What Is Lissencephaly?

Lissencephaly or LIS is a genetic neurological disorder characterised by brain malformation. Unlike the usual pattern of peaks (gyri) and grooves (sulci), patients with LIS have abnormally thick or absent brain folds resulting in a brain which appears smooth.

Lissencephaly occurs during the development of a foetus in utero due to mutations in genes controlling neuronal migration. During foetal development, progenitor cells differentiate and migrate to the cerebral cortex. Malfunctions in this genetically controlled process cause insufficient migration and abnormal gyri formation. LIS comprises a spectrum of disorders from agyria (lack of gyri), and pachygyria (thick gyri) to subcortical band heterotopia (abnormal neuronal bands beneath a normal cortex).¹ Symptoms usually present very early in life and include muscle weakness, feeding difficulties, developmental delay and seizures.²

This article will cover the causes, symptoms and diagnosis of Lissencephaly as well as the treatment and management options available.

Overview

Lissencephaly (LIS) is a rare neurological disorder resulting in abnormally thick gyri and shallow sulci also known as smooth brain.² The condition can be caused by mutations in genes controlling neuronal migration during foetal brain development, viral infection in the uterus or insufficient blood supply during brain development. Diagnosis can occur prenatally or within the first year of life via molecular genetic tests and foetal magnetic resonance imagery (MRI) scans. Postnatal (after birth) symptoms such as muscle weakness, feeding difficulties, developmental delay, and seizures start to present early in life.

Causes of lissencephaly

During foetal development, neurons are made by the differentiation of neuronal stem cells, which then migrate into their final position, slowly forming the structure of the brain. Each stage of development is tightly controlled by genes which decide when, where, and how each cell develops. Starting at four  weeks, the foetus’ brain grows at a staggering rate of 250,000 cells per minute.³   In the case of lissencephaly, viral infection, insufficient oxygen supply, and inherited mutations can cause the control mechanisms to falter. This can result in insufficient (type I) or over-migration (type II) of neurons to the cerebral cortex.⁴  Thirty-one mutations have been validated as lissencephaly associated with the majority occurring in the following genes: LIS1, DCX, ARX, TUBA1A, and TUBB2B.⁵  These mutations cause different presentations of disease which are divided into two main categories: classic lissencephaly (type i) and cobblestone lissencephaly (type II).

Non-genetic causes of lissencephaly 

Brain damage in utero caused by a viral infection or lack of oxygen can result in the brain malformation characteristic of lissencephaly. 

Genetic causes of lissencephaly

Genetic mutations cause disease by improperly instructing the body on how to make a protein. Proteins function as the machines of the body, carrying out molecular tasks, regulating genes, and creating structure. Genes are the blueprints on how to make them and a mistake in the instructions can result in malformation or no protein at all. This is a problem when the protein’s task is essential and its absence or lack of function causes disease. 

Genetic mutations can occur randomly but often they are inherited from parents. Depending on which gene is mutated these can be inherited in different ways and cause different manifestations of the disease. 

For example, X-linked lissencephaly which means the mutation is present on the X chromosome. In this case, only people assigned male at birth (AMAB) are affected because they only carry one copy of the X chromosome. In people assigned female at birth (AFAB), the pair of X chromosomes means that if one has the mutation the healthy allele on the second chromosome can correct for the mistake, and the individual AFAB  would be classified as a carrier. 

Signs and symptoms of lissencephaly

Depending on the causative mutation and whether it is part of another syndrome, the symptoms of lissencephaly are highly variable. Some children may develop normally with only slight learning disabilities, but the spectrum also ranges to more severe symptoms. Common symptoms associated with lissencephaly include:

• Seizures - which develop early within the first few years of life and occur in 9 out of 10 individuals 
• Difficulty swallowing (dysphagia) and feeding issues
• Mental disability and learning differences
• Muscle spasms
• Psychomotor function issues: coordination, movement, and dexterity
• Slow physical development in a baby or child
• A small head size (microcephaly)
• Congenital differences in limb shape or size (hands, fingers, or toes)

Microlissencephaly occurs in a subset of lissencephaly patients. This condition describes gyral malformation combined with severe congenital microcephaly or a child born with an unusually small head size.

Diagnosis

Lissencephaly can be diagnosed prenatally during the third trimester using ultrasound scans, foetal MRI scans, and genotype-histopathological correlation tests. The scans allow clinicians to view the shape and structure of the brain and determine whether the pattern of grooves in the brain appears normal. The correlation test is a genetic test that uses DNA extracted from the parent’s blood, amniotic fluid, or placenta. The tests check for all known LIS-associated pathogenic mutations. Should these tests return negative, whole genome sequencing from the same samples can test for causative mutations that may not yet be known these are variants of unknown significance and need to be validated before they can be considered pathogenic or disease-causing variants. 

Postnatally the same tests can still be used with the addition of head scans. Once a baby is born, computed tomography (CT) scans can be carried out which combines multiple X-ray photographs using a computer to generate a 3D image of your child’s brain.

Clinicians look for shallow grooves and wide gyri as well as a thickened cerebral cortex in their diagnosis.

Management and treatment for lissencephaly

Given that lissencephaly is an irreversible congenital condition, treatment revolves around managing symptoms. 

FAQs

How can I prevent lissencephaly?

Once a foetus has started developing, lissencephaly cannot be prevented. Families with a history of lissencephaly or an affected first child should seek genetic counselling before further pregnancies. 

How common is lissencephaly?

The estimated birth rate of infants with LIS is 1.2 out of 100,000 births.

Who is at risk of lissencephaly?

Developing foetuses with parents carrying genetic mutations in the following LIS risk factor genes: LIS1, DCX, ARX, TUBA1A and TUBB2B are at a risk for this condition. For mutations in DCX, children AMAB are at greater risk.²

What can I expect if my child has lissencephaly?

Children with lissencephaly are all different as the condition presents itself in many ways. Children will need more regular medical checkups and you will need to track their development and administer any treatments they may require. Depending on the severity of the child’s intellectual disability, they may need more support completing daily tasks. A lissencephaly diagnosis can be extremely challenging and overwhelming, but working with medical professionals and creating a rigorous treatment plan will allow your family to give the best care for your child.  

When should I see a doctor?

Once your child has been diagnosed it is important to have regular contact with your healthcare provider to assess their development and maintain the correct treatment plan. Seizures, difficulties with feeding,  and psychomotor function issues are symptoms of several neurological conditions and should be brought to the attention of a medical professional. 

What is the life expectancy for lissencephaly?

Most children with lissencephaly do not make it to the age of 10 with the main cause of death  being aspiration (breathing in food, liquids, or a foreign object into the lungs).

Summary

Lissencephaly is a rare and predominantly hereditary genetic condition resulting in brain malformation. Also known as smooth brain, patients with this condition have distinctly shallow sulci, wide gyri, and a thick cortex. This is a result of defective neuron migration during the development of the foetal brain in utero. It can be caused by genetic mutations, oxygen deprivation, or viral infection. It is diagnosed prenatally in the third trimester if the child is at risk due to the identification of mutation-carrying parents or postnatally after the onset of symptoms. In both cases, genetic tests and brain scans are used. The age of onset for symptoms of lissencephaly is under one year old. These may present as seizures, issues with feeding, lack of motor control, spasms, and slow development. Later in life children may experience severe intellectual disability. Children will need more support with usual daily tasks and a dedicated treatment plan.