Lissencephaly

Lissencephaly, which literally means smooth brain, is a rare brain formation disorder characterized by the lack of normal convolutions (folds) in the brain. It is caused by defective neuronal migration, the process in which nerve cells move from their place of origin to their permanent location. It is a form of cephalic disorder.

The surface of a normal brain is formed by a complex series of folds and grooves. The folds are called gyri or convolutions, and the grooves are called sulci. In children with lissencephaly, the normal convolutions are absent or only partly formed, making the surface of the brain smooth. Terms such as 'agyria' (no gyri) or 'pachygyria' (broad gyri) are used to describe the appearance of the surface of the brain.

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Symptoms

Symptoms of the disorder may include unusual facial appearance, difficulty swallowing, failure to thrive, and severe psychomotor retardation. Anomalies of the hands, fingers, or toes, muscle spasms, and seizures may also occur.

Diagnosis

Diagnosis of lissencephaly is made at birth or soon after. Diagnosis may be confirmed by ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI).

Causes

Causes of lissencephaly can include viral infections of the uterus or the fetus during the first trimester, 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)^[1], 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, and genetic testing, such as amniocentesis, can detect lissencephaly mutations during pregnancy.

Classification

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

A consensus has been reached for a classification based on associated malformations and etiologies. On the basis of this classification, five major groups of lissencephaly can be recognized (OMIM numbers are included where available):

• Classic lissencephaly (previously known as type 1 lissencephaly - 607432), which include :
  • lissencephaly due to LIS1 gene mutation, which subdivides into:
    • type 1 isolated lissencephaly (601545)
    • Miller-Dieker syndrome (247200)
  • lissencephaly due to doublecortin (DCX) gene mutation (300121)
  • lissencephaly, type 1, isolated, without other known genetic defects

• Lissencephaly X-linked with agenesis of the corpus callosum (ARX gene, 300382)

• Lissencephaly with cerebellar hypoplasia, including
  • Norman-Roberts syndrome (mutation of reelin gene, 257320)

• Microlissencephaly (lissencephaly and microcephaly)^[2]

• Cobblestone lissencephaly, which includes:
  • Walker-Warburg syndrome (236670), also called HARD(E) syndrome
  • Fukuyama syndrome (253800) -- see also Fukuyama congenital muscular dystrophy
  • Muscle-Eye-Brain (MEB) disease (253280)

Treatment

Treatment for those with lissencephaly is symptomatic and depends on the severity and locations of the brain malformations. 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.

The prognosis for children with lissencephaly varies depending on the degree of brain malformation. Many individuals show no significant development beyond a 3- to 5-month-old level. Some may have near-normal development and intelligence. Many will die before the age of 2, but with modern medications and care, children can live into their teens. Respiratory problems are the most common causes of death.

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