Types of Lissencephaly
Lissencephaly is currently best classified based on severity (grade) and gradient of gyral malformation, cortical thickness, and associated brain malformations, rather than the outdated "Type I" and "Type II" nomenclature. 1
Obsolete Classification System
The historical classification into "lissencephaly type I" (classic lissencephaly) and "lissencephaly type II" (cobblestone malformation) has been discarded because cobblestone malformation has a fundamentally different pathophysiology (over-migration rather than under-migration) and does not produce a truly smooth cortical surface. 1 The term "lissencephaly type II" should no longer be used. 1
Current Classification Framework
Severity-Based Categories
Lissencephaly exists on a spectrum based on the degree of gyral abnormality:
Agyria: Complete absence of sulci with a smooth brain surface, creating a characteristic "figure-of-eight" appearance on imaging with wide, vertically oriented Sylvian fissures. 1 This is extremely rare and most commonly seen in Miller-Dieker syndrome. 1
Pachygyria: Simplified convolutional pattern with few, broadened gyri and shallow sulci, representing incomplete lissencephaly. 1 This is more common than complete agyria. 1
Subcortical Band Heterotopia (SBH): A circumferential band of incompletely migrated heterotopic grey matter beneath the cortical mantle, now considered part of the lissencephaly spectrum due to shared genetic and etiological features. 1
Genetically-Defined Subtypes
Modern classification recognizes distinct histopathologic subtypes that correlate with underlying genetic defects:
LIS1-related lissencephaly: Classic 4-layer cortical architecture with posterior-to-anterior gradient (more severe posteriorly). 1, 2 Deletions of chromosome 17p13.3 are the most frequent cause of classical lissencephaly. 3
DCX-related lissencephaly: Unique cytoarchitecture distinct from LIS1, often showing anterior pachygyria with posterior subcortical band heterotopia in males. 1, 2
ARX-related lissencephaly: X-linked lissencephaly with agenesis of corpus callosum (XLAG syndrome), with distinct histopathology. 4, 2
TUBA1A-related lissencephaly: Bilateral perisylvian pachygyria with dysmorphic basal ganglia and brainstem abnormalities. 1
Major Clinical Groups
The broader classification includes four main categories:
Classic lissencephaly and variants: Thickened cortex with variable extra-cortical anomalies (corpus callosum agenesis, cerebellar hypoplasia). 4, 5
Microlissencephaly spectrum: Lissencephaly with severe microcephaly. 4, 5
Cobblestone cortical malformations: Includes Walker-Warburg syndrome, Fukuyama syndrome, and Muscle-Eye-Brain disease, characterized by uneven cortical surface with total cortical disorganization. 1, 4 These are no longer classified as lissencephaly but as separate entities. 1
Other lissencephalies: Forms with unknown pathogenesis or associated with polymalformative syndromes. 4, 5
Critical Clinical Pitfalls
Do not use "Type I" and "Type II" terminology in current practice, as this classification is outdated and pathophysiologically inaccurate. 1
Recognize that at least 4 distinct histopathologic subtypes exist that stratify with underlying genetic defects, requiring molecular cytogenetic studies (particularly fluorescence in situ hybridization) in all patients with classical lissencephaly. 3, 2
Understand that lissencephaly involves multiple organ systems beyond the brain, including eyes, face, muscles, genital organs, heart, and bones, requiring comprehensive evaluation. 5