A rare condition, present at birth (congenital), that causes a developing brain to appear smooth instead of having normal bumps and folds is called lissencephaly. Most of the time, it happens due to a genetic mutation, but non-genetic factors may also cause it.
In other words, lissencephaly is a spectrum of severe and rare brain malformations that negatively affect the developing features. Typically, the indentations and grooves in the brain are called sulci, but folds and bumps are called gyri. Lissencephaly affects the development of gyri and sulci, which makes the brain appear smooth. These parts of the brain are very important because they increase the brain’s surface area and cognitive ability.
Furthermore, there are more than 20 types of lissencephaly. Healthcare professionals have divided this disorder into 2 main categories. For example, classic lissencephaly (type 1) and cobblestone lissencephaly (type 2). While both of them share similar symptoms, they are caused by different genetic mutations. Sometimes, lissencephaly may occur on its own or as a part of other syndromes (including Miller-Dieker syndrome and Walker-Warburg syndrome).
Generally, lissencephaly occurs rarely, and it affects about 1 in 100,000 babies.
What Are The Symptoms of Lissencephaly?
This condition often causes a wide range of symptoms, but they depend on the type and severity of the disease. For instance, some children with this condition have mild symptoms, but others may experience more serious symptoms (including intellectual disability). Check some general symptoms of lissencephaly below:
- Seizures (usually, epilepsy develops in the first year of life in 9 out of 10 lissencephaly cases)
- Developmental delays
- Problems with psychomotor functions (including movement, dexterity, and hand-eye coordination)
- Muscle spasms
- Dysphagia (swallowing problems)
- Failure to thrive
- Microcephaly (small head size)
- Congenital (present at birth) differences that involve the baby’s hands, fingers, and toes
If any of the previous symptoms occur in your child, immediately contact your healthcare provider. Otherwise, it may lead to unpleasant outcomes.
Causes
This serious condition may occur due to genetic and non-genetic factors. Most of the time, it appears between the 12th and 24th weeks of pregnancy. These factors cause impaired neuronal migration of the outer region of the brain during fetal development. Moreover, the cerebral cortex is a part of the brain responsible for conscious movement and thought that normally should have several deep gyri and sulci. However, the cells do not travel to where they are supposed to, and the fetus does not receive enough layers of cells in their cerebral cortex.
Genetic Causes of Lissencephaly
In such cases, the condition occurs due to a mutation in one of the following genes. Genetic mutations involve a change in a part of the DNA responsible for carrying and giving information to the cells. When a part of DNA is damaged or missing, symptoms occur.
The abnormal genes that cause lissencephaly can pass from one or both biological parents during pregnancy. According to some research, people with lissencephaly have a mutation in one or several of the following genes. Examples include:
- LIS1 (PAFAH1B1) – A change (mutation) or deletion in the LIS1 gene is often associated with both isolated lissencephaly and Miller-Dieker syndrome.
- DCX – This gene is located on the X chromosome. Normally, males have one X chromosome and one Y chromosome, which makes them more likely to have this abnormal gene. Usually, female infants have milder forms of this condition because they have 2 X chromosomes.
- ARX – Commonly, babies with a mutation in the ARX gene have other symptoms along with lissencephaly (such as missing sections of their brain, abnormal genitalia, and severe epilepsy). This gene is also located on the X chromosome, which is a factor that causes more severe forms of lissencephaly in males.
- RELN – A mutation in this gene often causes Norman-Roberts syndrome, which includes lissencephaly.
Non-genetic Causes
These include:
- Viral infections during pregnancy (especially during the first trimester of pregnancy)
- Ischemia (a lack of oxygen-rich blood flow to the fetus)
What Happens if Lissencephaly is Left Untreated?
People with lissencephaly may also experience some complications. Check some examples below:
- Severe motor and cognitive impairment
- Epilepsy – About 90% of people who develop lissencephaly experience this complication. They may also have severe seizures in the first year of life.
- Muscle tone problems (including hypotonia and spasticity)
- Aspiration – People with hypotonia (weak muscle tone) may have swallowing problems, which may lead to aspiration of food or fluids into their lungs.
- Aspiration pneumonia
- Scoliosis
This document does not contain a full list of lissencephaly complications. However, you can consult with your healthcare professional about ways to reduce the risk or even prevent them. In addition, there is no way to prevent this condition in most cases (especially genetic ones). However, you can perform some genetic tests before pregnancy to make sure you do not have abnormal genes that cause this condition. It is very important to understand the risks of having children with lissencephaly.
Diagnosis
Sometimes, physicians can diagnose this condition during pregnancy. They often suspect it because of family history and/or prenatal ultrasound. Prenatal screenings include amniocentesis and fetal MRI (magnetic resonance imaging). When doctors are trying to diagnose this condition, they will look for a lack or reduction of the sulci and gyri on the baby’s brain. However, to confirm or rule out this disorder, doctors often perform the following tests. Check below some tests that are done before birth to diagnose lissencephaly:
- Cell-free fetal DNA – During this screening, physicians will extract DNA from the mother and fetus from a blood sample of the mother. Thereafter, a laboratory expert will screen the DNA for an increased chance of specific chromosome issues.
