April 1

Dr. van der Knaap discovers MLC

This paper is the first to describe MLC in a group of eight patients. At this time, patients were diagnosed based on the brain MRI pattern and clinical characteristics, which are defined in this paper.  

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April 10

Dr. Singhal discovers MLC in India

Dr. Singhal independently discovered MLC in India and described the disease in 30 Indian patients, most of them belonging to the Agarwal community.

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September 26

First brain pathology examination of MLC

This is the first description of how MLC affects the brain. Brain white matter was studied. This study shows that in MLC the myelin is present in relatively normal quantities. However, the swelling of the white matter seen on MRI is reflected by the extensive presence of fluid-filled balloons (vacuoles) in the myelin at the cellular level.

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April 11

Discovery of the first MLC gene

Prior to this research paper, there was no causal gene identified to cause MLC. Here, researchers discovered the first MLC gene, named MLC1, encoding a membrane protein. This discovery allows for patients to be diagnosed through genetic testing and paves the way for future studies on the function of the MLC1 protein.

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April 21

MLC is a disease affecting astrocytes

This study shows that the MLC1 protein is present mainly in a certain type of supportive brain cells called astrocytes, suggesting that these cells may be the most affected in MLC.

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April 16

MLC is a conformational disease

This study shows that most mutations in MLC1 cause problems with proper folding of the protein into the correct structure and therefore, pharmacological strategies that improve MLC1 expression could be useful to treat MLC patients.

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April 14

Discovery of the classic and improving phenotypes

This study is the first to describe that MLC patients without MLC1 mutations can show two different clinical phenotypes: they either have classical MLC or they show an improving phenotype.   

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April 13

Identification of the second MLC gene: GLIALCAM

In this paper, researchers identify the second MLC gene: HEPACAM (renamed to GLIALCAM). Patients with two so-called recessive GLIALCAM mutations had the classical form of MLC while patients with one specific dominant mutation had the improving phenotype. The authors also demonstrated that GlialCAM interacts with MLC1 and is expressed in neurons and astrocytes.

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May 19

How mutations in MLC1 and GlialCAM cause MLC

This study provides further proof that MLC1 and GlialCAM interact with each other. Mutations in MLC1 were found to decrease the amount of MLC1 protein in the brain while mutations in GlialCAM caused improper localization of these proteins.

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December 28

Defects in ion and water movement cause MLC

These four studies are the first to demonstrate a potential function of the MLC1 protein in regulating ion channels and transporters important for controlling ions and water homeostasis, which affects the volume of cells. These findings suggest that MLC may be caused by the fact that astrocytes in the brain are chronically swollen because of a defect in ion homeostasis.
Paper 1, Paper 2
2012: Paper 3, Paper 4

April 23

The first animal models of MLC

These studies include the generation and characterization of the first animal  models (mouse, zebrafish) for MLC. They describe mice or zebrafish with mutations in either MLC1 or GlialCAM. As a result, these animals show key features of MLC and can be used to study aspects of the disease.
2014: Paper 1, Paper 2, Paper 3
2017: Paper , Paper 4

April 14

MLC disease in Chinese patients

This study examines the clinical and genetic findings in a group of Chinese MLC patients and tracks the disease progression over time. This is important to expand the disease spectrum and prevalence of MLC.

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January 16

What causes seizures in MLC?

Using two of the previously generated mouse models, this is the first in depth study on the occurrence and cause of seizures in MLC. Specifically, dysregulation of ions and water were found to cause seizures in this disease.  

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September 20

A comprehensive clinical study on MLC

This clinical study provides data on a large group of MLC patients. The frequency of different clinical features of MLC in both the classical and improving MLC patients is documented. This is the most comprehensive clinical study on MLC to date.

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March 14

MLC1 plays a role in counteracting inflammation

This study provides further information on the function of the MLC1 protein by investigating its role in inflammation. The results here demonstrate that MLC1 helps control the response of astrocytes to inflammation.

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April 25

Generation of two new GlialCAM mouse models

In this paper, the researchers created two new GlialCAM mouse models with patient mutations: the first with autosomal recessive inheritance and one with autosomal dominant inheritance. Studying mice with different inheritance and human mutations is important to increase our understanding of the classical and improving disease presentations.

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April 15

The first therapeutic study of MLC

Here, the authors use a gene therapy approach in an MLC mouse model in an attempt to improve the disease. They inject a virus that delivers a healthy copy of the MLC1 gene into a strongly affected brain region of MLC mice. This leads to a local recovery of the myelin vacuoles in the white matter. It should be noted that applying such a gene therapy approach in the human brain is not possible at the moment. But despite this, the study shows that some MLC features are reversible if appropriate therapeutic options would be available.

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January 14

MLC1 is important for determining cell shape and movement

Further characterization of the MLC1 protein demonstrates that its localization to astrocyte end-feet is important for proper actin remodeling which controls cell shape and motility. MLC1 mutants demonstrated changes in actin dynamics, suggesting a potential disease mechanism of MLC.  

