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Lissencephaly

What is Lissencephaly?

Lissencephaly

Complete agyria. Arrows indicate underdeveloped perisylvian region that creates characteristic figure eight appearance.

Lissencephaly (LIS), which literally means “smooth brain”, is a rare, genetic brain malformation characterized by the absence of normal convolutions (folds) in the cerebral cortex. It is caused by defective neuronal migration during the 12th and 14th week of gestation. The normal structure of the brain should have folds and grooves on the grey matter’s surface or on the cerebrum. However, during pregnancy the structure of the brain did not develop properly, resulting smooth surfaced brain structure. Lissencephaly encompasses a continuous spectrum of malformations from complete agyria (smoothness) to variable degrees of agyria and pachygyria, to subcortical band heterotopia (SBH). Lissencephaly may be associated with other diseases including Miller-Dieker syndrome (MDS), Muscle-eye-brain disease (MEB), and Walker-Warburg syndrome (WWS).

Classification and known presentations

The spectrum of lissencephaly is only now becoming more defined as neuroimaging and genetics have provided more insights into migration disorders. There are approximately 20 different types of lissencephaly which make up the spectrum:

Anterior predominant or diffuse classic (four-layered) LIS and SBH

Clinically defined with unknown cause

Lissencephaly

Normal cortical folds

  • Anterior predominant LIS with abrupt transition and cerebellar hypoplasia (previously LCHe)
  • Anterior predominant or diffuse LIS (ILS)

Clinically defined with AR inheritance

  • Anterior predominant LIS (ILS) with AR inheritance
  • Winter–Tsukahara syndrome (Levin et al., 1993)

Clinically defined with AD (new mutation) inheritance

Lissencephaly

LIS1 Lissencephaly. T1-weighted axial section showing a simplified gyral pattern and a thick cortex that is smooth, particularily in the posterior brain.

Posterior predominant or diffuse classic (four-layered) and two-layered (without cell-sparse zone) LIS and SBH
Clinically defined with unknown cause

  • Posterior predominant or diffuse LIS with brainstem and cerebellar hypoplasia, with/without ACC (includes former LCHa, LCHc, LCHd, LCHf (Ross et al., 2001))
  • Posterior predominant or diffuse LIS (ILS) (Pilz et al., 1998,Dobyns et al., 1999)
  • Diffuse LIS with hair and nail anomalies (Celentano et al., 2006)
  • Perisylvian (central) pachygyria (ILS)
  • Ribbon like deep white matter heterotopia with/without ACC, thin overlying cortex

Clinically defined with AD inheritance

Genetically defined with AD inheritance (new mutation)

Lissencephaly

Axial T2-weighted showing complete agyria in the posterior, and near complete agyria in the anterior.

X-linked lissencephaly (three-layered, without cell-sparse zone) with callosal agenesis, ambiguous genitalia (XLAG)
Clinically defined with unknown cause

  • XLAG-like syndrome with temporal-posterior predominant LIS, ACC, microphthalmia and midline cleft lip and palate

  • XLAG with temporal-posterior predominant LIS and ACC with mutations in ARX at Xp22.13 (Bonneau et al., 2002)

Reelin-type LIS (inverted cortical lamination, without cell-sparse zone)
Clinically defined with AR inheritance

Genetically defined with AR inheritance

  • Frontal predominant mild LIS with severe hippocampal and CBLH with RELN mutation at 7q22 (Hong et al., 2000)

  • Frontal predominant mild LIS with severe hippocampal and CBLH with VLDLR mutation at 9p24 (Boycott et al., 2005)

Lissencephaly

Axial T2-weighted MRI showing anterior pachygyria and near complete posterior agyria in a 2 month old child. The cortex is thick, and a thin outer layer is separated by white matter from a broad layer of arrested neurons.

Variant LIS (other rare types exist but are poorly characterized)

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Different systems for classifying lissencephaly exist. Another major distinction is “classic” (type I) vs. “cobblestone” (type II). OMIM numbers are shown below in red.

Classic lissencephaly (607432)

  • LIS1: due to PAFAH1B1 gene mutation, which subdivides into:
    •  type 1 isolated lissencephaly (601545)
    •  Miller-Dieker syndrome (247200)
  • LISX1: lissencephaly due to doublecortin (DCX) gene mutation (300121)
  • Lissencephaly, type 1, isolated, without other known genetic defects

Cobblestone lissencephaly

  • Walker-Warburg syndrome (236670)
  • Fukuyama syndrome (253800)
  • Muscle-eye-brain disease (MEB)(253280)

Other types

  • LIS2: Norman-Roberts syndrome (257320)
  • LIS3: TUBA1A (611603)
  • LISX2: ARX (300215)
  • Microlissencephaly (lissencephaly and microcephaly)
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The following classification scheme for lissencephaly is based on severity (grades 1-6) and the gradient:

  • Grade 1: generalized agyria
  • Grade 2: diffuse agyria, with few folds at the frontal or occipital poles.
  • Grade 3: mixed agyria and pachygyria
  • Grade 4: diffuse pachygyria, or mixed pachygyria and normal or simplified gyri
  • Grade 5: mixed pachygyria (anterior) and subcortical band heterotopia
  • Grade 6: subcortical band heterotopia alone

Grade 1 and Grade 4 are very rare. Grade 2 is observed in children with Miller-Dieker Syndrome. The most common lissencephaly observed is Grade 3, usually consisting of frontotemporal pachygyria and posterior agyria.

Symptoms

Symptoms of the disorder may include difficulty swallowing/feeding, abnormal muscle stiffness (spasticity), seizures, low muscle tone (hypotonia), and intellectual difficulties. People without any folds in the brain (agyria) typically have more severe symptoms.

Causes

There are 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. About 60% of patients with lissencephaly carry genomic alterations or mutations in the LIS1 gene.  About 1-4% of patients with classic lissencephaly carry mutations in the TUBA1A gene.  About 30% of lissencephalies with cerebellar hypoplasia are the result of a TUBA1A mutation. Genetic counseling is usually offered if there is a risk of lissencephaly, coupled with genetic testing. Other causes of lissencephaly include viral infections of the uterus or the fetus during the first trimester, or insufficient blood supply to the fetal brain early in pregnancy.

Diagnosis

The diagnosis of lissencephaly is usually made at birth or soon after by ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI).

Before birth, complex ultrasounds performed routinely during pregnancy may indicate the presence of cerebral abnormality, but this method of diagnosis is usually complemented by other methods, such as genetic studies and NMR, and the examination is usually 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 is 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.

Treatment

Treatment for those with lissencephaly is symptomatic and depends on the severity and location of the brain malformation. 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.

Prevalence

Classic (type I) lissencephaly has a prevalence of 11.7 per million births (1 of 85,470), but the prevalence of milder phenotypes is unknown.

Prognosis

The prognosis for children with lissencephaly depends on the degree of brain malformation, early diagnosis, and early therapy (PT, OT, etc). Some may have near-normal development and intelligence. Many of the more severe cases will not survive beyond the age of 10 years, and will show no significant development beyond a 3-5 month-old level. The cause of death is usually aspiration on food or fluids, respiratory disease, or severe seizures.

Additional Resources

Sources

  1. De Rijk-van Andel JF, Arts WFM, Holman A, et al. Epidemiology of lissencephaly type I. Neuroepidemiology 1991; 10: 200-4.
  2. Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB. “A developmental and genetic classification for malformations of cortical development:  update 2012. Brain 2012. 10.1093/brain/aws019.