Lissencephaly type II

Last revised by Francis Deng on 4 Oct 2019

Lissencephaly type II is characterized by reduction in normal sulcation, associated with a bumpy or pebbly cortical surface (thus the term cobblestone lissencephaly), absent in lissencephaly type I. Unlike type I lissencephaly which is the result of neuronal undermigration, type II is due to overmigration. For a general discussion refer to the article lissencephaly

Lissencephaly type II is a heterogeneous group of disorders, characterized by a similar morphological change to the brain and congenital muscular dystrophy. The three most commonly included diseases / syndromes are:

Presentation will vary from patient to patient and particularly depending on the underlying syndrome. In general all have components of developmental delay, hypotonia and ocular abnormalities. 

Walker-Warburg syndrome patients are most severely affected with profound hypotonia, severe ocular abnormalities, and neurological impairment. Fukuyama syndrome is intermediate in severity, and muscle-eye-brain disease is least severe with patients exhibiting only mild hypotonia, mild ocular anomalies, and developmental delay 5

Although a number of different genetic abnormalities have been identified resulting in type II lissencephaly, they share a common feature, namely that neurons fail to normally stop migrating outwards. The underlying abnormality is within the glia limitans, the outermost layer of glial tissue formed by apposed astrocytes and astrocytic foot processes from deeper astrocytes, covered by a basal lamina composed of extracellular matrix, which itself lies in contact with the pia mater 1,3

In patients with type II lissencephaly alpha-dystroglycan, a highly glycosylated, extracellular peripheral-membrane protein crucial for the formation and stabilization of the glia limitans, is abnormally glycosylated and results in gaps within the glia limitans, allowing the passage of neurons through the glia limitans and into the subarachnoid space 1,3,4.

Each of the related syndromes occur as a result of one or more defects in gene products involved in the normal formation and function of the glia limitans. 

Regardless of the exact underlying genetic abnormalities, type II lissencephaly patients share similar gross brain imaging features, best appreciated on MRI. 

As the term 'cobblestone lissencephaly' suggests the primary imaging features are:

  • lack of normal sulcation
  • multinodular surface to the cortex (cobblestone), most pronounced anteriorly

There are numerous other features, seen with variable frequency in the three underlying syndromes. These are discussed in more detail in the respective articles Walker-Warburg syndrome, Fukuyama syndrome and muscle-eye-brain (MEB) disease. In general additional features encountered include 5:

  • hypomyelination of white matter
  • hydrocephalus
  • posterior cephalocele
  • abnormal brainstem
    • fused colliculi
    • small pons
    • dysmorphic mesencephalon
    • dorsal pontomedullary kink
  • abnormal cerebellum
    • vermian hypogenesis
    • cerebellar hypoplasia
    • cerebellar polymicrogyria
  • abnormal globes
    • uni- or bilateral microphthalmia
    • retinal dysplasia
  • lissencephaly type I
    • cortex is thicker and smoother
  • polymicrogyria
    • only affects a part of the brain, which is usually otherwise normal
    • often associated with schizencephaly
  • early fetal brain: prior to 22 weeks, the fetal brain lacks a normal gyral pattern

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