Introduction to lissencephaly 

This article will help describe and explain the meaning of lissencephaly, the cause of this and the brainstem and cerebellar abnormalities that occur as a result. 

Now, what is Lissencephaly? Lissencephaly includes severe brain malformations such as absent gyri, broad presenting gyri, and subcortical band heterotropia, resulting in the brain appearing smooth. Specifically, this occurs in the outer part of the brain, the cerebral cortex, leading to the lack of folds that cause lissencephaly. 

This smoothness is due to the abnormal neuronal migration observed. Neuronal migration occurs within the brain during the early developmental stages of a human, for instance between 12-24 weeks. This stage is the embryonic stage.¹ Neuronal migration is the fundamental process in which the neuronal cells move from their place of origin within the brain to the areas where they needed.² For example, the cerebellum. Therefore, as the child grows with lissencephaly, there are mental disabilities seen as well as delays in their development, such as learning. The severity of these disabilities presented depends upon the degree of brain abnormalities.³ 

There is an importance in studying this condition as there is no cure, so learning how to manage this condition is crucial for improvement in the quality of life. In addition, this condition is present in other animals as well, such as calves. Interestingly, a study had researched lissencephaly in these calves and analysed the differences in their brains.⁴ Figure 1 shows a calf with lissencephaly (A) displaying smoother folds of the brain compared to a normal control calf without lissencephaly (B). 

Type 1 and type 2 lissencephaly 

Lissencephaly can be classified into 2 main subtypes due to the variations in neuronal migration. 

• Type 1 (the classic lissencephaly) 
• Type 2 (the cobblestone lissencephaly) 

Type 1 (the classic lissencephaly) is caused by neuronal undermigration. 

This suggests that the neurons are failing to migrate properly to their place of function in the cortex. In this type, the cerebral cortex is unusually thicker, consisting of 2-4 layers. The broad gyri here are known by the term pachygyria. A person with lissencephaly would have a shorter lifespan and, on average, a much smaller head as the growth is significantly limited. Furthermore, these infants have difficulty feeding and a history of seizures and epilepsy. Seizures are noticed in 90% of these infants before the age of 6 months. Lissencephaly sufferers have a low survival rate where the majority live up to the age of 4, with a few exceptions living until 10 years of age. 

An associated form of this classic lissencephaly is the Miller-Dieker syndrome, recognised by prenatal imaging. This form arises from the deletion in the chromosome 17p13.3. 

Interestingly, Type 2 (the cobblestone lissencephaly) is caused by neuronal overmigration.

This results in a “rumpy and bumpy” appearance of the cortex as opposed to the smoothness of type 1. Severe cerebellar hypolasia can be seen in the most severe version of cobblestone lissencephaly. This condition is called Walker-Warburg syndrome. Magnetic resonance imaging (MRI) is a non-invasive technique used to analyse the brain anatomy by producing images via radiography. This can identify the subtypes of the condition.^5,6 

Causes of lissencephaly 

Genetic causes of lissencephaly 

Several mutations or deletions in genes are associated with the cause of lissencephaly: 

• LS1 - a mutation or deletion would cause the dysregulation of the dyenin protein. This would affect microtubule-based transport and cell growth⁷ 
• DCX - affects neuronal migration
• RELN - affects cerebellar development (hypoplasia) 
• ARX - affects the forebrain and contributes to epilepsy 

Other genes include: 

• VDLR 
• TUBG1
• ACTB
• ACTG1¹ 

Non-genetic causes of lissencephaly

Non-genetic factors can contribute to lissencephaly, particularly during the first trimester of pregnancy. These include viral infections contracted by the mother or the fetus, which contribute to a lack of oxygen supply to the fetal brain. An example is cytomegalovirus which has been linked to lissencephaly as it reduces the blood flow to the brain. Timing plays an important role as earlier infections lead to neuronal migration. Fetal MRI is beneficial in evaluating high-risk pregnancies. Lissencephaly reflects the brain injury noticed before 16-18 weeks’ gestation.^1,8 

