Lissencephaly: Expanded imaging and clinical classification

Am J Med Genet A. 2017 Jun;173(6):1473-1488. doi: 10.1002/ajmg.a.38245. Epub 2017 Apr 25.


Lissencephaly ("smooth brain," LIS) is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The LIS spectrum includes agyria, pachygyria, and subcortical band heterotopia. Our first classification of LIS and subcortical band heterotopia (SBH) was developed to distinguish between the first two genetic causes of LIS-LIS1 (PAFAH1B1) and DCX. However, progress in molecular genetics has led to identification of 19 LIS-associated genes, leaving the existing classification system insufficient to distinguish the increasingly diverse patterns of LIS. To address this challenge, we reviewed clinical, imaging and molecular data on 188 patients with LIS-SBH ascertained during the last 5 years, and reviewed selected archival data on another ∼1,400 patients. Using these data plus published reports, we constructed a new imaging based classification system with 21 recognizable patterns that reliably predict the most likely causative genes. These patterns do not correlate consistently with the clinical outcome, leading us to also develop a new scale useful for predicting clinical severity and outcome. Taken together, our work provides new tools that should prove useful for clinical management and genetic counselling of patients with LIS-SBH (imaging and severity based classifications), and guidance for prioritizing and interpreting genetic testing results (imaging based- classification).

Keywords: agyria; classification; lissencephaly; pachygyria; subcortical band heterotopia; tubulinopathy.

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • Adolescent
  • Adult
  • Cerebral Cortex / diagnostic imaging
  • Cerebral Cortex / physiopathology*
  • Child
  • Child, Preschool
  • Classical Lissencephalies and Subcortical Band Heterotopias / classification
  • Classical Lissencephalies and Subcortical Band Heterotopias / diagnostic imaging
  • Classical Lissencephalies and Subcortical Band Heterotopias / genetics
  • Classical Lissencephalies and Subcortical Band Heterotopias / physiopathology
  • Doublecortin Domain Proteins
  • Doublecortin Protein
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Lissencephaly / classification
  • Lissencephaly / diagnostic imaging
  • Lissencephaly / genetics
  • Lissencephaly / physiopathology*
  • Magnetic Resonance Imaging*
  • Male
  • Microtubule-Associated Proteins / genetics
  • Mutation
  • Neuropeptides / genetics
  • Phenotype
  • Young Adult


  • DCX protein, human
  • Doublecortin Domain Proteins
  • Doublecortin Protein
  • Microtubule-Associated Proteins
  • Neuropeptides
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • PAFAH1B1 protein, human