Genetic Factors In Fibromuscular Dysplasia

Overview

Fibromuscular Dysplasia (FMD) is a condition that enlarges the arterial walls which results in the narrowing of blood vessels. Although incidents of FMD with severe physical consequences are rare, those that do develop into clinically significant conditions cause a range of life-threatening cardiovascular conditions, including hypertension, aneurysm, and arterial dissection. Due to its low prevalence, there is insufficient data to make conclusive statements regarding its prognosis, risk factors, and disease mechanism. However, recent advances in genomic analysis have revealed that some genes that contribute to the onset of multiple cardiovascular diseases, also increase the probability of developing FMD. Such findings are projected to be the foundation towards a more clarified understanding of FMD.

Defining FMD

FMD is a non-inflammatory and non-atherosclerotic disease, meaning there is no involvement of the immune system or build-up of plaque in developing the disease.^１ It is simply caused by the enlargement of vessel walls due to irregular growth. This results in the lumen of arteries being narrowed down, which is a condition known as stenosis. The disorganised systemic structure of blood vessels gives off an appearance coined as a “string of beads”, which is typically found in patients with FMD. Such abnormalities develop mostly in the arteries that carry blood to the kidney (renal arteries) and the brain (carotid arteries). 

Classification

FMD can be broadly classified into three subtypes –

• Medial FMD – 85% of total cases of FMD. In medial FMD alternating ridges of collagen and loss of elasticity are observed, which results in the formation of a “string of beads”. The internal elastic lamina is unaffected.
• Intimal FMD – 5% to 10% of all cases. There is deposition of collagen at the internal elastic lamina, resulting in fragmentation.
• Adventitial FMD – Only 1% of all cases. There is dense deposition of collagen at the adventitia which narrows down the artery.
• Further variants can be classified as either focal or multifocal FMD depending on the number and length of stenosis observed.

Figure 1 – Basic structure of the artery (Made with BioRender)

Sex difference and prevalence

The female-to-male ratio of the disease is 9:1, with mostly women during their child-bearing age being affected.² According to the UK Kidney Association, the prevalence of FMD is as low as 0.4%, while contrastingly, around 5% of potential kidney donors are incidentally diagnosed with FMD during testing. This means that FMD is more likely to be found by chance, rather than patients recognising it themselves. As evident from this, FMD is a highly asymptomatic condition, with only less than 1:1000 cases being clinically significant. However, this small pool of cases represents patients who developed a range of life-threatening cardiovascular abnormalities from FMD, including renovascular hypertension, ischemic nephropathy stroke, and renal artery aneurysms. 

Symptoms and complications

Although FMD lacks any apparent symptoms, patients with carotid FMD may notice the following 

• Dizziness
• Headache
• Neck pain
• Tinnitus (ringing sound in the ear)
• Changes in vision
• Speaking ability
• Weakened limbs
• Fatigue

Complications of FMD that develop into severe cardiovascular conditions include stroke, arterial dissection or aneurysm, which is the bulging/ballooning of an artery. Adding on to this, treatment of FMD generally involves highly invasive approaches such as angioplasty or reconstructive surgery, which together with its symptoms, makes the treatment of FMD highly problematic.

Causes of FMD

Non-genetic factors

Despite efforts, many unelucidated elements remain in research for FMD. One of these includes its precise disease mechanism. The higher incidence in women suggests a possible role of female hormones, although the use of birth control pills seems to have no significant effect on FMD (Mayo Clinic). There are suggestions that mechanical stress may increase the vulnerability of arteries which can lead to arterial dissection. 

