Introduction

Lissencephaly is a rare neural disorder that affects foetuses. When the brain folds, it develops a smooth surface, known as a “smooth brain”.¹ This leads to a series of neurodevelopmental impairments, like motor dysfunction and intellectual disability.¹ Lissencephaly is extremely rare; it affects approximately 1 in every 100,000 live births, according to researchers.¹

Imaging techniques and genetic testing are used to make an accurate diagnosis. Neuroimaging techniques, such as MRIs, can visualise the brain abnormalities. Genetic testing can reveal the characteristics of the brain folds. It detects any malformations and their severity for different lissencephaly types. Genetic data and imaging scans are essential for the diagnosis of lissencephaly and for predicting outcomes.¹

This article explains how lissencephaly is identified through imaging and genetic information.

What Is Lissencephaly?

Lissencephaly is an uncommon brain deformity that shows a smooth cerebral surface on scans. During the development of the foetus, between 12 to 24 weeks, the neural migration (the movement of brain cells to their proper positions) is disrupted, resulting in reduced folds. ‘Gyri’ are the folds, and ‘sulci’ are the indents in your brain. While the foetus is in gestation, neurons travel from the deep parts of the brain’s ventricles to the outer layers of the cerebral cortex. This will form proper gyri and sulci. With lissencephaly, the transfer of neurons fails during brain development, which leads to functional abnormalities and deformation.²

The clinical presentation of lissencephaly during foetal development includes:^1,3

• Seizures (epilepsy can occur in lissencephaly cases starting in infancy) 
• Developmental delays (achieving actions like rolling over, sitting, standing, walking, etc.) 
• Hypotonia (low muscle tone)
• Spasticity (stiff muscles)
• Microcephaly (abnormally small head)
• Slow physical development
• Muscle spasms
• Learning disability 

Depending on the severity of the deformation, symptoms will vary.

There are two main forms of lissencephaly. Classic lissencephaly (type 1) and cobblestone (type 2). The difference between them is their genetic mutation.¹  

Classic lissencephaly results in a smooth brain. The genetic mutations occur due to the failure of neural migration, which affects LIS1 or DCX (genes that help brain cells move to the right place during early brain development). This can affect only the brain or other organs.²

Cobblestone Lissencephaly is the over-migration of the neurones to the outer surface of the brain, presenting abnormal bumps that look like cobblestones. This develops muscle and eye disease.²

Imaging Criteria in Lissencephaly Diagnosis 

To diagnose lissencephaly accurately, imaging is required. This includes prenatal screenings and magnetic resonance imaging (MRI). A foetal MRI provides a detailed view of the brain and is painless. Typical findings of an MRI scan are the reduction of the gyri and sulci, a smooth surface, and a thickened cortex. These are neural defects to look out for during brain development. ¹

Different patterns can identify the severity of lissencephaly. The brain abnormalities are not the same all around the brain. The posterior (back) of the brain has most of the malformations compared to the anterior (front). The problems can differentiate the type of lissencephaly, and there are two types.⁴

Classic (Type 1) 

The posterior of the brain shows a smoother surface and a thickened cortex. Gradually, towards the anterior, there are fewer gyri, and there are more abnormalities in the back, less severe in the front.

Cobblestone (Type 2) 

The irregular, bumpy/cobblestone cortex with abnormal layering due to over-migration of the neurons. The patterns do not show a clear distinction between the front and the back of the brain, as it affects multiple parts.