- Amniocentesis – This test is often performed in the second or third trimester of pregnancy to check the amniotic fluid. Doctors often use a needle to take a sample of this fluid for testing. It often helps detect genetic disorders and gene mutations (including those that cause lissencephaly).
- Chorionic villus sampling (CVS) – During this procedure, physicians will take a sample of chorionic villi from the placenta for testing. In some cases, they may take the sample through the cervix or the abdominal wall.
When doctors suspect lissencephaly but do not diagnose it during pregnancy, they may perform additional tests after birth. These include:
- Brain MRI scans
- Head CT (computed tomography) scans
- Head ultrasound
In rare cases, doctors may also perform an electroencephalogram (EEG), which is used to measure the electrical activity of the brain.
Treatment
Unfortunately, there is no way to cure this condition. That’s why the treatment goal is to reduce the symptoms, prevent serious complications, and improve your child’s quality of life. Moreover, treatment for people with lissencephaly requires a healthcare team, which often includes neurologists, pediatricians, gastroenterologists, nutritionists, respiratory therapists, and occupational and physical therapists. Check below the most common treatment options recommended by doctors for people with lissencephaly:
- Ventriculoperitoneal (VP) shunt – This treatment is used to treat hydrocephalus (a fluid buildup in the brain).
- Occupational and physical therapy – These therapies often help with motor development and muscle stiffness.
- Anti-seizure medicines to prevent or treat seizures.
- Options to improve intake of nutrients for children – These include swallowing therapy, speech therapy, and a gastrostomy tube (G-tube).
Frequently Asked Questions
What is the prognosis for lissencephaly?
The outlook for this disorder varies among people because it depends on several factors. These include the severity and type of the condition, age, and your response to treatment. While many children with this condition remain at an early developmental level, others may develop properly with mild learning differences only. Usually, starting the following therapies as soon as possible helps improve the outcome of this disorder. Examples include occupational therapy, physical therapy, vision therapy, and speech therapy.
What is the life expectancy of a child with lissencephaly?
Generally, the life expectancy of children with this condition is short. Usually, most children die before they reach 10 years of age. One of the most common causes of death is aspiration and respiratory diseases.
When should I see my healthcare provider about lissencephaly?
Once your child is diagnosed with lissencephaly, you should make sure the treatment is working and assess their developmental progress. Usually, it is recommended to see a doctor if you notice your child has new or worsening symptoms.
Can lissencephaly be detected before birth?
Sometimes, lissencephaly can be suspected during pregnancy through prenatal ultrasound, especially in the second half of pregnancy when the brain’s folds should become more visible. However, fetal MRI often provides more detailed images of the developing brain. If there is a family history of lissencephaly or a known genetic mutation, genetic testing through chorionic villus sampling (CVS) or amniocentesis may also help confirm the diagnosis before birth.
Is lissencephaly an inherited condition?
Most diagnosed cases are caused by spontaneous genetic mutations that occur for the first time in the affected child. However, some forms of lissencephaly are inherited in an autosomal dominant, autosomal recessive, or X-linked pattern, depending on the specific gene involved. Families with a history of lissencephaly may benefit from genetic counseling before planning future pregnancies.
Can children with lissencephaly learn to walk or talk?
It depends on the severity of the brain malformation. Children with milder forms of lissencephaly may achieve some developmental milestones, including limited speech and walking with assistance. However, children with more severe forms often have profound developmental disabilities and require lifelong assistance with daily activities, communication, and mobility.
Does lissencephaly always cause seizures?
No, but seizures are extremely common. Approximately 80% to 90% of children with lissencephaly develop epilepsy, often during the first year of life. Some children experience infantile spasms or difficult-to-control seizures that require multiple anti-seizure medications and close monitoring by a pediatric neurologist.
What specialists are involved in caring for a child with lissencephaly?
Because lissencephaly affects multiple body systems, treatment usually involves a healthcare team. This team may include pediatric neurologists, geneticists, developmental pediatricians, gastroenterologists, pulmonologists, nutritionists, physical therapists, occupational therapists, speech-language pathologists, orthopedic specialists, and social workers. Regular follow-up appointments help manage symptoms and improve the child’s quality of life.
Can adults have lissencephaly?
Yes. Although severe forms often shorten life expectancy, some people with milder forms of lissencephaly survive into adolescence and adulthood. Adults with lissencephaly may continue to require medical care for epilepsy, muscle stiffness, mobility limitations, feeding difficulties, and other long-term (chronic) complications. Their level of independence depends largely on the severity of the condition.
Should families consider genetic counseling after a diagnosis of lissencephaly?
Yes. Genetic counseling is strongly recommended after a diagnosis because it can help identify the underlying genetic cause, determine whether the mutation was inherited or occurred spontaneously, estimate the risk of recurrence in future pregnancies, and discuss available reproductive options and prenatal testing. Genetic counseling can also help families better understand the condition and connect them with appropriate support resources. Ask your healthcare provider if you have additional questions.
