Lissencephaly

What is lissencephaly (smooth brain)?

Lissencephaly (pronounced li-suhn-SEH-fuh-lee), which means “smooth brain,” is a spectrum of severe and rare brain malformations (abnormally shaped) that affects developing fetuses. Gyri are the folds or bumps in your brain, and sulci are the indentations or grooves. In lissencephaly, the lack of normal development of brain gyri and sulci makes an affected baby’s brain appear smooth.

Gyri and sulci are important because they separate brain regions and increase your brain's surface area and cognitive ability.

There are more than 20 types of lissencephaly. Most of them are separated into two main categories: classic lissencephaly (Type 1) and cobblestone lissencephaly (Type 2). Each category shares similar symptoms but different genetic mutations.

Lissencephaly can occur on its own (isolated lissencephaly) or as part of certain syndromes, such as Miller-Dieker syndrome and Walker-Warburg syndrome.

Children with lissencephaly often have significant developmental delays and mental disability, but these vary from child to child depending on the severity of the condition.

Who does lissencephaly affect?

Lissencephaly affects developing fetuses. It usually develops during the 12th and 24th weeks of fetal development during pregnancy and is often caused by genetic mutations (changes). In rare cases, it’s caused by non-genetic factors.

How common is lissencephaly?

Lissencephaly is rare. Researchers estimate that lissencephaly affects about 1 out of every 100,000 babies.

What are the symptoms of lissencephaly?

Lissencephaly can cause a wide range of symptoms. It all depends on how severe the condition is and if it’s a part of a syndrome. Some children may develop as expected with a mild learning difference, while others may have many severe symptoms. The severity of symptoms can also vary widely.

Since symptoms and their severity can vary so much, it’s important to talk to your child’s healthcare provider about what you can expect from their type of lissencephaly.

Symptoms of lissencephaly may include:

• Seizures (epilepsy develops in the first year of life in 9 out of 10 lissencephaly cases).
• Difficulty swallowing (dysphagia) and eating.
• Developmental delays.
• Mental disability and learning differences.
• Muscle spasms.
• Issues with psychomotor functions, such as hand-eye coordination, movement and dexterity.
• Failure to thrive (slow physical development in a baby or child).
• A smaller-than-normal head size (microcephaly).
• Congenital limb differences involving their hands, fingers or toes.

What causes lissencephaly?

Lissencephaly is caused by non-genetic and genetic factors and develops in fetuses between the 12th and 24th weeks of pregnancy.

These factors cause impaired neuronal migration of the outer region of the brain during fetal development. Your cerebral cortex, the part of your brain that’s responsible for conscious movement and thought, normally has several deep gyri and sulci (grooves and folds).

During fetal development, new cells that’ll later turn into specialized nerve cells normally migrate (travel) to the surface of the fetus's brain. This is called neuronal migration, and it results in the formation of several cell layers. These layers form gyri.

In cases of lissencephaly, the cells don’t migrate (travel) to where they’re supposed to, and the fetus doesn’t have enough layers of cells in their cerebral cortex. This causes a lack of or underdevelopment of gyri.

Non-genetic causes of lissencephaly

Non-genetic causes of lissencephaly include:

• Viral infections of the pregnant parent or fetus, especially during the first trimester (the first to twelfth week of pregnancy).
• A lack of oxygenated blood (ischemia) to the fetus’s brain while they’re developing in the uterus.

Genetic causes of lissencephaly

Genetic causes of lissencephaly are due to genetic mutations. A genetic mutation is a change in a sequence of your DNA. Your DNA sequence gives your cells the information they need to perform their functions. If part of your DNA sequence isn’t complete or is damaged, you might experience symptoms of a genetic condition.

A baby can inherit a genetic mutation from either or both of their biological parents, depending on how the mutation is passed down, but some mutations occur randomly with no previous history of the mutation in your family.

Scientists have discovered several gene mutations that can cause lissencephaly. Some of the affected genes include:

• LIS1 (PAFAH1B1): A mutation or deletion in the LIS1 gene is associated with both isolated lissencephaly and Miller-Dieker syndrome.
• DCX: DCX is located on the X chromosome. Since people assigned male at birth (AMAB) have one X chromosome and one Y chromosome, infants AMAB are more likely to be severely affected by this gene mutation that causes lissencephaly. Infants assigned female at birth (AFAB), who have two X chromosomes, with the same mutation usually have a milder version of the condition.
• ARX: Infants with an ARX gene mutation have other symptoms along with lissencephaly, such as missing sections of their brain (agenesis of the corpus callosum), abnormal genitalia and severe epilepsy. ARX is also located on the X chromosome, so infants AMAB are typically more severely affected by this mutation than infants AFAB.
• RELN: A mutation of the RELN gene causes Norman-Roberts syndrome, which includes lissencephaly.

How is lissencephaly diagnosed?

Healthcare providers can sometimes diagnose lissencephaly during pregnancy if they suspect the condition because of family history and/or prenatal ultrasound. They can diagnose lissencephaly through prenatal screenings, such as amniocentesis, and fetal magnetic resonance imaging (MRI).

Otherwise, providers typically diagnose lissencephaly at birth through physical evaluation and head imaging tests.

When diagnosing lissencephaly with imaging tests, providers look for a lack or reduction of the sulci and gyri (grooves and folds) on the surface of your baby’s brain and a thickened cerebral cortex.

What tests will be done to diagnose lissencephaly?

