — are treated with appropriate therapies. They also noted the relevance of genetic counseling for follow-on care.