Lissencephaly (, meaning 'smooth brain') is a set of rare brain disorders whereby the whole or parts of the surface of the brain are smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a lack of development of brain folds (gyri) and grooves (sulci). It is a form of cephalic disorder. Terms such as agyria (no gyri) and pachygyria (broad gyri) are used to describe the appearance of the surface of the brain.

Children with lissencephaly generally have significant developmental delays, but these vary greatly from child to child depending on the degree of brain malformation and seizure control. Life expectancy can be shortened, generally due to respiratory problems.

Signs and symptoms

thumb|MRI scan showing the characteristic smooth brain of an individual with lissencephaly

Affected children display severe psychomotor impairment, failure to thrive, seizures, and muscle spasticity or hypotonia. Other symptoms of the disorder may include unusual facial appearance, difficulty swallowing, and anomalies of the hands, fingers, or toes.

Symptoms of lissencephaly are detected via ultrasound at about twenty-three weeks of gestation and require confirmation via prenatal MRI. It is characterized by absence or reduction of the sulci and gyri of the cerebral surface and a thickened cortex.

There are anatomical symptoms that differ across the two main types of lissencephaly, Classical (Type I) and Cobblestone (Type 2). In classical lissencephaly, the cerebral cortex becomes thickened and has only four identifiable layers rather than the usual six. or insufficient blood supply to the fetal brain early in pregnancy. There are also a number of genetic causes of lissencephaly, including mutation of the reelin gene (on chromosome 7), as well as other genes on the X chromosome and on chromosome 17. Genetic counseling is usually offered if there is a risk of lissencephaly, coupled with genetic testing.

Neuronal migration

Folding of the cerebral cortex is important in the development of overall brain function and cognitive abilities. Neuronal migration is the process by which neurons migrate to the final position in the brain during the development of the nervous system. This development of the nervous system occurs between 12 and 16 weeks of gestation.

The lack of gyri causing a smooth appearance of the cerebral cortex is due to abnormal neuronal migration in the developmental stages of the nervous system. The cause of lissencephaly has been linked to both genetic and non-genetic factors. Three main types of lissencephaly have been identified and although all types display the similar symptoms the pathogenesis of each type varies. Mutations in LIS1, DCX (doublecortin), ARX (aristaless related homeobox), RELN have all been identified to cause lissencephaly. Viral infections can also cause lissencephaly.

The known genetic and viral causes are listed below:

LIS1

LIS1 (also known as PAFAH1B1) is the most widely studied. LIS1 is located on chromosome 17p13.3. Miller-Dieker syndrome, however, has additional deletions of adjacent genes on chromosome 17 causing facial and other congenital abnormalities and defects.

DCX

DCX or doublecortin encodes for the doublecortin protein which is similar to LIS1 as it encodes a microtubule associated protein that is related to microtubule function and transport in developing neuronal processes. DCX is localised to the X chromosome and thus this mutation may be inherited however it still can appear randomly. As it is an X chromosome linked abnormality males who inherit the gene are more likely to be severely affected. Females who inherit the DCX mutation have a more mild version of the syndrome.

Viral infection

Lissencephaly has been recorded to have been caused by viruses and insufficient blood supply to the developing fetal brain. Cytomegalovirus (CMV) is a herpes-related virus that can cause congenital defects. computed tomography (CT), or magnetic resonance imaging (MRI). However, these results should be interpreted cautiously since even experienced radiologists can misdiagnose polymicrogyria, a different developmental malformation of the brain, as lissencephaly.

Before birth, complex ultrasounds performed routinely during pregnancy may indicate the presence of a cerebral abnormality, but this method of diagnosis should be complemented by other methods, such as genetic studies and NMR, and the examination is not recommended as part of routine ultrasound examinations, unless family medical history or other reasons for suspecting brain malformation are present. The earliest point during gestation when it is possible to observe abnormal development of the brain surface is approximately in week 20, although ultrasound examinations in week 25–30 are more common. Up to this time, the fetal brain normally has a smooth appearance. If lissencephaly is suspected, chorionic villus sampling can test for some lissencephaly variants, but only those with a known genetic mutation.

Classification

The spectrum of lissencephaly is only now becoming more defined as neuroimaging and genetics have provided more insights into migration disorders. There are around 20 types of lissencephaly that make up the spectrum. Other causes which have not yet been identified are likely as well.

Different systems for classifying lissencephaly exist. One major distinction is "classic" (type I) vs. "cobblestone" (type II), but some systems add additional forms that fit into neither of these categories.

Some types of lissencephaly are described below (OMIM numbers are included where available):

{| class="wikitable"

! Category !! Types

|-

| Classic (or Type 1) lissencephaly – ||

  • LIS1: lissencephaly due to PAFAH1B1 gene mutation, which subdivides into:
  • type 1 isolated lissencephaly ()
  • Miller–Dieker syndrome ()
  • LISX1: lissencephaly due to doublecortin (DCX) gene mutation ()
  • lissencephaly, type 1, isolated, without other known genetic defects

|-

| Cobblestone (or Type 2) lissencephaly ||

  • Walker–Warburg syndrome (), also called HARD(E) syndrome
  • Fukuyama syndrome ()
  • Muscle–eye–brain disease (MEB) ()

|-

| Other types ||

  • LIS2: Norman–Roberts syndrome (mutation of reelin gene, )
  • LIS3: TUBA1A,
  • LISX2: ARX,
  • Microlissencephaly (lissencephaly and microcephaly)

|}

Treatment

Treatment for those with lissencephaly is symptomatic and depends on the severity and locations of the brain malformations. Treatment is tailored towards the symptoms of the individual. Therapies for lissencephaly are to deal with the symptoms as the syndrome is congenital. Supportive care may be needed to help with comfort and nursing needs. Seizures may be controlled with medication and hydrocephalus may require shunting. If feeding becomes difficult, a gastrostomy tube may be considered.

There are a number of organisations that raise awareness and funding for rare disabilities such as lissencephaly. They also seek to increase the quality of life for individuals living with related disabilities. In the United States, these organizations include Arc of the United States, National Organization for Rare Disorders, and March of Dimes.

Prognosis

The prognosis for children with lissencephaly varies depending on the malformation and severity of the syndrome. Many individuals remain at a 3–5 month developmental level. Life expectancy is short and many children with lissencephaly will die before the age of 10. Some children with lissencephaly will be able to roll over, sit, reach for objects, and smile socially. Aspiration and respiratory disease are the most common causes of illness or death. In the past, life expectancy was said to be around two years of age. However, with advances in seizure control, and treatments for respiratory illness, most children affected can live well beyond that age. With other advances in therapy and the broader availability of services and equipment, some children with lissencephaly are able to walk with varying degrees of assistance and to perform other functions once thought too advanced.

See also

  • CEP85L—Gene associated with posterior predominant lissencephaly in a 2020 study
  • Gyrification

References

  • GeneReviews/NCBI/NIH/UW entry on DCX-Related Disorders
  • OMIM entries on DCX-Related Disorders
  • GeneReview/NIH/UW entry on LIS1 Lissencephaly