Prenatal imaging is important for early detection. Foetal MRI’s are more accurate as it offers high-resolution images to assess the structure of the brain before birth and any other abnormalities, to provide the next steps for the patient and counseling. Ultrasounds cannot provide precise results as scans may show a smoother-than-expected brain, but it is a warning sign and is useful for early detection.^1,4

Genetic Basis of Lissencephaly

Genetic mutations are the main cause of lissencephaly because they interfere with brain development early in life. To confirm the diagnosis and for the family to plan ahead, doctors need to test the genetics as it is important for inheritance and possible risks.²

The main genetic causes are:

LIS1 (PAFAH1B1) 

Identified first and is the common gene. Deletion or mutation of this gene results in a smooth brain surface and a thickened cortex near the back of the brain. This is associated with Lissencephaly and Miller-Dieker syndrome. ^{2, 5}

DCX (doublecortin) 

Essential for neural migration. It is located on the X chromosome, is X-linked to lissencephaly, and Interacts with LIS1. The DCX mutation causes errors in neural migration. Males are more affected than women. Appearance change near the front of the brain.^2,6

Other genes:²

• TUBA1A – involved in neuronal structure 
• ARX –  associated with lissencephaly 
• RELN – promote cortical disfiguration 
• DYNC1H1 – affects neural development 

The inheritance patterns may be X-linked or autosomal dominant.²

Genetic testing is an essential tool used to find genes to complement imaging. This includes whole-exome sequencing (WES) and targeted gene panels to identify specific gene mutations that cause lissencephaly. Testing can help MRI findings detect gene alterations that imaging scans cannot pick up on.³

In lissencephaly, genotype-phenotype correlation (linking genes to visible features) is needed to link certain gene variations to characteristic brain patterns.² For example, the LIS1 gene mutates near the posterior region (back of the brain), the main area it affects in lissencephaly. DCX mutations lead to anterior lissencephaly (affecting the front of the brain), which is more severe. Males with the abnormal DCX gene have it in the front, but for females, a subcortical band heterotopia (extra layer of misplaced brain cells) can form. This is because the neurons make a double layer of cortex. These patterns are important to recognise to tailor clinical care to the patient.⁷

Classification Systems 

Lissencephaly is categorised and graded based on the neuroimaging features and genetic tests conducted for diagnosis and clinical management.

Imaging-based classification

To measure the severity of lissencephaly, there is a grading system called the Barkovich classification. These grades them from 1-6 based on how smooth the brain is.⁸

• Grade 1: no gyri around the brain
• Grade 2-3: mixed gyri appearances, as seen in gene mutations LIS1 and DXC
• Grade 4-6: quite large gyri with only a few grooves⁹

The grading system helps MRI scans evaluate the thickness of the cortex, any white matter abnormalities, and ventricular size. Doctors will assess the intensity of the malformation from the scans.⁸

Genotype-based classification

Genetic mutations can be held accountable to help doctors understand the genes' involvement with distinct brain patterns and inheritance. Different genes affect brain growth.¹⁰ As stated previously, the mutated genes are:

• LIS1 is most severe at the back of the head, and can be inherited by an autosomal dominant pattern, or can occur sporadically, meaning randomly^2,10
• If it is DCX-related, then the males will have it severely at the front of the brain. For females, they would develop a “double cortex,” which is a mild form of lissencephaly, as females have two X chromosomes. This is because the neurons are misplaced in the brain, creating that thick second layer^2,10

Other related genes are  ARX, RELN, TUBA1A, and DYNC1H1. They have close, distinct patterns that can be picked up through genetic testing.

LIS1 and TUBA1A are autosomal dominant mutations, meaning if one parent has it, then it is 50% likely the child will have it.¹¹

DCX and ARX are both X-linked, as it closely linked to the X chromosome, which can also affect genital abnormalities.²

In many cases, lissencephaly can happen out of the blue, even without shared genetics and family history. This can be explained by unexpected new mutations.

