Abstract
Migration of post-mitotic neurons from the ventricular zone to the cortical plate during embryogenesis comprises one of the most critical stages in brain development. Deficiency of this process often results in major brain malformations, including human lissencephaly (smooth brain). Since discovery of the first genetic cause of lissencephaly, deletions of chromosome 17p13.3 in Miller–Dieker syndrome, rapid progress in our understanding of neuronal migration has been made based on advances in both brain imaging technology and molecular genetics. This progress has resulted in a new system of classification that began with pathological descriptions and has evolved to include patterns on brain imaging, causative genes and most recently the molecular pathways and proposed modes of migration involved. In this review, we summarize current knowledge regarding five genes that cause or contribute to human lissencephaly, including LIS1, 14-3-3ε, DCX, RELN and ARX. Each of these is associated with a characteristic pattern of malformation that involves the cerebral cortex and sometimes other brain structures. Based on detailed genotype–phenotype analysis, we can now infer the most likely causative gene based on brain imaging and other clinical findings, and inversely are becoming able to predict clinical severity based on the specific mutations detected. We also hypothesize, for the first time, a relationship between the specific type of lissencephaly observed and deficiency of specific modes of neuronal migration.
INTRODUCTION
Migration of post-mitotic neurons from the ventricular zone to form the cortical plate comprises one of the most critical stages in brain development. Our understanding of this complex process has progressed based on studies of human malformations and mouse mutants with deficient neuronal migration, particularly the malformation known as lissencephaly (LIS) or ‘smooth-brain’. LIS is characterized by a smooth or nearly smooth cerebral surface. It encompasses a spectrum of gyral malformations from complete agyria (absent gyri) to regional pachygyria (broad gyri), and merges with subcortical band heterotopia (SBH). LIS is always associated with an abnormally thick cortex, reduced or abnormal lamination and diffuse neuronal heterotopia (1,2). SBH or ‘double cortex’ consists of circumferential bands of heterotopic neurons located just beneath the cortex and separated from it by a thin band of white matter (3,4).
Several different types of LIS have been recognized. The most common type, known as classical LIS (previously type I), has a very thick 10–20 mm cortex and no other major brain malformations. This is the only type associated with SBH. Less common types are associated with agenesis of the corpus callosum (ACC) or severe cerebellar hypoplasia (5,6).
In this paper, we review recent discoveries regarding the molecular mechanisms that regulate or effect neuronal migration to the cerebral cortex, emphasizing those derived from studies in humans with LIS. Other genes and proteins identified in humans with periventricular nodular heterotopia or cobblestone complex malformations (previously type II LIS), or in mouse mutants have been reviewed elsewhere (7–11).
HUMAN LISSENCEPHALY GENES
To date, five genes have been identified that cause or contribute to LIS in humans: LIS1, 14-3-3ε, DCX, RELN and ARX. Their respective subtypes and syndromes are shown in Figures 1 and 2, and can usually be distinguished based on detailed analysis of the phenotype as shown in Figure 3.
LIS1
LIS1 or PAFAH1B1 was the first human neuronal migration gene to be cloned, and encodes the non-catalytic alpha subunit of the intracellular Ib isoform of platelet-activating factor acetylhydrolase (12,13). The gene is located in human chromosome 17p13.3 and consists of 11 exons with a coding region of 1233 bp. LIS1 protein is expressed predominantly in fetal and adult brain (14), and interacts with tubulin to suppress microtubule dynamics (15). It is a highly conserved protein with near-identity between mouse and human, and 42% homology to NudF, an ortholog found in Aspergillus nidulans (16). Studies of NudF and related genes such as NudE have shown that LIS1 participates in cytoplasmic dynein-mediated nucleokinesis, somal translocation and cell motility (17) as well as mitosis (neurogenesis) and chromosome segregation (18). In animal experiments including human cells, Lis1 acts via a signaling pathway that includes NudE, NudeL, cytoplasmic dynein, dynactin, and CLIP-170 (19–26).
14-3-3ε
This gene belongs to the 14-3-3 family of proteins that bind to phosphoserine and phosphothreonine motifs in a wide variety of proteins (27–31). It is also located in chromosome 17p13.3, about 40 kb telomeric to LIS1, and has six exons that encode 255 amino acids. The gene codes for a highly conserved protein that binds to and protects phosphorylated NUDEL from dephosphorylation by protein phosphatase 2A (PP2A). It is required for NUDEL localization and cytoplasmic dynein function, and appears to be important for neuronal migration based on mouse studies (Tokyo-oka et al., submitted).
