Lissencephaly: Expanded imaging and clinical classification

Abstract

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.

Figure 1. Brain imaging patterns in four patients with lissencephaly (LIS) or LIS with cerebellar hypoplasia (LCH) showing diffuse forms

(A–C) thin LCH with diffuse agyria, thin cortex, absent corpus callosum, dysplastic basal ganglia, thin brainstem, thick tectum and severe cerebellar hypoplasia; (D–F) thick LCH with the same features except for a thick cortex; (G–I) diffuse agyria without other features as seen in Miller–Dieker syndrome; (J–L) severe microcephaly, diffuse agyria, thin cortex, absent corpus callosum, remarkably severe brainstem hypoplasia, possibly enlarged tectum, and severe hypoplasia or absent cerebellum as seen in Barth microlissencephaly syndrome. Black arrow point to an enlarged tectum (A, D), while white asterisks denote cerebellar hypoplasia (A, D) or absence (J). Different gyral patterns are shown for the right hemispheres only with triple white arrows marking agyria. These images were selected from subjects LR12-176 (A–C), LR09-393 (D–F), LR12-311 (G–I), LR01-051 (J–L).

Figure 2. Brain imaging patterns in patients with posterior predominant forms

(A–C) Frontal pachygyria and posterior agyria as seen in most patients with LIS1 deletions or mutations; (D–F) complete pachgyria more severe posteriorly without other features; (G–I) complete pachgyria more severe posteriorly with short corpus callosum and mild cerebellar hypoplasia; and (J–L) diffuse tubulinopathy-associated dysgryia with absent corpus callosum, mildly dysplastic basal ganglia, thin dysplastic brainstem, moderate cerebellar hypoplasia, and mildly enlarged posteriior fossa or “mega-cisterna magna” (mcm), white asterisk denotes cerebellar hypoplasia. Different gyral patterns are shown for the right hemispheres with agyria (triple white arrows), pachygyria (double white arrows) and dysgyria (single white arrows) marked. These images were selected from subjects LR14-023 (A–C), LR12-381 (D–F), LR12-162 (G–I), and LR09-250 (J–L).

Figure 3. Brain imaging patterns in three patients with lissencephaly (LIS) showing diffuse and anterior predominant forms

(A–C) Diffuse agyria and mild cerebellar vermis hypoplasia as seen with severe DCX mutations in males; (D–F) anterior pachygyria as seen with mild DCX mutations in males or with mutations of ACTB or ACTG1; (G–I) anterior pachygyria that transitions to posterior subcortical band heterotopia as seen with mutations of ACTB or ACTG1, rarely DCX; (J–L) equivalent normal images at 18 months. White line points out agenesis of the corpus callosum (G), while white asterisk shows cerebellar hypoplasia (D). Different gyral patterns are shown for the right hemispheres only with agyria (triple white arrows) and pachygyria (double white arrows) marked. These images were selected from subjects LR03-352 (A–C), LR00-092 (D–F), LR13-123 (G–I), LR13-006 (J–L),

Figure 4. Brain imaging patterns in three patients with rare lissencephaly forms

(A–C) anterior predominant “thin” LIS and severe nearly afoliar cerebellar hypoplasia as seen with RELN mutations; (D–F) rare anterior predominant “thin” LIS with no other features typical for CRADD mutations; (G–I) temporal and posterior predominant “thin” LIS with absent corpus callosum and dysplastic basal ganglia as seen with severe ARX mutations in males; and (J–L) equivalent normal images at 7 weeks. White line denotes agenesis of the corpus callosum (G), while white asterisks denotes cerebellar hypoplasia (A). Different gyral patterns are shown for the right hemispheres only with “thin” LIS marked with long single white arrows. These images were selected from subjects LR14-063 (A–C), LR13-378 (D–F), LR00-185 (G–I), AND LR16-043 (J–L).

Figure 5. Brain imaging patterns in four patients with subcortical band heterotopia (SBH)

(A–C) diffuse thick, (D–F) diffuse thin, (G–I) frontal thin and (J–L) posterior thin bands. T1-weighted midline sagittal (A, D, G, J) images are normal, except for mild cerebellar vermis hypoplasia in the second row (D). Axial T2-weighted (B–C, H–I) or three-dimensional (E–F, K–L) images through low or high lateral ventricles show the bands (white arrows) as well as simplified gyri with shallow sulci and a thin layer of white matter between the cortex and bands. These images were selected from patients LR10-053 (A–C), LR01-042 (D–F), LR16-044 (G–I), and LR11-302 (J–L).