There are a few syndromic associations that lissencephaly is part of, such as

• Miller-Dieker syndrome is the removal of the LIS1 gene. This condition is quite fatal and causes the outer part of the brain to be smooth¹²
• Walker-Warberg Syndrome appears like type 2 (cobblestone). The genetic conditions associated with lissencephaly are the irregular grooves/sulci^13,14

Diagnostic Workflow

The clinical approach towards lissencephaly starts with developmental delays towards the foetus. This is because of early signs that raise clinical suspicions. Other symptoms doctors may look out for are seizures and poor muscle tone.¹ 

Once the symptoms have been noted, an MRI is scheduled and performed to assess the brain structure. The scan will confirm the multiple brain malformations, and the patient will need to be referred for genetic counselling and further testing. These tests include WES and other gene panels.¹ 

Doctors will also consider family history to see if there is a genetic factor and to avoid future risks if the patient has any future pregnancies. Lissencephaly can happen inconsistently, meaning that variants in the genes can happen without inheritance. Every foetus must be carefully assessed.¹ 

The importance of combining imaging and genetic results for full diagnosis and prognosis lies in providing genetic data and unique insights. Imaging in lissencephaly will help with anatomical cases, while genetic classifications aid in molecular cases.¹ 

The specialists involved in the case are radiologists for the imaging scans, neurologists to discuss the brain malformations, geneticists for the genetic factors of lissencephaly, and other developmental specialists. This healthcare team will give the best care plan going forward and support the family with their problem with educating the disorder and guidance.¹

Prognosis and Implications

The hypothesis of lissencephaly is tied to the brain becoming irregular and how the underlying gene mutations. The children who have brain abnormalities and a completely smooth brain have more severe complications than other cases who have a semi-smooth brain. The mutated genes like LIS1 and DCX can influence the brain and life expectancy.¹

Common complications can begin early in life and are difficult to manage. This includes the cognitive delays in the brain’s motor functions and drug-resistant epilepsy. Children will need life-long assistance in any daily activities because symptoms like muscle weakness and seizures may occur at any time.¹

If doctors can get a diagnosis early, then seizures can be managed and the patient can go into supportive care like therapies to help with early development challenges. The plan can also include any medical needs and forthcoming possibilities. The family will need counselling to understand the importance of this disorder that may happen in future pregnancies, so the family can think about any reproductive decisions.¹

There is no cure for lissencephaly, only long-term care and improvement in the patient’s and family's life.

Summary

Lissencephaly is a rare brain disorder caused by a defect in neural migration during the development of a foetus. Unfortunately, lissencephaly cannot be prevented. Lissencephaly is known for its ‘smooth brain’ appearance in imaging scans and a range of neurological symptoms like seizures, developmental delays and motor function impairment. MRI imaging is important for high-resolution images of the brain to confirm the diagnosis, along with genetic testing for the identification of underlying mutations.

Both imaging and genetic approaches are needed for accurate classification, as it can be hereditary or sporadic. To determine the findings, doctors need to assess the severity and guide the prognosis. It is better to find out early on to access the therapy services and inform the family to get the next steps. It will involve clinical management and other specialists to get the utmost care for the family to guide them through their daily life and improve upon it as families stick together.

FAQs 

What causes lissencephaly?

Lissencephaly is caused by the neurological disfigured development of the foetus during its 12-24 week gestation. The neurons in the brain travel incorrectly, which can lead to malformations of the grooves in the brain and smoothen its surface.

Can lissencephaly be diagnosed during pregnancy?

In some cases, yes. An ultrasound can detect it early, but not clearly. So, an MRI is needed to confirm if the foetus has lissencephaly to get a clearer image and confirm it later in the pregnancy. Brain abnormalities are subtle, so they may go unnoticed after birth.

Is lissencephaly hereditary?

Some forms of lissencephaly are hereditary because of specific mutations. Other cases can happen occasionally out of the blue. LIS1 and DCX are gene mutations that are linked to the family as DCX is from the X chromosome. LIS1 is autosomal dominant, meaning one of the parents can pass it down.

Can children with lissencephaly live into adulthood?

Depending on the severity, a patient with lissencephaly can make it all the way to adulthood, but the life expectancy is quite uncertain. This is because of the severity of the brain malformations and the seizures that come along with it. With enough support, patients can live throughout childhood and teenage life. However, growing up will also bring some physical challenges and developmental problems.¹