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 five 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).

MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance

“…We next searched our large brain-malformation databases ($3,300 subjects) and identified the same pattern in another five children for a total of eight, including monozygotic twin sisters and one previously reported Japanese girl (Figures 1, 2, S1, and S2). 4 Phenotype According to our revised classification system for LIS, 5 the cortical malformation consists of diffuse pachygyria with thick cortex and a mild posterior gradient more severe than the anterior gradient; it varied from ''thin'' LIS with mildly thick cortex (7-10 mm) in six of eight individuals to classic LIS with very thick cortex (10-15 mm) in two of eight individuals. We found thin anterior commissures and mildly dysplastic hippocampi in all eight individuals and mildly thin corpus callosum in six of eight subjects.…”

A De novo Loss-of-Function Mutation in PAFAH1B1 Identified in a Single Case with Agyria–Pachygyria Complex

“…30 which was modified recently. 1,11 Taken together, this study identified a de novo nonsense mutation (c.265C > T, p.R89 Ã ) of PAFAH1B1 in an affected infant with seizures, cerebral palsy, and speech impairment. The spectrum of the clinical manifestations in this case is consistent with previous experience that agyria-pachygyria complex is associated with epilepsy, developmental delay, and motor deficits.…”

Exploring classification of birth defects severity in national hospital discharge databases compared to an active surveillance program

“…For instance, the Risk Adjustment for Congenital Heart Surgery (RACHS‐1) method, the Aristotle score, and the Society of Thoracic Surgeons‐European Association for Cardio‐Thoracic Surgery (STS‐EACTS) mortality score all evaluate complexity of congenital heart defects for assessment of surgical risk and outcomes (Jenkins et al, ; Lacour‐Gayet et al, ; O'Brien et al, ). Similarly, Di Donato et al have developed an imaging‐based classification system for lissencephaly, Yao et al have proposed an objective severity scale for unilaterial cleft lip, and numerous grading scales have been in used in clinical settings to assess severity of clubfoot (Catterall, ; Di Donato et al, ; Dimeglio, Bensahel, Souchet, Mazeau, & Bonnet, ; Harrold & Walker, ; Ponseti & Smoley, ; Yao et al, ). However, to our knowledge there is no existing comprehensive and objective mechanism to classify severity across all of the congenital defects.…”

“…grading scales have been in used in clinical settings to assess severity of clubfoot (Catterall, 1991;Di Donato et al, 2017;Dimeglio, Bensahel, Souchet, Mazeau, & Bonnet, 1995;Harrold & Walker, 1983;Ponseti & Smoley, 1984;Yao et al, 2019). However, to our knowledge there is no existing comprehensive and objective mechanism to classify severity across all of the congenital defects.…”