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April 14

Relationship between MLC proteins and Connexin 43

Gap junctions which connect astrocytes are very important to move ions between different cells. Two studies indicate that gap junctions are impaired in MLC. This impairment might contribute to the presence of epilepsy in MLC.

Paper 1, Paper 2

June 17

Identification of potential therapeutic targets

A study of MLC1 and GlialCAM protein interactions identifies possible therapeutic targets. Beyond an important role in volume regulation and localization, there are still many unanswered questions about the exact function of MLC1 and GlialCAM. This paper seeks to answer this question by examining what proteins MLC1 and GlialCAM interact with. Importantly, these proteins were discovered to interact with two G-protein coupled receptors (GPCRs). GPCRs have important roles in signaling interactions in the body and are promising drug targets for future studies.

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October 20

Brain vasculature is affected in MLC

This study uses an MLC mouse model to investigate how brain vasculature is altered in MLC. It was discovered that the interactions between astrocytes and blood vessels are disrupted in this disease.

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May 5

Two new genes that cause MLC

In this study researchers identified two new genes that cause MLC, named AQP4 and GPRC5B. Along with MLC1 and GLIALCAM, this now makes a total of 4 genes associated with MLC, although mutations in AQP4 and GPRC5B appear to be more rare.  AQP4 encodes Aquaporin-4, an important brain water channel expressed in astrocytes. GPRC5B is what we call a G protein-coupled receptor, which is a broad family of membrane proteins of various functions.  The family of receptors to which GPRC5B belongs is targeted by many human drugs, making GPRC5B an interesting target for future therapy development.

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October 26

First Published Consensus Statement by our MLC Consortium

This is the first published statement from our MLC consortium, a team of clinical MLC experts.  Here, the consortium delves into a recent case report of two MLC patients taking Anakinra. While the original study hinted at positive effects, the experts caution that it is difficult to interpret these results as there is no comparison with kids who did not receive Anakinra and these patients did not show significant or uncharacteristic improvements. Because Anakinra has its risks – daily painful shots and possible side effects – the consortium suggests more research before giving it to MLC patients.

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AAV vector = AAV stands for adeno-associated virus. It is a virus commonly used in gene therapy to deliver the healthy gene to the correct tissue or cell type in the body.

Astrocytes = a type of brain cell that performs many important functions including providing energy and support to neurons, responding to injury and regulating the balance of ions and water

Astrocytic vascular contacts = the site where astrocytes connect to the blood vessels in the brain

Astrocytoma cell line = astrocytomas are a type of brain tumor that begin in cells called astrocytes. These cells can be removed from the tumor and cultured as an immortal human cell line. Since access to human brain cells is rare and unethical to procure, these are often used to study human astrocyte function and diseases affecting these cells, such as MLC.

Biomarkers = a measurable indicator found in the body that can be used to assess disease progression or how the body responds to a treatment

Cell membrane = also known as the plasma membrane, is a thin layer that surrounds the exterior of a cell, creating a barrier that controls what enters and exits the cell

Cellular morphology = the physical appearance and shape of cells

Cellular motility = the ability of cells to move or change positions  

Gene expression = genes can be turned ‘on’ or ‘off’ in the body. It’s expression is a measurement of how much turned on or off it is.

Gene therapy = a medical approach that modifies an individual’s genes to treat or cure a disease

Cerebellum = a section of the brain located at the back of the head. Its main function is to maintain motor balance and coordination.

Glia cells = also known as glial cells or just glia, are a type of support cell in the nervous system. There are several types of glia cells including astrocytes, the cell type of interest in MLC1

Differentiation = the process of turning a stem cell into a different specialized cell type

Histopathological = studying diseased tissue using a microscope

In vivo = the Latin word for living. Refers to work done in a living organism.

Induced pluripotent stem cells = stem cells that can be differentiated into any cell type in order to study a disease in the most relevant cell. These are created by taking skin or blood samples from an individual and ‘reprogramming’ them back to a stem cell.

Intronic mutation = during the production of a protein, the body must first read the DNA of the gene and copy it into a form (mRNA) that can be translated into a protein. This gene includes sections called introns and exons. Exons are the parts of the genes that become proteins, while introns are ‘cut out’ of the gene before it is translated to the protein. Intronic mutations are mutations in the intron. Most mutations occur in exons since it is the part of the gene that is directly read by the body to become protein. However, in some cases introns can contain mutations that cause disease.

Knockout mice = mice that have been engineered to have little or no expression of a specific gene. This is done in order to study the effect of a particular gene on an organism or to approximate a human disease in a mouse model.

Murine models = rat and mouse models, used as an animal model to study the disease

Myelin vacuolation = a characteristic finding in MLC where the layers of the myelin sheath are separated from each other

Pathogenesis = the pathology or pathogenesis of a disease is the way that a disease develops, often referred to as the disease mechanisms.

