Lissencephaly: Update on diagnostics and clinical management

A de novo Non-sense Nuclear Factor I B Mutation (p.Tyr290*) Is Responsible for Brain Malformation and Lung Lobulation Defects

“…Lissencephaly, which literally means “smooth brain,” was first described in 1914 ( 16 , 17 ). Patients with lissencephaly also manifest intellectual disabilities, developmental delays, seizures, and muscle spasms ( 18 , 19 ). In the present study, a novel non-sense NFIB variant (NM_001190737:c.870C > A;p.Tyr290*) was identified by using WES.…”

Lissencephaly causing refractory neonatal seizures in a term neonate

“…LIS is a malformation of cortical development with broad gyri, shallow sulci and thickened cortex characterised by developmental delays and seizures. The recent advancement in molecular genetics has led to the identification of 31 LIS-associated genes with an overall diagnostic yield of over 80% 11 12. It can be graded clinically and radiologically as mild (subcortical band heterotopia), moderate (pachygyria) and severe (agyria).…”

Teleost Fish and Organoids: Alternative Windows Into the Development of Healthy and Diseased Brains

“…This is a group of highly heterogeneous conditions, which can show mixed features, including microcephaly or other cerebral malformations ( Sheen et al, 2006 ; Lui et al, 2011 ; Buchsbaum and Cappello, 2019 ; Table 2 ). Among NMDs, lissencephaly (also known as “smooth brain”) refers to a large number of heterogeneous conditions, mostly characterized by an aberrant and reduced cerebral folding, in combination with other cerebral malformations; while gray matter heterotopia specifically refers to abnormally located neuronal clusters ( Watrin et al, 2015 ; Di Donato et al, 2017 ; Buchsbaum and Cappello, 2019 ; Buchsbaum et al, 2020 ; Koenig et al, 2021 ). Furthermore, neuronal migration errors ( Guerrini and Parrini, 2010 ) or aberrant proliferation of glia precursors ( Rash et al, 2019 ) also lead to polymicrogyria, characterized by architectural anomalies and cytological variations involving the number of cortical convolutions.…”

“…KD in zebrafish embryos(Guemez-Gamboa et al, 2015): early postnatal lethality and microcephaly with brain-blood barrier disruptionDefective neuronal migration and connectivityLissencephaly typeI : simplification or absence of normal cortical convolutions in the cerebral cortex, often accompanied by secondary microcephaly (microlissencephaly)(Di Donato et al, 2017;Subramanian et al, 2020;Koenig et al, 2021) Cobblestone lissencephaly typeII : global disorganization of cerebral organogenesis with an uneven cortical surface and a cobblestone appearance as well as demyelination(Devisme et al, 2012;Subramanian et al, 2020;Koenig et al, 2021) TubulinopathiestypeI TUBA1A, TUBA3 (associated to PMG, #611603) TUBB2B (associated to PMG, #610031) KATNB1 (associated to microcephaly, #616212) LIS1 (#607432, #247200) Isolated lissencephaly and Miller-Dieker syndrome (MDS), often accompanied with subcortical band heterotopia and/or PMG DCX (#300067) X-linked lissencephaly and double cortex syndrome (subcortical band heterotopia, see below) ARX#300215 -X-linked lissencephaly with agenesis of corpus callosum (XLAG) • TUBA1A deficient human iPSCs (Bamba et al, 2016): inhibition of neurit eextension in young neurons • MO-mediated katnb1 KD in zebrafish embryos (Mishra-Gorur et al, 2014): microcephaly with decreased midbrain size • MDS-induced human iPSCs and COs (Bershteyn et al, 2017): reduced organoid size, increased apoptosis and horizontal cell division with vertical spindle orientation of NPCs, prolonged mitosis of oRGCs and neuronal migratory defects in patient-derived COs • DCX deficient human iPSCs (Shahsavani et al, 2018): impaired migration and prolonged proliferation of neural stem cells, defective neuronal differentiation and neurite extension • arx KO zebrafish embryos (Griffin et al, 2021): reduction in the forebrain interneuron density, hypoactivity associated with unprovoked seizures identified by electrophysiology Reelinopathies typeI RELN (#257320) VLDLR (#224050, LDLR-Associated Cerebellar Hypoplasia associated with mild signs of lissencephaly) DAB1 (Smits et al, 2021) • reln, vldlr and dab1a mutant zebrafish embryos (Nimura et al, 2019): aberrant positioning of Purkinje cells (reln, vldlr and dab1a), eurydendroid cells (projection neurons), and Bergmann glial cells in the cerebellum (reln) accompanied to ectopic neurons in the tectum (reln, vldlr, and dab1a) Muscular dystrophy-causing dystroglycanopathies (i.e., Walker Warburg syndrome, WWS) associated with brain, eye/retinal defects, lissencephaly and PMG/agyria) typeII POMGnT1 (#253280) POMT1 (#236670) POMT2 (#613150) POMK (#615249) LARGE1 (#613154) • pomgnt1 sny7 and pomgnt1 sny47 mutant zebrafish embryos (Liu et al, 2020): retinal photoreceptor (PR) degeneration associated with impaired O-mannosyl glycosylation, loss of matriglycan and retention of EYS-enriched secretory vesicles (synaptotagmin-1-positive) in the PR outer nuclear layer • MO-mediated b3gnt1, b3galnt2, fktn and fkrp KD in zebrafish embryos: muscle defects (U-shaped somites) with sarcolemma disruption and degeneration associated with reduced glycosylation of αDG (Buysse et al, 2013, b3gnt1), ER stress and loss of dystroglycan-ligand interactions (Lin et al, 2011) (fktn and fkrp) or reduced mobility, hydrocephalus and mild retinal degeneration (Stevens et al, 2013) MO-mediated ispd KD in zebrafish embryos (Roscioli et al, 2012): WWS model showing hydrocephalus, reduced eye size, muscle defects and degeneration associated with hypoglycosylated αDG Polymicrogyria (PMG): excessive number of...…”