Lissencephaly is a rare, gene-linked brain malformation characterized by the absence of convolutions (folds) in the cerebral cortex and an extremely small head (microcephaly). The word lissencephaly literally means "smooth brain." Children with lissencephaly usually have head sizes in the expected range at birth. Children with a smaller head size at birth are typically diagnosed with microlissencephaly.

Lissencephaly is caused by defective neuronal migration during embryonic development, the process through which nerve cells move from their place of origin to a permanent location within cerebral cortex gray matter. Symptoms of the disorder may include:

• Facial differences
• Difficulty swallowing
• Failure to thrive (slow physical development)
• Muscle spasms
• Seizures
• Severe psychomotor impairment
• Congenital limb differences in the hands, fingers, or toes

Lissencephaly may be associated with other diseases including isolated lissencephaly sequence, Miller-Dieker syndrome, and Walker-Warburg syndrome. Sometimes it can be difficult to distinguish between these conditions clinically so consultation with national experts is recommended to help ensure correct diagnosis and possible molecular testing. The prognosis for children with lissencephaly depends on the degree of the disease.

Lissencephaly can be caused by non-genetic and genetic factors. Non-genetic factors include viral infections of the mother or the fetus, especially during the first trimester and insufficient supply of oxygenated blood to the brain during fetal development. There are several genetic causes also.

Some of the known genetic causes are listed below:

• LIS1

LIS1 (PAFAH1B1) is the most studied. This gene is located on chromosome 17p13.3. LIS1 regulates the motor protein dynein, which is linked to neuronal nuclei movement along microtubules. The mutation or deletion in the LIS1 gene is associated with both isolated Lissencephaly syndrome and Miller-Dieker syndrome.

• DCX

DCX is located on the X chromosome. DCX encodes for the doublecortin protein, which encodes a neuronal microtubule-associated protein, which is known to be essential for neuronal migration. DCX mutation causes defects in neuronal migration and reduced folding in the cerebral cortex. Males with DCX mutation are more likely to be severely affected, while females with the same mutation have a milder version of the syndrome.

• ARX

The ARX gene encodes for the aristaless related homeobox protein, which is a transcription factor with an important role in the forebrain and other tissue. Children with ARX mutation present with other symptoms such as the absence of portions of the brain (corpus callosum agenesis), abnormal genitalia, and severe epilepsy.

• RELN

RELN gene encodes reelin, an extracellular matrix glycoprotein. The mutation of this gene is involved in lissencephaly associated with cerebellar hypoplasia and hippocampal abnormalities.

• Other genes:

Several genes have established a relationship with lissencephaly. Those genes are VLDLR, ACTB, ACTG1, TUBG1, KIF5C, KIF2A, and CDK5.

Cytomegalovirus (CMV) has been associated with developing lissencephaly by reducing blood supply to the fetal brain. The severity of CMV infection depends on the gestational age. Early infection is more likely to cause lissencephaly because neuronal migration takes place early in the pregnancy.

Lissencephaly has different levels of severity and symptoms.

Symptoms may include seizures, feeding difficulty, muscle spasm, mental disability, severe psychomotor impairment, failure to thrive, developmental delays, and sometimes hands, finger, or toe anomalies. However, some children may develop normally with a mild learning disability.

Epilepsy develops in the first year of life in 9 out of 10 lissencephaly cases.

Lissencephaly is usually diagnosed at birth through clinical evaluation and head imaging (ultrasound, computed tomogram (CT), or magnetic resonance imaging (MRI)). It is characterized by the absence or reduction of the sulci and gyri of the cerebral surface and a thickened cortex. To confirm the diagnosis, DNA studies like chromosomal analysis or/and specific gene mutational analysis are needed to find a mutation. Another test that can aid in the diagnosis is the electroencephalogram (EEG).

Management for children with lissencephaly is symptomatic and supportive. Treatment aims to improve the intake of nutrients in patients with feeding difficulties and the use of anticonvulsant drugs to prevent or control seizures. Genetic counseling is usually offered to families of affected children, coupled with genetic studies.

The prognosis varies depending on the severity of the syndrome. Many children may remain in an early developmental level. Life expectancy is short, and many will die before the age of 10 years. The most common cause of death among lissencephaly patients is aspiration and respiratory disease.

Lissencephaly may affect some areas of the brain more severely than others. The gradient of severity is dependent on the lissencephaly type and gene mutations.