DCX
DCX or XLIS was first identified as the gene causing X-linked LIS and SBH (32,33). It is located in chromosome Xq22.3–q23 and has nine exons (six coding exons) that code for a 360 amino acid protein. The DCX protein contains two tandem evolutionarily conserved repeats (doublecortin domain) that form a b-grasp superfold. Each of the repeat binds to tubulin but not to microtubules, so that both repeats are necessary for microtubule polymerization and stabilization (34–37), and possibly for direct interactions with LIS1 (38). DCX is expressed exclusively in fetal brain, including forebrain and cerebellum.
RELN
Reln was cloned as the causative gene for the reeler mutant mouse, which has abnormal lamination of the cerebral and cerebellar cortices including inversion of the normal ‘inside-out’ pattern found in mammals (39,40). The human gene is located in chromosome 7q22 and consists of 65 exons covering more than 400 kb of genomic sequence. It encodes a large extracellular matrix protein with 3460 amino acids that is secreted by Cajal–Retzius cells in the preplate (41) and has 94.2% homology with the mouse ortholog (42). Reln functions in a signal transduction pathway via the apolipoprotein E2 (ApoER2) and very low-density lipoprotein receptors (Vldlr) (43,44), which activate the downstream cytoplasmic protein Dab1 (45,46). The brains of mutant mice strains with disruptions of mDab1 or of both ApoER1 and Vldlr closely resemble the brain of the reeler mouse (44,47).
ARX
ARX is a paired-class homeobox gene that shows significant homology with the Drosophila al (aristaless) gene in the homeodomain and C-peptide or aristaless domain (48). The gene is located in human chromosome Xp22.13 and consists of five exons that encode a protein of 562 amino acids (49,50). ARX is specifically expressed in interneurons of the forebrain and in the interstitium of the male gonad (48,50). It is involved in differentiation of the testes and the embryonic forebrain, especially in proliferation of neural precursors and differentiation and tangential migration of interneurons (50).
GENOTYPE–PHENOTYPE CORRELATION WITH MUTATIONS OF KNOWN LISSENCEPHALY GENES
LIS1
The most important characteristics of LIS in patients with LIS1 mutations are the very thick 10–20 mm cortex, gyral malformations that are more severe in posterior than anterior (p>a gradient) brain regions (51,52) and prominent cell sparse zone in the cortex. The corpus callosum and cerebellum appear normal or mildly hypoplastic on brain MRI (6,52).
Mutations of LIS1 cause isolated lissencephaly sequence (ILS) or rarely isolated SBH, both with a clear p>a gradient. We found a significant correlation between LIS–SBH severity and mutation type in these disorders. Patients with submicroscopic deletions of 17p13.3 that include LIS1 and those with null mutations in the coiled coil (MAP1B homology) domain in exons 2–5 usually had LIS grade 2–3, with a mean grade of 2.43 for the latter group (52,53). Patients with null mutations distal to the coiled coil domain usually had LIS grades 3–4, with a mean grade of 3.18. Patients with missense mutations of LIS1 had even less severe LIS unless a critical amino acid residue was involved, with a mean grade of 4.20 (53–55).
All but one of the missense mutations are associated with milder phenotypes than patients with null mutations, which suggests some residual LIS1 protein function. However, in vitro assays show that all mutant proteins completely lose the capacity to interact with NUDE as well as the 29 and 30 kDa subunits of platelet activating factor acetylhydrolase, PAFAH1B2 and PAFAH1B3 (22,56). Thus, the basis for differing severity among patients with missense mutations is unclear. The mildest LIS1-associated phenotype known consists of infrequent seizures, mild clumsiness and normal intelligence with pachygyria limited to the posterior parietal and occipital lobes. The affected boy had a missense mutation in the second WD repeat resulting in substitution of serine for glycine (G162S). This is predicted to be a mild mutation, as serine is found at the same position in other WD family proteins (55,57).