The impact on the brainstem and cerebellum

The brainstem is important to involuntary functions such as breathing, sleeping and heart rate. This is divided into 3, namely the medulla oblongata, midbrain and pons sections.⁹ Additionally, the cerebellum is in charge of controlling the voluntary functions like motor coordination and balance.¹⁰ 

Within the Walker-Warburg syndrome, there is a “Z-shaped” underdeveloped brainstem. Common features include an enlargement of the brain’s ventricles. The cerebellum may be affected as there is an underdevelopment (hypoplasia), particularly in the midline region, a reduction in size and unusual folding patterns. A RELN mutation would cause significant changes to the cerebellum.^5,11 Additionally, microtubule-related genes can disrupt this early brain development. Ogema et al concluded that the alpha and beta tubulin genes can cause these malformations in cortical development. Brainstem dysplasia is common and occurs in approximately 80% of cases.¹² 

FAQs 

What is lissencephaly? 

In short, Lissencephaly, meaning “smooth-brained”, is a term used to describe someone with a rare brain abnormality. This brain abnormality is due to the absence of the brain folds in the outer part of the brain (cerebral cortex). 

What is the difference between type 1 and type 2 lissencephaly? 

Type 1 (the classic type) has neuronal undermigration, meaning the useful neurons do not reach their places of function and there are no folds in the cerebral cortex. Type 2 (the cobblestone type) has an overmigration of these neurons, meaning the cerebral cortex appears ‘rough and bumpy’. 

What is the cause of lissencephaly? 

The cause of lissencephaly is linked to a “smooth brain”. This is due to gene mutations in particular genes related to neuronal migration and brain development (such as LIS1, DCX, RELN or TUBA1A). These genes are commonly seen in the function of mitosis (cell division and growth) and in the transportation of cells, supported by microtubules. Viral infections may be a non-genetic cause of lissencephaly where the mother or fetus obtains an infection, such as cytomegalovirus, affecting the oxygenated blood supply to the fetus' brain. The first trimester will highly impact this. 

Why is research into lissencephaly important? 

Unfortunately, there is no cure for lissencephaly. Individuals with this condition must be properly cared for with the appropriate nutritional support as well as physical support for improved movement. Thorough research into this topic is important for improved treatment for the sufferers and is more likely to improve their quality of life. 

What does the cerebellum do?

The cerebellum, located at the back of the brain, controls important functions, including posture, balance and voluntary movement such as walking. 

What does the brainstem do? 

The brainstem connects the cerebrum of the brain to the spinal cord and the cerebellum. This is divided into 3 sections: the medulla oblongata, midbrain and pons. The functions of the brainstem are crucial for involuntary movements such as breathing, heart rate and sleep. 

What are the cerebellar and brainstem abnormalities caused by lissencephaly?

The cerebellar abnormalities, such as hypoplasia and dysplasia, mean an underdevelopment or a malformation in the cerebellum/brainstem, and this can affect the motor function overall and result in mental and physical disabilities. 

Summary 

To summarise, lissencephaly is a rare brain condition whereby the folds in the cerebral cortex of the brain are modified to the degree of neuronal migration. A smooth cerebral cortex appearance is characterised by the undermigration of neurons, which is type 1 (classic) lissencephaly. Type 2 (cobblestone lissencephaly) creates a rough and bumpy appearance on the cerebral cortex, often affecting cerebellar hypoplasia. 
These brain images can be analysed through prenatal screenings and fetal magnetic resonance imaging. Cerebellar abnormalities may include hypoplasia, atrophy, or abnormal folding patterns, while the brainstem may appear underdeveloped and malformed. The type and severity of these abnormalities are often linked to specific genetic mutations. As there is no cure, thorough research should be conducted to help the quality of life and increase the rates of survival past the age of 4. Therefore, established early detection tools would be beneficial.