Pharmacological treatments = the treatment of a disease using medication/drugs

Preclinical = research occurring before clinical testing in humans, investigations to determine if a therapy (e.g. drug, procedure, treatment) will be useful to treat the disease

Prenatal molecular diagnosis = diagnosis diseases and disorders in a fetus (unborn baby)

Reprogramming = the process of turning a specialized cell back into a stem cell

Splice site mutation = during the production of a protein, the body must first read the DNA of the gene and copy it into a form (mRNA) that can be translated into a protein. This gene includes sections called introns and exons. Exons are the parts of the genes that become proteins, while introns are ‘cut out’ of the gene before it is translated to the protein. The process of cutting out the introns and ‘pasting’ together the exons is called splicing. A splice site mutation is when the DNA has a mutation in the region where this ‘cutting and pasting’ occurs. This can affect the ability of the body to properly ‘paste’ the sequence of the protein together, thereby impacting the structure of the protein.

Transport membrane protein = a type of protein found at the membrane of the cell which is involved in moving molecules into and out of the cell

Vascular system = also called the circulatory system. This is the system of arteries and veins that carries blood through the body delivering oxygen and nutrients to different tissues.


Meet the Researchers

Elena Ambrosini, PhD

Elena Ambrosini, PhD

The aim of the research group working at the Istituto Superiore di Sanità in Rome is to understand the dysfunctional molecular mechanisms causing MLC disease. MLC is mainly due to mutations in MLC1, a protein highly expressed in the brain by a population of cells called astrocytes.

Assumpció Bosch, PhD

Assumpció Bosch, PhD

Assumpció Bosch, full professor in Biochemistry and Molecular Biology, is working at the Institute of Neurosciences at the Universitat Autònoma de Barcelona (UAB), in Spain. She has more than 25 years of experience in the characterization of murine models of disease and in preclinical gene therapy studies for rare disorders involving the nervous system.

Binbin Cao, MD, PhD

Binbin Cao, MD, PhD

Binbin Cao is a pediatric neurologist at Xi’an Jiaotong University. In 2005, her team was the first to begin studying Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC) in China.  Their focus included researching clinical and genetic features and the pathogenic mechanism of the disease.

Martine Cohen-Salmon, PhD

Martine Cohen-Salmon, PhD

The laboratory of Dr. Cohen-Salmon is located in the Centre interdisciplinaire de Recherche en Biologie (CIRB) Collège de France in Paris. They are a fundamental neurobiology laboratory focusing on the role of specific cells of the brain: the astrocytes. These cells have the unique property to contact and regulate the vascular system in the brain and she studies these specific regulations.

Raúl Estévez Povedano, PhD

Raúl Estévez Povedano, PhD

Raúl Estévez, full professor in Physiology, is working at the Faculty of Medicine and Health Sciences in the University of Barcelona (UB)/Institute of Neuroscience and IDIBELL, belonging also to CIBERER, a network of Spanish groups working in rare diseases. He started to work in Megalencephalic Leukoencephalopathy with subcortical cysts (MLC) 20 years ago.

Marjo Van der Knaap, MD, PhD

Marjo Van der Knaap, MD, PhD

Studying MLC has been a focus of researchers at the Amsterdam Leukodystrophy Center (ALC) for the past 30 years. The ALC is headed by Prof. Marjo van der Knaap, child neurologist and world leading expert on leukodystrophies. She saw her first MLC patient in 1991 and has studied the disease since then.

Hyun-Ho Lim, PhD

Hyun-Ho Lim, PhD

Hyun-Ho Lim, Ph.D. is a Principal Investigator of the Korea Brain Research Institute (KBRI). Dr. Lim received his Ph.D. in Molecular Neurobiology in 2005 from Gwangju Institute of Science and Technology. 

Rogier Min, PhD

Rogier Min, PhD

Rogier is a cell biologist trained in electrophysiology and advanced live cell imaging. By combining studies on cell physiology with insights from the clinic, the ALC team aims to better understand disease mechanisms and identify therapeutic opportunities. Ultimately, the aim of these laboratory studies is to help develop the urgently needed MLC therapy and bring it to the clinic.

Kenji Tanaka, MD, PhD

Kenji Tanaka, MD, PhD

Kenji Tanaka, full professor in Neurochemistry, is working at Institute for Advanced Medical Research, Keio University School of Medicine in Japan. He has been conducting glial cell research for more than 20 years and has been working on several leukodystrophy mouse models since 2003.

Jingmin Wang, MD, PhD

Jingmin Wang, MD, PhD

Dr. Wang is a Professor of Pediatrics at Peking University First Hospital. In 2005, Dr. Dr. Wang along with Dr. Binbin Cao and her team were the first to begin studying Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC) in China.  Their focus included researching clinical and genetic features and the pathogenic mechanism of the disease.



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