Overview 

Any diagnoses of neural or brain-related issues can be very overwhelming and frightening especially when it affects an infant. When you add complicated and difficult words like the Cerebellar Agenesis or Lissencephaly, the fear worsens. Conditions such as Cerebellar Agenesis and Lissencephaly are rare diseases that are caused by malformations in the aforementioned parts of the brain and are important to understand. These conditions can vary in severity from case to case and can be managed with various techniques to improve the quality of life in people who are affected.¹

Let us start by explaining what all the related scientific terms signify for an easier reading experience. Firstly, the cerebellum is a part of the brain that is located at the back of the brain. It controls voluntary actions (picking up a glass), maintaining balance (even while walking), and motor skills(catching a ball). It also plays a part in other functions like memory and language learning. The cerebral cortex is an outer layer that covers the brain. It is responsible for more difficult and higher level functions, including memory, consciousness, thoughts, etc.²

Cerebellar Agenesis

Cerebellar Agenesis is a term used to describe when there is an absence or partial absence of the cerebellum leading to its inability to perform its function, causing a lack of balance, motor skills, and bodily coordination. Cerebellar Agenesis is usually associated with Lissencephaly or other brain malformations.² Lissencephaly is a disease where there are malformations in the brain, due to which the brain does not develop correctly or fully. Both of these diseases occurring together can cause delays in brain development, lack of motor skills, other intellectual disabilities, seizures, etc. There has been no cure found for this condition, but it can be managed with genetic counselling, early detection, and other supportive therapies. 

As mentioned before, the cerebellum is a part of the brain that is located at the back. It is located under the two hemispheres (right and left) of the brain. The “Cerebellar” part of Cerebellar Agenesis refers to the cerebellum, while the “Agenesis” refers to the lack of development, indicating its complete or almost complete absence of the cerebellum.³

Lissencephaly

Lissencephaly is associated with Cerebellar Agenesis, and it means a “smooth brain”. In this condition, the brain is physiologically observed to have no grooves or folds. This indicates a malformation in the cerebral cortex, which is strongly associated with epilepsy. This malformation leads to a lack of correct communication within the brain. Cerebellar Agenesis and Lissencephaly can be classified under the same group of diseases called neuronal migration disorders, which are caused by the irregular movement of neurons during the development of the fetus in the womb.⁴

Origins in Syndromic and Biological

There are multiple reasons for cerebellar agenesis and lissencephaly to occur. Firstly, it can be due to genetic mutations, as several genes have been identified to be connected to lissencephaly, like L1S1 and DCX. These genes control the movement of neurons in the brain and how they settle during their formation in the womb. Examples of genes that can cause cerebellar agenesis are RELN and VLDLR. This shows us that research is being done to identify the cause of such diseases, which is important so that further innovation can be done to manage these diseases and eventually find a cure for them.⁵ Secondly, it can be caused by chromosomal deletions. Chromosomal deletions occur when there is an abnormality during fertilisation, causing the embryo to have fewer than 46 chromosomes, which is the normal amount needed for accurate development of the foetus. The genes that are responsible for managing the neuronal movement and all other functions in our body are stored on the chromosomes. When one of the chromosomes gets deleted, the genes also get deleted, which leads to a lack of all the functions that all the genes on the chromosome are responsible for. This can include the ones responsible for brain development and neuronal movement, so their absence can lead to any of these diseases. Lastly, it can be due to environmental causes, which are not common but can happen. It can either occur due to an infection in the brain or restricted blood flow to the baby during the pregnancy. These conditions often overlap, so cerebellar agenesis can happen with lissencephaly or other malformations like heterotopia. Heterotopia is a disease that occurs when there are neurons in abnormal locations, leading to various neurological issues.⁶

Diagnosis

The clinical presentations of these diseases are different when only cerebellar agenesis is present and when it is present with the addition of lissencephaly. Cerebellar Agenesis can present itself with symptoms like a lack of balance and consistent falling, slow or decreased motor skills, including bodily coordination and improper speech. When lisscephaly is also present, the symptoms include seizures, abnormally large heads, a delay in development, and intellectual disabilities. It is very rare for people with only cerebellar agenesis to go into adulthood with only motor difficulty, as the condition deteriorates over time and leads to high dysfunction. Patients who are affected by both diseases have been found to have great amounts of neurological disability and are unable to perform daily activities.⁴

These diseases are usually diagnosed using MRIs which can be done as either pre-natal or post-natal. The prenatal MRIs can only detect major brain malformations and cannot pick up on smaller ones. The postnatal MRI is considered to be the most accurate as it can pick up cerebellar agenesis and lissencephaly where we can clearly see the symptoms. Another way to diagnose these diseases is via genetic testing but this is only applicable if this malformation has happened due to a gene we already know about. DNA mutations can be very complex and difficult to understand making genetic testing only partially reliable. One significant side effect of these diseases is seizures which can cause more harm to the patient. The seizures can be asssesed by an Electroencephalogram to understand its severity and activity.⁷

As mentioned before, there is no cure for cerebellar agenesis or lissencephaly but these conditions can be managed by a myriad of ways. Firstly, nutrional support is required in all affected individuals to ensure good growth and support when required. Some people may experience trouble swallowing which necessitates a feeding tube or a gastronomy tube. Secondly, physical activity is of utmost importance to keep practicing motor skills. It could even be as small as picking up an object. The type of training and activity required will depend on the severity of the disease. In most cases, seizures are very common and having them at very short intervals can prove to be very harmful so using medication to stop them is required. Depending on the severity of the seizures or the epilepsy, the treatment can vary from dieting to surgical intervention. 

Summary

Cerebellar agenesis is a brain malformation that occurs mostly due to genetic mutations and causes the absence of the cerebellum. This disease is often found with another disease called lissencephaly which causes the brain to be smooth. A normal brain has an outer layer causing its grooves and texture but lissencephaly is a disease where the cerebral cortex is not present and the brain is smooth. These diseases can cause a severe impairment in motor skills, speech, and seizures. There has been no cure found for these diseases but they can be managed by various types of therapies, nutrition, and seizure control.