Genetic factors

Role of novel genomic techniques in studying FMD

It is found that 4% of patients with FMD also share the disease with a family member (UK Kidney Association). Moreover, studies have revealed that FMD is an autosomal dominant disease, although with variable penetrance. This means that individuals with the genetic mutation that is thought to have the disease, may not necessarily develop the disease.³

Such foundations have provided reasonable evidence for researchers to accept the potential role of genetics in the development of FMD. Novel genomic techniques, including genome-wide association sequencing (GWAS), have revolutionised the field of genomic analysis of diseases, and the study of FMD has certainly received benefits too. GWAS was used to identify 4 genes that are closely associated with FMD – PHACTR1, LRP1, ATP2B1 and LIMA1.⁴ PTGIR and COL5A1 have gathered interest as potential genetic risk too.⁵ Such genes are involved in molecular functions of actin cytoskeleton, intracellular calcium levels, and vascular contraction, which, explains their contribution to the onset of other cardiovascular diseases too, including coronary artery disease (CAD), hypertension, and aneurysm.⁴ It is also thought that they contribute to pathophysiological molecular interactions including the TGF-beta signalling pathway, PDGF receptor beta and CD-2 associated protein, while PTGIR and COL5A1 have gathered interest as a potential genetic risk too.⁵ Despite this, the exact effect of mutation in these genes remains unanswered as of today.

The PHACTR1 Gene

Taking one of the genes as an example, mutation at the PHACTR1 gene has been identified as a genetic risk of FMD.⁵ It is also a gene that codes for a regulatory protein that controls the endothelin-1 (EDN-1) activity on chromosome 6.⁶ EDN-1 is known to be a key controller of blood pressure and vasoconstriction, while PHACTR1 is responsible for tubule formation and endothelial survival, corroborating its role in a wide range of cardiovascular abnormalities.^{7, 8} With that said, it is still unclear how such genetic mutations trigger precise changes in vessel structure that lead to FMB. Further advancements in genomic/proteomic study, as well as improved imaging techniques and biomarkers, would be a significant step toward revealing the full picture of FMD.

Management of disease

Diagnosis

As mentioned previously, many cases of FMD are found incidentally. Clinics may ask for testing for their family member if a person is diagnosed with FMD, due to its inconspicuous and asymptomatic nature. Tests used for diagnosis of FMD include:

• Blood test
• Angiogram
• Imaging techniques such as magnetic resonance (MR) or computerised tomography (CT)

FMD is a systemic disease, which can be mistaken for vasculitis, another cardiovascular disease. Since both diseases can develop into severe conditions, but require distinctive medical interventions, distinguishing the two conditions is crucial.⁹

Treatment and prognosis

Doctors may consider angioplasty to restore vessel size and allow normal blood flow. This is achieved by inserting small tubes known as stents into the artery (National Institute of Neurological Disorders and Stroke). Other than invasive surgical procedures, doctors may consider less aggressive interventions in an attempt to manage the disease or prevent more serious conditions such as aneurysm and stroke. This can include the usage of anti-hypertensive medication (e.g. Renin Angiotensin blockade) or anti-platelets (UK Kidney Association). Due to its invasive complexion, surgical interventions are only conducted for symptomatic patients, or when antihypertensive drugs are ineffective.¹⁰

Prognosis of FMD is considered to be difficult due to the lack of data available, although carotid FMD in youth is considered to be more serious as it can affect the function of cranial nerves.^１ To prepare and predict the potential aggravation of FMD, it is important for doctors and clinics to constantly monitor the patient's condition.

Summary

Many questions remain regarding the causes and pathophysiology of FMD, and despite its benign nature, the rare cases with devastating consequences must not be ignored. Since serious cases require invasive interventions, early diagnosis and long-term management are key to avoiding such scenarios. Advancements in genomic analysis have been a major contributor to revealing the genetic risk factors of the disease, which allows incidental diagnosis of FMD within a family. These have also helped to illustrate hypothetical pathophysiologies based on the role of the affected genes, for example, the role of actin cytoskeleton in vessel function. 

Frequently asked questions

How long can people live with FMD?

There is no evidence that people with FMD have shorter life expectancies – except for those who develop more serious cardiovascular diseases. It is common for people with FMD to live as long as healthy people

Can I get disability insurance for FMD?

If symptoms of FMD are severe and affect your daily life, it is possible to get appropriate insurance or support.

What diet is good for FMD?

There is a lack of scientific evidence about the effect of diet on FMD. However, having a well-balanced, vegetable-rich, and low-sodium diet would help prevent the development of hypertension and achieve overall good cardiovascular health.