Lissencephaly

What is Lissencephaly?

Lissencephaly is a term that covers a variety of serious brain deformities, such as agyria, or having no brain folds, pachygyria, meaning the brain folds are wide, and subcortical band heterotopia. “Lissencephaly” translates to “smooth brain”, as the brain’s surface appears smooth in this condition. It can occur alone or alongside certain syndromes, like the Miller-Dieker syndrome.

This condition happens when the neurons, or nerve cells, don’t move to their proper places while the baby is developing in the womb, usually between 12 to 24 weeks of pregnancy. This irregular movement results in the brain not forming its natural folds and creases. Children with lissencephaly can experience considerable delays in their development and mental disabilities, but the severity can vary for each child. It depends on how severely the brain is malformed and whether the child has constant uncontrollable seizures, also known as intractable epilepsy.

What Causes Lissencephaly?

Lissencephaly, a condition that affects brain development, can occur due to both genetic and non-genetic reasons. Non-genetic causes may include viral infections in the mother or unborn baby, particularly in the early stages of pregnancy. Similarly, if there’s not enough blood carrying oxygen to the baby’s brain during development, this could lead to the condition. Several genes have also been linked to the disorder.

Here are some genes that are known to be connected to the condition:

LIS1: This gene, which lives on chromosome 17p13.3, is one of the ones we know the most about. It controls a protein known as dynein, which helps move nerve cell contents along structures called microtubules. Changes or deletions in LIS1 can lead to Lissencephaly or another condition known as Miller-Dieker syndrome.

DCX: The DCX gene on the X chromosome is responsible for creating a protein that’s crucial for neuron movement and is necessary for the brain to fold properly. When this gene has a mutation, it causes defects in neuron movement and a decrease in brain folds. Men with a DCX mutation are usually more severely affected, while women often have a milder form of the syndrome.

ARX: This gene creates a protein that’s crucial in the development of the forebrain and other tissues. Children with ARX mutations may exhibit a number of symptoms such as missing parts of the brain, unusual genitalia, and significant epilepsy.

RELN: The RELN gene makes a protein called reelin. Mutations in this gene have been linked to lissencephaly, along with underdeveloped cerebellum and abnormalities in another part of the brain called the hippocampus.

Several other genes like VLDLR, ACTB, ACTG1, TUBG1, KIF5C, KIF2A, and CDK5 have been related to lissencephaly as well.

An infection with cytomegalovirus (a kind of virus) can also contribute to developing lissencephaly by reducing the blood supply to the baby’s brain in the womb. The severity of the impact of this virus on brain development depends heavily on when in the pregnancy the infection occurs, with early infection more likely to result in lissencephaly because the neurons, or brain cells, start to move early in pregnancy.

Risk Factors and Frequency for Lissencephaly

Lissencephaly is a fairly uncommon brain disorder, and we’re not completely sure how often it happens. In the Netherlands, research suggests it occurs in around 1.2 out of every 100,000 births. As our imaging technology gets better, we’ll be able to diagnose lissencephaly more often.

Genetic studies have linked 17 different genes to lissencephaly. The most common issue, found in 40% of cases, is a mutation or deletion in the LIS1 gene. Other significant mutations were found in the DCX gene (23% of cases), TUBA1A (5%), and DYNC1H1 (3%).

Signs and Symptoms of Lissencephaly

Lissencephaly is a condition with varying degrees of severity and symptoms. It can cause issues like seizures, difficulties in feeding, muscle spasms, mental disabilities, and severe delays in physical and mental development. It can also lead to a failure to grow and develop at the expected rate, along with possible abnormality in hands, fingers, or toes. Yet, it’s important to note that some children with less severe forms of lissencephaly may develop normally with only minor learning difficulties. Additionally, a large majority (9 out of 10) of children with lissencephaly will experience epilepsy within their first year of life.

