Lissencephaly

Lissencephaly, also known as “smooth brain,” is a group of rare brain conditions that are caused by the abnormal development of the brain gyri, which are the ridges or folds on the outer layer of the brain that increase the surface area of the cerebral cortex. The cerebral cortex is the part of the brain responsible for conscious thought; movement; sensation; and higher intellectual functions, such as learning, reasoning, and problem-solving. The brain gyri allow for more tight packing and organization of neurons and thus greater cognitive processing. With lissencephaly, there can be fewer gyri (i.e., pachygyria) or complete absence of gyri (i.e., agyria), which causes a “smooth” appearance of the brain surface in an affected individual.  

There are several different types of lissencephaly, and they all share similar clinical characteristics but differ in genetic components. Most cases of lissencephaly can be categorized as classic lissencephaly, also called type 1 lissencephaly, or type 2 lissencephaly, also known as cobblestone lissencephaly. Additionally, isolated lissencephaly is when lissencephaly occurs without an associated syndrome, like with other genetic conditions, such as Miller-Dieker syndrome or Walker-Walburg syndrome.  

Lissencephaly can be caused by non-genetic and genetic factors. Most cases are caused by non-genetic factors, such as intrauterine infection like toxoplasmosis, inadequate oxygen supply during fetal development, or trauma during pregnancy.  

On the other hand, one of the most common genetic causes of lissencephaly is a mutation or deletion in the LIS1 gene. The LIS1 gene is an essential component in neuronal migration that occurs during fetal brain development, usually between 12 and 24 weeks of gestation. During normal fetal development, specialized nerve cells migrate to the surface of the brain and form various cellular layers known as gyri and sulci. With lissencephaly, these cells malfunction and don’t move to the brain’s surface, causing neuronal dysmigration. Lissencephaly, therefore, mainly affects infants. Lissencephaly can have a genetic cause inherited from a parent, or it can occur de novo, meaning the mutation occurs randomly and is not inherited.  

Lissencephaly is diagnosed shortly after birth through a clinical assessment and diagnostic imaging, which can include a CT scan or MRI of the brain. Imaging will usually show a decrease or absence of the gyri on the cerebral surface. Genetic blood testing, like a chromosomal analysis, can be conducted to confirm the diagnosis if a genetic mutation is the cause. An electroencephalogram (EEG) can also be used diagnostically to evaluate those with lissencephaly that may exhibit unusual brain electrical impulses. 

Lissencephaly can also be diagnosed during pregnancy beginning with an ultrasound screening and confirmed with cell-free fetal DNA testing, amniocentesis, or chorionic villus sampling.   

Treatment of lissencephaly is aimed at supportive measures to help manage symptoms. For example, if an infant is experiencing issues feeding, a feeding tube, like a gastrostomy tube, may be inserted to provide nutrients. With seizures, anticonvulsants, like phenobarbital or vigabatrin, can be used to help prevent or reduce the number of seizures the infant is experiencing.  

Treatment of lissencephaly usually requires a multidisciplinary approach with a variety of healthcare providers, like pediatricians, genetic counselors, and neurologists, involved in the child’s care. Life expectancy with lissencephaly is short with most affected dying during early childhood due complications like severe respiratory disease.