Introduction

Marfan syndrome is a hereditary disease in which the proteins responsible for constructing healthy connective tissue undergo genetic changes. This condition can affect individuals of all ages, genders, races, and backgrounds. Marfan syndrome follows an autosomal dominant pattern, meaning it can be inherited if even just one parent carries the syndrome. The genetic mutation responsible for Marfan syndrome is located in a gene called Fibrillin-1 (FBN1). Mutations in the FBN1 gene can lead to complications in the development of connective tissues, which are the fibers that provide support and anchor various organs and structures in the body. Marfan syndrome can potentially damage blood vessels, the heart, eyes, skin, lungs, as well as bones in the hips, spine, feet, and ribcage.

Clinical symptoms: Individuals with Marfan syndrome often exhibit distinctive physical characteristics, including unusual height and slenderness, disproportionately long limbs, fingers, and toes. They may also present with a breastbone that either protrudes outward or dips inward, a high-arched palate, and dental crowding. Additionally, clinical features of Marfan syndrome can encompass heart murmurs, severe nearsightedness, scoliosis, and flat feet.

The severity of Marfan syndrome can vary significantly among affected individuals, with some experiencing mild effects and others facing life-threatening complications, such as aortic aneurysms. An aortic aneurysm can result in the weakening and tearing of the aortic wall, potentially leading to blood leakage from the heart.

Symptom of longer fingers Source

Tests available

Marfan syndrome is a rather challenging disease to diagnose because of the large spectrum that exists within the disease, and other connective tissue disorders have similar symptoms and signs. In some cases, a person may have some features of Marfan syndrome, but not enough to be clinically diagnosed with the disease.

To diagnose Marfan syndrome, there are many tests including physical exams, eye exams, echocardiogram, and genetic testing.

Treatment available

Currently, there is no cure for Marfan syndrome, primarily due to the wide range of symptoms that patients may experience. However, various medications and therapies are available for patients to choose from, depending on the specific areas of their body affected by the syndrome. With modern treatments, individuals with Marfan syndrome can now anticipate a more typical lifespan compared to those in the past who often faced shorter life expectancies.

Doctors commonly prescribe medications such as blood pressure-lowering drugs to prevent the enlargement of the aorta and reduce the risk of rupture and dissection. Vision problems may be addressed with therapies like contact lenses or glasses. In cases where symptoms necessitate surgical intervention, there are numerous surgical and other medical procedures available to patients. These procedures may include aortic repair, scoliosis treatment, breastbone corrections, or eye surgeries. Regarding lifestyle and mental health, doctors may recommend specific lifestyle changes to enhance the patient's overall quality of life.

Molecular Biology of Marfan Syndrome:

Fibrillin is a protein that exists in three different isoforms: FBN1, FBN2, and FBN3.

• FBN1 is responsible for producing two proteins: extracellular matrix and hormone asprosin. It is predominantly expressed in the placenta.
• FBN2 is a protein component of connective tissue microfibrils and may play a role in elastic fiber assembly. Elastic fibers provide support and elasticity to tissues that undergo repeated stretching, such as large arteries and the lungs. Mutations in FBN2 can lead to congenital contractural arachnodactyly, a genetic disorder that shares similarities with Marfan syndrome. Similar to FBN1, FBN2 is mainly expressed in the placenta.

3D structure of a healthy human fibrillin-1 protein (Source)

• FBN3, the most highly expressed member of the fibrillin protein family in fetal tissues, is localized in extracellular microfibrils found in developing skeletal elements, skeletal muscle, skin, kidney, and lungs. This gene is potentially associated with Weill-Marchesani syndrome.

Gene involved with mutation

The mutation responsible for Marfan syndrome is located in the Fibrillin (FBN) 1 gene. FBN1 gene expression is highest in the placenta (RPKM 47.2) and second highest in fat tissue (RPKM 27.5). It is situated on chromosome 15 at the 15q21.1 segment. FBN1 is a member of the fibrillin protein family and plays a crucial role in generating two proteins: the extracellular matrix and the hormone asprosin.

• Extracellular matrix functions as a component of calcium-binding microfibrils, providing structural support with force-bearing capabilities in both elastic and non-elastic connective tissues throughout the body.
• Asprosin is secreted by white adipose tissue and plays a regulatory role in glucose homeostasis.

Mutations in the FBN1 gene are linked to several conditions, including Marfan syndrome, the related MASS phenotype, Ectopia Lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome, and Neonatal Progeroid syndrome.

Research

Conducted in October 2022, research was done to alter the mutations in Marfan Syndrome. In the splice site of exon 64, they identified the noble pathogenic mutation that changed the nucleotide from guanine to cytosine.

After summarizing studies of pathogenic splice-altering mutations and learning that this mutation was confirmed to cause two different truncated transcripts, a conclusion was drawn. For the first time, it was reported that splice-altering simultaneously leads to two abnormal transcripts.

Another study discovered a possible molecular mechanism that develops a large copy number variant (CNV) in the FBN1 gene in a patient diagnosed with Marfan syndrome. It is noted that a small portion of mutations that occur in FBN1 are CNVs recombination-based, replication-based mechanisms or retrotransposition. The conclusion for this research stated that the large deletions in the exons 46 & 47 in the FBN1 gene resulted in the loss of the 31st and 32nd calcium-binding domains. Through this finding, they reasoned that the CNV formation of this mutation was generated by a rare event based on the known microhomology mediated break-induced replication.