• Seizures
• Feeding difficulty
• Muscle spasm
• Mental disability
• Severe physical and mental development delay
• Failure to thrive
• Hand, finger, or toe abnormalities
• Mild learning disability (in some cases)
• Epilepsy (commonly develops within the first year of life)

Testing for Lissencephaly

Lissencephaly, a brain disorder, is usually identified at birth through a physical exam and brain imaging procedures such as an ultrasound, CT scan, or MRI. These tests can reveal abnormal brain features, such as smoothness in the brain’s surface where there should typically be small dips and folds (sulci and gyri), and a thicker than usual outer layer of the brain (cortex).

To verify the diagnosis, DNA tests such as a chromosome analysis or checking for specific gene mutations are required. These tests can help doctors determine if there is a genetic mutation causing the disorder.

Another valuable test in diagnosing Lissencephaly is an electroencephalogram (EEG), a procedure that measures the electrical activity in the brain. This can help doctors identify any abnormal brain patterns associated with this condition.

Treatment Options for Lissencephaly

Kids with lissencephaly, a rare brain formation disorder, need care that focuses on managing symptoms and providing support. The main goal of treatment is to help these children maintain a healthy diet, especially if they have trouble eating. Also, to manage or prevent seizures, doctors may use medications that help control seizures.

Parents or families of children with lissencephaly are typically offered genetic counseling. This involves working with a healthcare professional who can help families understand the genetics of lissencephaly. They may also recommend further genetic testing to understand the specifics of a child’s condition.

What else can Lissencephaly be?

Lissencephaly is a brain disorder with over 20 types, but most fall under two main categories: Classic lissencephaly (Type 1) and Cobblestone lissencephaly (Type 2). Although the symptoms are often similar, each type is associated with different genetic mutations.

When we look at a brain affected by Type 1 lissencephaly, we see a cerebral cortex with four layers instead of the usual six. On the other hand, Type 2 lissencephaly involves a disorganized cerebral cortex that appears bumpy or nodular. This happens due to the replacement of the cerebral cortex with clusters of cortical neurons mingled with glio-mesenchymal tissue, a type of connective tissue. Patients with these conditions often have abnormalities in their muscles and eyes.

Here are some subtypes of each category:

• Classic lissencephaly (type 1):
  • LIS1: Isolated lissencephaly and Miller-Dieker syndrome, a version of the condition associated with facial abnormalities.
  • LISX1: This version results from a DCX gene mutation and involves a cerebral cortex with six layers, not four.
  • Isolated lissencephaly with no known genetic defects.
• Cobblestone lissencephaly (type 2):
  • Walker-Warburg syndrome
  • Fukuyama syndrome
  • Muscle-eye-brain disease
• Other types that don’t fit into the first two categories:
  • LIS2: Norman-Roberts syndrome, a condition similar to Type 1 lissencephaly or Miller-Dieker syndrome, but without a deletion of the chromosome 17.
  • LIS3
  • LISX2
  • Microlissencephaly: This form involves both a lack of normal folding in the cerebral cortex and an unusually small head. While children with common lissencephaly have a normal head size at birth, those with small heads at birth typically receive a diagnosis of microlissencephaly.

It’s worth mentioning that lissencephaly should not be confused with polymicrogyria, another brain development disorder that is completely different.

What to expect with Lissencephaly

The future health outcome for children with this syndrome depends on its seriousness. A lot of these children might not progress beyond an early stage of development. Unfortunately, their life expectancy is usually quite low, and many children may not live past the age of 10. For children with lissencephaly – the condition we’re discussing – the most common causes of death are issues related to swallowing and diseases that affect the ability to breathe.

It’s important to note that lissencephaly can affect some parts of the brain more intensely than others, and this can vary depending on the type of lissencephaly a child has and the specific gene mutations present.

Possible Complications When Diagnosed with Lissencephaly

Each person with lissencephaly has unique challenges, but the most frequently witnessed issues include difficulty breathing, trouble with eating, and experiencing seizures.

Common Problems:

• Difficulty in breathing
• Feeding problems
• Seizures

Preventing Lissencephaly

It’s critical to educate families on how to look after loved ones who may have feeding difficulties, learning challenges, or experience seizures. Such support can substantially improve their quality of life. Additionally, if there’s a chance of lissencephaly—a rare brain formation disorder—appearing in the family, seeking genetic counseling could be beneficial. This service can help families understand and manage this potential risk.