Megalencephalic Leukodystrophy - Types, Causes, Diagnosis, and Treatment

What Is Megalencephalic Leukodystrophy?

Megalencephalic leukodystrophy with a subcortical cyst (MLC) is a rare genetic disorder. It usually develops during the first year of life.

The disease is explained as follows:

• Megalencephalic: It refers to the enlarged brain.

• Leukodystrophy: The white matter in the brain consists of nerve fibers covered by a protective layer (myelin sheath). The damage to the brain’s white matter is referred to as leukodystrophy.

• Subcortical Cyst: Cysts are fluid-filled sacs formed below the cerebral cortex (outer covering of the cerebrum) in individuals with MLC.

The disease also has other names as listed below:

• Van der Knaap disease.

• Leukoencephalopathy with swelling and cyst.

• Vacuolating leukoencephalopathy.

What Are the Types of Megalencephalic Leukodystrophy?

Megalencephalic leukodystrophy with the subcortical cyst (MLC) is classified as follows:

• Classic Type: MLC 1 and MLC 2A.

• Improving Type: MLC 2B.

How Is Megalencephalic Leukodystrophy Caused?

MLC is an inherited disorder. It is caused by the alterations (mutations) in specific genes as listed below:

• MLC type 1 occurs due to the mutation in the MLC 1 gene. The MLC 1 gene commands the MLC 1 protein production found in the specialized brain cells (glial cells).

• The mutation in the HEPACAM gene causes MLC type 2A and 2B. It gives instructions for the production of GlialCAM protein, which functions primarily in the brain.

• The mutation in the MLC 1 gene and HEPACAM gene leads to defective protein production in brain cells. But, the exact mechanism of these faulty proteins in causing brain abnormalities is not known.

What Are the Signs and Symptoms?

1. In MLC Types 1 and 2A:

• Large Head (Macrocephaly): It usually develops in the first year of life. The size of the head is measured in percentile. Above 98 % is called macrocephaly, which means the baby’s head is more significant than 98 % of other babies. The rate of head growth normalizes after one year.
• Motor Skills: Motor development in infants is normal till one year of age. Specific motor skills are delayed. It includes unstable walking, frequent falls while walking, and decreased muscle tone. The motor functions get deteriorate over the years, such as:
  • Lack of muscle control in extremities and trunk.
  • Slurred speech (dysarthria).
  • Dysphagia (swallowing difficulty).
  • Dystonia (movement disorder).
  • Apparent Babinski’s Sign: The big toe heads up, and the other toes fan out in Babinski’s sign. It is common in infants less than two years of age. Due to brain disorders, it may persist even after two years.
  • Few children lose their ability to walk independently, and they become dependent on wheelchairs at 10 to 20 years of age.

• Cognitive Skills: Intellectual and behavioral problems occur. Poor school performance is observed in later years of life.
• Seizure: Most children below 20 years experience at least one seizure. It usually occurs a few years after birth.

2. In MLC Type 2B: The individuals have normal motor and cognitive development with macrocephaly.

• Macrocephaly: It is more common at present at birth for 90 % of children. The head growth reduces after one year of life, and in 50 % of children, the head size becomes normal.
• Motor Skills: Delayed and unstable walking is expected during the first year of life. However, motor skills improve after 2 to 3 years of age. But the decreased muscle tone persists.
• Cognitive Skills: It is normal in most children. Only a few are observed with intellectual disabilities.
• Seizures: The individuals mostly lack any history of seizures.

How Is Megalencephalic Leukodystrophy Diagnosed?

Physical Examination: The individuals are examined to obtain a history of macrocephaly at one year of age and developmental delays. The loss of motor function, behavioral problems, and slurred speech are a few other classical signs that are suspected of MLC during the examination.

Magnetic Resonance Imaging (MRI): The imaging of the brain evaluates various abnormalities as follows:

• The Classic Type (MLC 1 and MLC 2A):The brain’s white matter is abnormal and swollen in certain areas. Subcortical cysts are also visualized in the frontal regions of the brain. The cyst increases in number and size, and the whiter matter swelling decreases over the years.

• In Improving Type (MLC 2B): The imaging shows similar features to the classical type in the first year of life. However, over time, the MRI of the brain appears normal with a minor subcortical cyst.

Molecular Genetic Testing: It is done to evaluate the changes in MLC 1 gene and HEPACAM gene responsible for causing MLC.

What Are Similar Disorders?

• Canavan Disease: Canavan disease is an inherited disorder that affects the nerve cells in the brain, and the white matter swells. The symptoms develop at 3 to 6 months of age. It includes developmental delays, macrocephaly, and the inability to walk. Magnetic resonance imaging is done to obtain an accurate diagnosis.

• Alexander Disease: It also belongs to a group of leukodystrophy diseases, where the myelin sheath is damaged. The symptoms appear at the age of 2 and include delayed development, seizures, and an enlarged head. The disease progresses in children and adults, causing difficulties in coordination, speech, and swallowing.

How to Treat Megalencephalic Leukodystrophy?

There is no specific cure for MLC. But the following is done to alleviate the symptoms.

• Antiepileptics:Antiepileptics like Carbamazepine, Phenytoin, etc., are suggested in case of seizures. However, in MLC 2B, seizures are less common.

• Physical Therapy: Specialists provide therapies to decrease muscle pain and improve its function. The ease of muscular movement is also increased.

• Speech Therapy: The speech becomes slurred in children and adults. Therefore a speech therapist assesses the level of speech disturbance and provides the best therapy.

• Avoiding Trauma: Even minor trauma to the head can deteriorate motor function and cause seizures. Therefore, children should avoid outdoor activities.

Conclusion:

Megalencephalic leukodystrophy with a subcortical cyst is a rare disorder. The intensity of symptoms depends on the type of MLC. Prenatal diagnosis helps decrease the risk of disease development in infants. Specialist team support is essential in guiding parents and children to lead better lives.