What is lissencephaly?

Lissencephaly (li-suhn-SEH-fuh-lee) is a broad condition that affects 1 in 100,000 births, where the development of the folds characteristic of the brain (called gyri and sulci on the cerebral cortex) is absent, causing it to appear smoother.¹ Development of these folds is important as they increase the brain’s surface for activity and neuronal transmission, as well as separate the respective regions and functions. It can be caused by both genetics and environmental factors, usually between 12 to 24 weeks of embryonic development.² These causes can include:

• Viral infection during pregnancy of the mother within 1 to 12 weeks of pregnancy
• Lack of oxygen supply during foetal development
• Metabolic disorders
• A mutation of the DNA sequence during development that damages or alters the genetic sequencing
• Genetic inheritance of disease

The main symptoms may include, but are not limited to:

• Seizures e.g epilepsy
• Neuronal impairment and learning disabilities
• Lack of coordination
• Muscle spasms 
• Difficulty swallowing and communicating
• Physical abnormalities, e.g sunken face (midface hypoplasia)

The symptoms vary depending on severity and can occur in isolation or together with other syndromes such as Miller-Dieker syndrome³ and manifest in over 20 variations of lissencephaly. Children with milder symptoms can be classified with Pachygyria. 

Diagnosis and differentiation of lissencephaly

How is lissencephaly diagnosed?

Lissencephaly is usually diagnosed at birth through ultrasound, computed tomogram (CT) or magnetic resonance imaging (MRI) during pregnancy. This is further confirmed by DNA chromosomal microarrays, brain malformation panels and whole exome sequence analysis, where DNA is extracted from blood samples from the mother to check for missing or extra chromosomes, genes associated with the condition and the whole genome itself. Electroencephalograms (EEG) may also be performed on the baby out of the womb to check the electrical activity of the brain.⁴

Through these procedures, the type of lissencephaly can be found, as symptoms can be similar between different types with different genetic reasons for onset. The main categories of lissencephaly include: Classic lissencephaly (usually referred to as Type 1) and Cobblestone lissencephaly (usually referred to as Type 2).

What is classic lissencephaly?

Classic lissencephaly (also known as Type 1 lissencephaly) shows the cerebral cortex of the brain consisting of 4 poorly organised layers compared to 6 in normal patients due to undermigration of neurons. This happens between weeks 12 to 24 of gestation, leading to a simplified brain structure. This can be seen through scanned radiograph images, where the brain takes on an hourglass appearance with a thickened cortex of 10 to 20mm.⁵ A smooth surface area can also be seen on the scan, with poorly defined zones in the brain.⁴

More specific variations of classic lissencephaly, like LIS1, explain lissencephaly with facial dysmorphism and LISX1, a variation due to DCX gene mutation. DCX is located on the X chromosome, which therefore means males have a higher probability of developing this mutation due to only having one X chromosome.¹

What is cobblestone lissencephaly?

Cobblestone lissencephaly (also known as Type 2 lissencephaly) shows the cerebral cortex of the brain to be more disorganised, with a bumpy and pebbled appearance compared to classic lissencephaly, hence ‘cobblestone’. This is due to the clustering of cortical neurons in the brain tissue by overmigration, as glial limitants do not function normally to stop neurons from migrating to the brain's surface. Common disorders from cobblestone lissencephaly are the development of muscle and eye disease. However, presentations of symptoms are different depending on the underlying syndrome, such as muscle-eye-brain (MEB) disease, Walker-Warburg and Fukuyama syndrome, being the main conditions that accompany cobblestone lissencephaly, which all cause muscle weakness.⁶

Both classic and cobblestone lissencephaly have an abnormal distribution of grey matter. To determine the difference between classic and cobblestone lissencephaly, X-ray scans show classic lissencephaly to have a thicker cortex in the brain compared to cobblestone lissencephaly.

Prognosis and treatment of lissencephaly

What is the prognosis of lissencephaly?

As there is no cure for lissencephaly in both isolated and associated lissencephaly, most individuals have stunted growth till 3 to 5 months old.⁴ Children with Miller-Dieker syndrome (MDS), along with lissencephaly, have a lower prognosis, with most only surviving the first two years, compared to isolated lissencephaly, with half of the individuals reaching the age of 10.¹ 

Unfortunately, as this condition affects the brain and cannot be prevented, life expectancy is short, and most patients fail to reach past the age of 10 due to respiratory disease and aspiration. This can be extremely stressful for both the caregiver and patient; talking with a relevant health professional regarding lissencephaly can help reduce this while receiving expert advice.

What treatments are available for lissencephaly?

There is no specific treatment to prevent or cure lissencephaly, and instead, consistent checkups, therapy and medication are used to prolong life expectancy and to reduce the discomfort of the patient.⁴ 

Therapies can include speech, physical and coordination to develop motor control and prevent muscle stiffness. Anti-epileptic medication can be administered to control and reduce the frequency of seizures, and other medications, such as laxatives, sleep-inducing medications, can be used to treat constipation and provide comfort in sleep.⁴ Patients with difficulty swallowing may need a gastrostomy tube (also known as a feeding tube) to improve food intake and nutrient absorption.¹ They also may need a ventriculoperitoneal (VP) shunt if they are diagnosed with hydrocephalus to prevent fluid buildup in the brain to relieve pressure in the head. Other treatments and therapies include communication aids, mobility equipment and specialised diets

Summary and overview

Lissencephaly is a rare condition that affects the structure of the brain as soon as a child is born. There are different classifications depending on the appearance of the brain and the different symptoms accompanying it. Lissencephaly can develop from other syndromes and worsen depending on the condition and stage of the patient. While both classical and cobblestone lissencephaly result in brain impairments, the underlying genetic mechanisms for these cases cause symptoms that are distinct to each type. Understanding the genetic basis and development is essential to increase prognosis and proper treatment to manage this disease.

If your child has been diagnosed with either classic lissencephaly or cobblestone lissencephaly, checkups with a professional healthcare team with dedicated researchers will help you understand ways to care for your child. Closely monitoring development and quality of life can help tailor therapies and treatments to ensure they get the support they need.