If your healthcare provider suspects lissencephaly due to family history and/or the results of prenatal ultrasound, they may order specialized testing during pregnancy. These tests include:

• Cell-free fetal DNA: During cell-free fetal DNA screening, a provider extracts DNA from the birthing parent and fetus from a blood sample of the birthing parent. A laboratory expert screens the DNA for an increased chance of specific chromosome problems.
• Amniocentesis: Amniocentesis is a testing procedure usually performed during the second or third trimester of pregnancy. During amniocentesis, your provider uses a thin needle to remove a small amount of amniotic fluid from the sac surrounding the fetus. A laboratory expert then tests this fluid sample. Amniocentesis can diagnose certain genetic conditions and gene mutations, such as those that cause lissencephaly.
• Chorionic villus sampling (CVS): CVS is a procedure in which your provider takes a sample of chorionic villi from your placenta for testing. They can take the sample through your cervix (transcervical) or your abdominal wall (transabdominal). Chorionic villi are tiny projections of placental tissue that look like fingers and contain the same genetic material as a fetus. Chorionic villus sampling can reveal whether the fetus has a chromosomal condition and other genetic conditions.

Providers use the following imaging tests to help diagnose lissencephaly once your baby is born:

• Head ultrasound: Ultrasound (also called sonography or ultrasonography) is a noninvasive diagnostic imaging test. It uses high-frequency sound waves to create real-time pictures or videos of internal organs or other tissues, such as blood vessels.
• Head computed tomography (CT) scan: A CT scan is a type of test that combines X-rays with a computer to produce many 3-dimensional (3D) images of the body part being scanned — in this case, your child’s head and brain.
• Magnetic resonance imaging (MRI) brain scan: An MRI brain scan is a painless test that produces very clear images of the structures and tissues in your child’s brain. MRI uses a large magnet, radio waves and a computer to produce these detailed images. It doesn’t use X-rays (radiation).

Your provider may also perform an electroencephalogram (EEG) on your baby. An EEG measures and records your child’s brain’s electrical signals. During an EEG, a technician places small metal disks (electrodes) on your child’s scalp. The electrodes attach to a machine that gives their provider information about your child’s brain’s activity.

To confirm the diagnosis, providers use DNA studies, such as chromosomal analysis and specific gene mutational analysis, to find the mutation responsible for lissencephaly.

How is lissencephaly treated?

There’s no cure or main treatment for lissencephaly. Instead, healthcare providers target treatment toward the specific symptoms that each child with lissencephaly has.

Treatment may require the coordinated efforts of a team of specialists, including:

• Pediatricians.
• Neurologists.
• Gastroenterologists.
• Nutritionists.
• Respiratory therapists
• Occupational and physical therapists.

Common treatments include:

• Measures to improve the intake of nutrients for children with feeding difficulties, such as a gastrostomy tube (G-tube) and/or speech and swallowing therapy.
• Anti-seizure medications to help prevent, reduce or control seizures.
• Occupational and physical therapy to help with motor development and muscle stiffness.
• Placing a ventriculoperitoneal (VP) shunt to treat hydrocephalus (a buildup of fluid in the brain).

Your provider will likely recommend genetic counseling if your child has lissencephaly.

Can lissencephaly be prevented?

Unfortunately, most cases of lissencephaly can’t be prevented. If you plan on having a biological child, talk with your healthcare provider about genetic testing to understand your risk of having a child with a genetic condition or a condition that can be caused by an inherited genetic mutation, such as lissencephaly.

What is the prognosis (outlook) for lissencephaly?

The prognosis (outlook) for lissencephaly varies depending on the severity of the condition and if it’s part of a syndrome. Many children with lissencephaly remain at an early developmental level. But others develop normally with only mild learning differences.

Early and consistent therapy can be very helpful for some children. Therapies may include:

• Physical therapy.
• Occupational therapy.
• Speech therapy.
• Vision therapy.

Most children with lissencephaly need daily medications to prevent seizures and treat other complications.

What is the life expectancy of a child with lissencephaly?

The life expectancy of lissencephaly is generally short. Many children with the condition die before they reach 10 years of age. The most common cause of death among people with lissencephaly is aspiration (breathing in a foreign object, such as sucking food into your airway) and respiratory disease.

What can I expect if my child has lissencephaly?

It’s important to remember that no two children with lissencephaly are affected in the same way. It’s impossible to predict with certainty how your child will be affected. The best way you can prepare for the future is to talk to healthcare providers who specialize in researching and treating lissencephaly.

How can I take care of my baby with lissencephaly?

To help take care of your child with lissencephaly, follow their healthcare provider’s instructions for:

• Giving any medications as prescribed.
• Getting developmental assessments and therapies.
• Going to all follow-up medical visits.

Lissencephaly can cause cognitive (intellectual), neurologic and/or psychomotor issues. Most children with lissencephaly will have problems with their development and may need help with daily tasks throughout their lives.

Your child’s healthcare team can answer questions and offer support. They also might be able to recommend a local or online support group.

When should I see my healthcare provider about lissencephaly?

If your child has been diagnosed with lissencephaly, they’ll need to see their healthcare team regularly to make sure their treatment is working and to assess their developmental progress.

A note from Cleveland Clinic

Understanding your child’s lissencephaly diagnosis can be overwhelming. Your healthcare team will offer a robust treatment plan that’s unique to your child’s symptoms. It’s important to make sure your child is getting the love and support they need throughout their life and to stay attentive to their health to address any new symptoms that arise.