The CLCN2 gene, responsible of a new undetermined leukodystrophy: leukoencephalopathy with intramyelinic edema

Written on Friday 16 May 2014

In 2009, ELA launched a PUSH project dedicated to indeterminate leukodystrophies. Under the direction of Pr. Jean-Louis Mandel, a member of the ELA Foundation Scientific Council, this project has as its aim to promote the identification of new genes responsible for indeterminate leukodysrophies that represent 30% of the leukodystrophies catalogued by ELA.
This initiative has allowed Dr. Frédéric Sedel and his team, based at the Pitié-Salpêtrière Hospital (Paris), in collaboration with Pr. Marjo van der Knaap at the VUMC Medical Centre in Amsterdam (Holland), to identify the gene responsible for a new indeterminate leukodystrophy, leukoencephalopathy with intramyelinic edema.

What does it consist of?

Leukoencephalopathy with intramyelinic edema is a “leukodystrophy that we have identified in three adult patients for the moment, who all originated from the same region of North Africa and who show very few symptoms” explains Dr. Frédéric Sedel. The patients have essentially defects in equilibrium, vision and very characteristic MRI abnormalities that concern certain regions of the white matter. The disease affects both adults and children.

What is the use of the gene?

The CLCN2 gene was discovered thanks to very high-throughput genetic sequencing of patients’ DNA (three adults and three children). This gene codes for the ClC-2 protein, which belongs to the chlorine canal family, proteins with a hollow centre whose role is to flush chlorine out of the cell. “This chlorine canal has long been known”, adds Dr. Sedel. Expressed practically throughout the whole organism, it acts in concert with two other canals (GLIALCAM and MLC1) that are both implicated in macrencephalic leukodystrophy with cysts, or MLC, and are thought to play a role in water equilibrium and cerebral ionics. “Mice with a mutated ClC-2 canal also have leukodystrophy and extremely severe visual damage. In man, we don’t know why, but the gene is responsible for only a very moderate form of leukodystrophy that begins very late and gives relatively few symptoms” underlines Dr. Sedel.

The role of ELA in this discovery

“Thanks to ELA and its project aiming to identify new leukodystrophies of indeterminate causes, we have had the opportunity to sequence these patients’ DNA completely. This approach allowed the identification in these three patients of deleterious mutations in the CLCN2 gene straight away, with the proof today that they are responsible for this leukodystrophy”, he continued. “It is complicated to find the genes responsible for indeterminate leukodystrophies, because we are dealing with orphan diseases, i.e. extremely rare ones, that in fact interest few people. It is thus difficult to obtain funding via public research organizations to carry out research into three patients for whom we do not yet know the disease. It was there that the support of ELA was a key element”.

Interview with Dr. Frédéric Sedel

Source : Christel Depienne, Marianna Bugiani, Céline Dupuits, Damien Galanaud, Valérie Touitou, Nienke Postma, Carola van Berkel, Emiel Polder, Eleonore Tollard, Frédéric Darios, Alexis Brice, Christine E. de Die-Smulders, Johannes S. Vles, Adeline Vanderver, Graziella Uziel, Cengiz Yalcinkaya, Suzanna G. Frints, Vera M. Kalscheuer, Jan Klooster, Maarten Kamermans, Truus E. M Abbink, Nicole I. Wolf, Frédéric Sedel, Marjo S. van der Knaap. Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurology 2013, 12(7):659-68.