What is Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC)?

Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is a genetic disorder that affects the nervous system and causes neurologic symptoms. It usually presents in children in the first year of life. Most patients have the classic disease type, which tends to be progressive, meaning symptoms worsen over time. In a subset of patients with MLC, improvement of neurologic symptoms occur; this type is called the improving disease type.

What are the symptoms of MLC?

In most patients, the first symptom is an increase in head circumference in the first year of life. Patients often have a mildly delayed initial motor development with subsequent slow neurological deterioration. Symptoms may include the following:

  • Macrocephaly: an abnormally large head
  • Normal or mildly delayed early development
  • After several years, slow deterioration of motor functions, with ataxia (loss of the ability to coordinate muscular movement) and spasticity (stiffness of muscles and muscle spasms)
  • Seizures (present in ~75% of patients and most often well controlled with medication)
  • Temporary exacerbation of signs and symptoms after minor head trauma
  • Difficulties with learning
  • Mental decline (generally milder than the motor problems)
  • Autism

There is a wide variability in pace and severity of neurological decline. Many patients with classic MLC lose the ability to walk as teenagers and become dependent on others for most daily tasks, while some mildly affected patients are still able to walk in adulthood and have normal jobs.

Because the disease has been known for a relatively short time, information about the life span of MLC patients is limited. While some patients have died in their teens or twenties, others are alive in their fifties.

In patients with the improving phenotype, after the first years of life a remarkable recovery is seen. Motor and cognitive functions improve or normalize; some patients with the improving phenotype have stable intellectual disability with or without autism.

The initial macrocephaly may persist or the head circumference may also become normal.

What Causes MLC?

Most patients with the classic type of MLC have pathogenic variants in both copies of the MLC1 gene (this disease type is called MLC1). A small group of patients with classic MLC have pathogenic varients of both copies of the GLIALCAM gene (this gene is also called HEPACAM; the disease type is called MLC2A). Clinically these classic MLC patients are indistinguishable. The improving disease type (called MLC2B) is caused by a dominant pathogenic variant in one copy of the GLIALCAM gene.

Pathogenic varients in the genes MLC1 or GLIALCAM both result in loss of function of the MLC1 protein. The exact function of this protein is still unclear. The protein is mainly present in astrocytes, crucial supportive brain cells. One of the main roles of astrocytes is to regulate the flow of water and ions (such as sodium, potassium, and chloride) in the brain. In MLC this process is compromised, resulting in build-up of water in the brain which results in chronic brain swelling.

How is MLC Inherited?

Classic MLC is inherited in an autosomal recessive manner. This means that both parents carry one pathogenic variant of either the MLC1 or GLIALCAM gene, and pass it on to their child, who then has two defective copies of the gene and develops the disease. Parents who have one pathogenic variant of the gene and a second normal gene are genetic carriers, but do not have symptoms. For each pregnancy carrier parents have a 25% chance of having a child affected by the disorder.

Improving MLC is inherited in an autosomal dominant manner. This means that having one pathogenic variant of the GLIALCAM gene results in the disease. Most patients inherit the genetic defect from one of the parents, who also has the disease, although the disease may no longer be manifest. In some cases the disorder results from a new (de novo) mutation that occurs during the formation of reproductive cells or early in embryonic development. In these cases, the child’s parents are unaffected, but the child may pass the condition on to his or her own children (50% chance).

How is MLC diagnosed?

MLC is diagnosed by the characteristic abnormalities observed with brain Magnetic Resonance Imaging (MRI). The MRI scan of MLC patients shows a distinct pattern of abnormal and swollen white matter of the brain and the presence of cysts (cavities filled with fluid). The next step is genetic testing of the MLC1 and GLIALCAM genes. Pathogenic variants in MLC1 are observed in approximately 75% of patients and pathogenic variants in GLIALCAM in approximately 20%.

How is MLC treated?

There is currently no cure for this disease. Treatment for MLC is directed at the symptoms as they arise. Such treatments can include physical therapy to improve motor function, speech therapy and special education. Anti-seizure medication should be considered in patients with epilepsy. Minor head trauma can lead to temporary motor deterioration, seizures or (in rare cases) come. Therefore the wearing of a helmet should be considered for situations in which there is increased risk of head trauma.

How is research on MLC progressing towards better treatments?

Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) was identified in 1995. Several laboratories worldwide have since studied the disease. This has led to the discovery of the MLC1 gene in 2001 and the discovery of the GLIALCAM gene in 2011. Studies in cells from patients and in genetic animal models for the disease have led to an increased understanding of the roles of the proeins MLC1 and GlialCAM in the brain. The ultimate aim of this research is to identify a much needed treatment for the disease.

Are there other names for MLC?

Other names for MLC include:

  • Vacuolating Megalencephalic Leukoencephalopathy with Subcortical Cysts
  • LVM
  • Leukoencephalopathy with swelling
  • VL
  • van der Knaap Syndrome