FBN1 splice variants in marfan Syndrome patient(c.8051+1G>C) (Source)

Other ongoing areas of research for Marfan's syndrome are:

• Genetic Studies: Researchers continue to investigate the genetic basis of Marfan syndrome to identify new mutations and variations associated with the condition. This research aims to improve our understanding of the genetic factors involved and may lead to more targeted therapies.
• Early Diagnosis: Early diagnosis and intervention are crucial for managing Marfan syndrome effectively. Researchers are working on developing more sensitive and specific diagnostic tools, such as advanced imaging techniques and genetic testing, to enable earlier detection of the syndrome.
• Cardiovascular Research: Given the significant cardiovascular implications of Marfan syndrome, ongoing research focuses on developing innovative treatments and surgical approaches to manage aortic aneurysms and prevent dissections. This includes exploring the use of medications and minimally invasive surgical techniques.
• Drug Therapies: Scientists are investigating potential drug therapies that could help manage specific aspects of Marfan syndrome, such as reducing aortic enlargement or improving connective tissue health. Clinical trials are ongoing to evaluate the safety and efficacy of these treatments.
• Orthopedic and Musculoskeletal Research: Research in this area aims to improve the management of musculoskeletal issues associated with Marfan syndrome, such as scoliosis and joint problems. Surgical techniques and rehabilitation strategies are continually evolving.
• Patient Outcomes and Quality of Life: Researchers are studying the long-term outcomes and quality of life of individuals with Marfan syndrome. This includes assessing the impact of various treatments and interventions on patients' overall well-being.
• Gene Therapy: Emerging gene therapy approaches offer the potential to address the underlying genetic mutations responsible for Marfan syndrome. Researchers are exploring gene-editing techniques, such as CRISPR-Cas9, to correct or modify the FBN1 gene.
• Patient Registries: Establishing patient registries and collecting comprehensive data on individuals with Marfan syndrome are essential for tracking disease progression, treatment outcomes, and potential complications. These registries facilitate research and improve patient care.
• Supportive Care: Ongoing research aims to develop better supportive care strategies, including psychological support, educational resources, and guidance for individuals and families affected by Marfan syndrome.
• Collaborative Efforts: Researchers are increasingly collaborating across institutions and countries to pool resources and expertise in the study of Marfan syndrome. International research networks help accelerate progress in understanding the condition and developing effective treatments.

Overall, ongoing research in Marfan syndrome is multidisciplinary and collaborative, with the goal of improving the lives of individuals affected by this complex genetic disorder.

Working model

A working module of the pathophysiology of Marfan syndrome Source

This model shows the effect of the FBN 1 mutations on the building of the connective tissue. Latent transforming growth factor (LTBP) is a group of extracellular multi-domain proteins and transforming growth factor - beta (TGF-β) are binding domains. These two components are crucial to controlling growth factors. Fibrillin is responsible for building connective tissues for the body. However, with the mutation in FBN 1, it will cause increased, excessive TGF-β activity. This increased TGF-β activity will lead to diverse intracellular signaling pathways such as SMAD, mitogen-activated protein kinase (MARK), p42/44 (EAK), JNK8 and p38 which signal angiotensin ii signaling. The selective angiotensin II receptor 1 (AT1) blocker can inhibit the activation and overactivity of TGF-β and reduce the side effects of Marfan syndrome such as aortic aneurysm.

Future directions of research

Marfan syndrome is a disease that affects one's connective tissues. Through large samples of data which display the patterns in people with Marfan syndrome, it is noticeable that many patients are diagnosed with scoliosis. Roughly 60% of patients are diagnosed with scoliosis. Marfan syndrome directly influences the probability of someone with Marfan syndrome to have scoliosis due to the loose ligaments in the spine. Dural ectasia is where the dural, a membrane that surrounds the spinal cord and the brain, can be abnormally enlarged in patients with Marfan syndrome. This widening of the dural sac may result in posterior vertebral scalloping and is also associated with herniation of nerve root sleeves.

Patient with Marfan syndrome with Dural EctasiaSource

While sequencing exomes of individuals within a multigenerational family with a dominant Mendilian inheritance of Idiopathic Scoliosis (IS), they identified a rare missense variant in HSPG2. HSPG2 is a gene that codes the perlecan protein which is responsible for binding and cross-linking extracellular matrix components and cell-surface molecules. After further sequencing in different patients, they found 21 other potentially damaging variants in HSPG. Through a gene burden analysis, they discovered that variants within the fibrillin (FBN) 1 and 2 genes were associated with IS. The mutations in HSPG2 and FBN 1 both affect the extracellular matrix proteins and the mutation in the FBN 1 gene is associated with Marfan syndrome. This clearly links Marfan syndrome with Idiopathic scoliosis, signaling the possibility of a big breakthrough regarding the causes of IS in patients with Marfan syndrome.

Conclusion

Marfan syndrome is a rare genetic disorder, affecting approximately 1 in 5,000 individuals. While it is often inherited from a parent, there are also instances of spontaneous mutations, where patients are the first in their family to develop the syndrome. The primary cause of this condition is a mutation in the FBN1 gene, which impairs the body's ability to produce essential proteins for building connective tissue.

Due to this genetic mutation, various parts of the body are affected, as connective tissue is distributed throughout the human body. This wide-ranging impact has prompted extensive research and specialized studies focusing on the different affected body systems.

Regrettably, as of today, there is no known cure for Marfan syndrome. Nevertheless, medical foundations and researchers are dedicated to advancing treatment options, including therapies and surgical interventions, with the goal of enhancing the quality of life for individuals living with this condition.

References

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_By: Emma Chang_

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