Megalencephalic Leukodystrophy with Subcortical Cysts (MLC)

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 affects 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 some children with MLC, improvement in 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 can have a delayed development and may subsequently show neurological deterioration Symptoms may include the following:

  • Macrocephaly: an abnormally large head
  • Seizures (present in ~75% of patients and most often well controlled with medication)
  • Ataxia: loss the ability to coordinate muscular movement Spasticity: stiffness of muscles and muscle spasms
  • Difficulties with learning
  • Mental decline (generally milder than the motor problems)
  • Autism

There is a wide variability in pace and severity of neurological decline. Some patients with classic MLC lose the ability to walk a few years after disease onset 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. 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 have stable intellectual disability with or without autism.

What Causes MLC?

Patients with the classic type of MLC have two mutations in either the MLC1 gene (this type is called MLC1) or GLIALCAM gene (this disease type is MLC2A). The improving disease type (called MLC2B) is caused by one mutation in the GLIALCAM gene. Mutations in these genes both result in loss of function of the MLC1 protein. In recent years, researchers showed that this protein has an important role in the regulation of volume in the brain.

How is MLC Inherited?

Classic MLC is inherited in an autosomal recessive manner. This means that both parents carry one mutated copy of either the MLC1 or GLIALCAM gene, and pass it along to their child, who then has two copies of the mutated gene and develops the disease. Parents who have one copy of the mutated gene and a second normal gene are genetic carriers of the abnormal gene, 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 mutated copy of GLIALCAM results in the disease. Most patients inherit the genetic defect from one of the parents, who also have the disease. 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 on the condition to his or her own children (50% chance).

How is MLC diagnosed?

MLC is diagnosed by a combination of clinical signs and symptoms and characteristic abnormalities on 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. Mutations in MLC1 are observed in approximately 80% of patients and mutations 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, for instance anti-epileptic drugs to treat seizures, and is largely supportive.

How is research on MLC progressing towards better treatments?

Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) was identified in 1995, and scientists continue to study this disease, which leads to a growing knowledge of role of the MLC1 and GLIALCAM genes in the brain. Eventually, a better understanding of the disease mechanism underlying MLC can help scientists to identify potential new treatments 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

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