Piecing together the primary lymphoedema puzzle


What causes lymphoedema, the swelling of parts of the body from the build-up of lymph fluid? Until recently, no one knew. This was before research carried out by Prof. Miikka Vikkula and his Human Molecular Genetics Laboratory, which has identified a new gene responsible for primary lymphoedema. It’s one more piece in the puzzle.

Imagine a huge jigsaw puzzle, each piece of which corresponds to a gene that can cause lymphoedema. The entire puzzle would fully illustrate the cause of this pathology. The added difficulty is that no one knows how many pieces are in the puzzle. The team of UCLouvain de Duve Institute Prof. Vikkula has been working on this for years. They started by looking at the causes of vascular anomalies (such as venous malformations and angiomas). After many years of study, the team has developed models of therapy in mice, and these are currently in the clinical study stage. The field of lymphoedemas is less documented; Prof. Vikkula took interest in it 20 years ago and the research work of several teams, including Prof. Vikkula’s, have identified 28 pieces of the puzzle, explaining +/- 30% of the causes of primary lymphoedemas. Recently, his team discovered a new gene responsible for the disease. This breakthrough was just published, on 9 September, in Science Translational Medicine.

What is lymphoedema?

Lymphoedema is a chronic disease resulting from abnormal functioning of the lymphatic system. Lymph, the transparent biological fluid which helps drain our body’s tissues, is no longer drained, accumulates – most often in the lower limbs – and causes hypertrophiesfibrosis, and a predisposition to secondary infections. Some forms of lymphoedema are associated with an accumulation of chyle (lymph mixed with lipids absorbed by the intestines) in the abdomen or chest. In Europe, more than a million people are affected by this pathology, which is still too often underdiagnosed. Lymphoedema can be primary and result from a cause not known at the time of diagnosis, or secondary and caused by infection or cancer treatment.

© Reprinted by permission of VM Leppänen et al., Sci. Transl. Med. 12, eaax8013 (2020).
Soothe rather than cure

Currently, there’s no cure for lymphoedema. ‘The therapy is limited to repeated manual lymphatic drainage and the use of compression garments,’ explains Prof. Vikkula. ‘And in some more severe cases surgery may be necessary, but we still don’t have a cure.’ In order to envision a future with appropriate therapy, Prof. Vikkula’s team decided to continue their efforts to better understand the causes of primary lymphoedema. Because today it remains a mystery. ‘Even though many cases are genetic, it’s not known why a person develops primary lymphoedema.’

The valuable contribution of bioinformatics

For nearly 25 years, Prof. Vikkula and his team have been collecting samples from patients with vascular anomalies and lymphoedemas. ‘This sampling work was made possible through close collaboration with clinicians who classify lymphoedemas according to clinical signs,’ he says. Today, the lab has collected samples from nearly 900 patients (and their families) with primary lymphoedema. To analyse them, the lab team used Whole-Exome Sequencing (WES), a technique for sequencing all the coding parts of genes in our genome. ‘We then compared these sequences with the human reference sequences, filtering out variants one by one. However, there are between 20,000 and 60,000 variants per person. And we believe that one of these variants is responsible for the disease. In a multigene disease like lymphoedema, the more samples we have, the better we can compare and hope to find a gene that’s more common in patients with lymphoedema. It’s the magic and strength of genetics combined with bioinformatics.'

A mutating gene

Through analysis of these samples, Prof. Vikkula's team identified a new gene. Its name: angiopoietin 2 (ANGPT2). Its codes for ligand, which is a protein that reversibly binds to another targeted protein. This receptor is found on cells that form the walls of lymphatic vessels. It therefore contributes to the development of the lymphatic system. ‘We were able to identify this gene because we observed ANGPT2 mutations. These mutations induce the development of sometimes too few, sometimes too many lymphatic vessels. In patients with primary lymphoedema, the protein’s secretion is decreased, and this prevents the lymphatic system from developing normally. This is the first time that mutations in this gene have been identified which cause disease in humans.’

What now?

The gene’s discovery provides great hope not only for the diagnosis of patients but also future treatment. ‘Now that we have a very precise target,’ Prof. Vikkula says, ‘we have clear avenues for creating models that will allow us to develop new therapies. However, too many puzzle pieces are still missing for the idea of treatment to become reality. That’s why, in addition to focusing on ANGPT2, we’ll continue to analyse samples and piece together the remaining 70% of the puzzle, which would provide a complete picture of the causes of primary lymphoedema. I have a lot of hope, especially because technologies are evolving at breakneck speed.’


Bio of Mikka Vikkula

Born in Espoo, Finland, Miikka Vikkula received his master’s degree in medicine from the University of Helsinki in 1992 and completed his PhD in molecular genetics in 1993. From 1993 to 1997, he attended Harvard Medical School as part of a postdoctorate. It was there that he became interested in vascular and lymphatic abnormalities. He moved to Brussels in 1997 and joined the UCLouvain de Duve Institute, where he developed his own research laboratory on human genetics. He has been part of the de Duve Institute management team since 2004. In 2009, his team discovered that the cause of non-hereditary vascular anomalies is also genetic (due to so-called ‘somatic mutations’), and in 2015, the team demonstrated the effectiveness of a drug treatment that improves the quality of life of patients with certain vascular anomalies. He became a WELBIO researcher in 2011, and in 2019 received the first Belgian Generet for Rare Disease Research award (managed by the King Baudouin Foundation) for his research in the genetics of vascular anomalies.

Published on September 10, 2020