LIS1 and 14-3-3ε
The association between LIS and deletions of 17p13.3 was first recognized in patients with Miller–Dieker syndrome (MDS), which consists of LIS and facial abnormalities including prominent forehead, bitemporal hollowing, short nose with upturned nares, prominent upper lip with downturned vermilion border and small jaw, and sometimes other congenital anomalies (58,59). Our previous studies suggested that patients with MDS have more severe LIS than patients with ILS, and that deletions in MDS extend further toward the 17p telomere than in ILS, suggesting that another gene involved in brain development is located distal to LIS1 (52,60).
We recently completed a contig across most of this 400 kb region, and studied 30 patients with MDS or ILS and deletions of the region with a set of FISH probes and somatic cell hybrids (61). MDS was always associated with LIS grade 1 (essentially complete agyria), and the deletion in MDS extends from LIS1 to include all or part of BAC RPCI11-818O24, which contains the CRK and 14-3-3ε genes. The 14-3-3ε gene is the best candidate to account for the more severe LIS phenotype in MDS, as the mouse knockout has mild defects of neuronal migration, although a Crk knockout has not yet been reported. As would be predicted from our results in humans, mice compound heterozygous for 14-3-3ε and Lis1 display more severe brain defects than either heterozygous mutant mouse alone (Toyo-oka et al., submitted).
DCX
The most important characteristics of LIS in patients with DCX mutations are the very thick 10–20 mm cortex, gyral malformations that are more severe in anterior than posterior (a>p gradient) brain regions, prominent cell sparse zone and the occurrence of SBH rather than LIS in heterozygous females (3,51,52). Hypoplasia of the cerebellar vermis is sometimes associated with LIS caused by either LIS1 or DCX mutation, classified as LIS with cerebellar hypoplasia group a (6,52).
In contrast to LIS1, missense mutations of DCX are more common than truncations. However, genotype–phenotype correlation is complex. Our experience has shown that the same (presumably severe) mutations that cause LIS grade 1 or agyria in males cause diffuse thick SBH in females. Similarly, the same (presumably mild) mutations that cause LIS grade 4 or frontal pachygyria in males cause diffuse thin or partial frontal SBH in females. A few missense mutations have led to partial frontal SBH in males and either very mild or normal phenotypes in their carrier mothers, who had germline mutations and random X inactivation (54,62).
Despite substantial experience, predicting the phenotype based on the genotype remains difficult due to incomplete knowledge regarding function of specific amino acids within the two microtubule-binding or doublecortin domains in exons 4–6, and relatively frequent post-zygotic mosaicism. Our recent data have shown that truncation mutations in all but the last two exons (exons 8 and 9) cause a severe phenotype, while truncation mutations in exon 9 cause a variable phenotype suggesting nonsense-mediated mRNA decay in DCX transcripts. No truncations in exon 8 have been reported. Missense mutations of DCX cluster in the doublecortin domains in exons 4–6, where they cause a variable phenotype (36,37,51,63). Missense mutations in exons 7–9 have never been observed, and so presumably cause a very mild or no phenotype (63). Finally, post-zygotic mosaicism appears to be an important mechanism in both sexes. In males, post-zygotic mosaicism ameliorates the phenotype, resulting in SBH or mild LIS (grades 5 and 6) rather than severe LIS (grade 1 or 2) (64–66). In females, post-zygotic mosaicism has been found in mothers of several affected patients (64). Owing to the difficulty in detecting mosaicism in heterozygous females, a high index of suspicion is required, and must be taken into account when providing genetic counseling.
RELN
Mutations of RELN have been reported in six children with a LIS variant from two unrelated families (67). Both families showed exon skipping resulting in undetectable or reduced levels of RELN protein. The same pattern of LIS was described in four patients from two unrelated Japanese families, one of whom had reduced levels of RELN protein in serum (6,68). These patients have been classified as LIS with cerebellar hypoplasia group b (6). In these children, the malformation is characterized by a moderately thick 5–10 mm cortex, LIS that appears more severe in anterior than posterior (a>p gradient) brain regions, malformed hippocampus and very small cerebellum virtually lacking folia.
ARX
Mutations of ARX cause a wide range of phenotypes that correlate closely with the type of mutation. Hemizygous males with null and non-conservative missense mutations have a well-delineated syndrome known as X-linked lissencephaly with abnormal genitalia (XLAG) (5). The most important characteristics of LIS in patients with XLAG are a moderately thick 5–10 mm cortex, gyral malformations that are more severe in posterior than anterior (p>a gradient) brain regions, deficiency of small granular neurons throughout the cerebral cortex, abnormal signal of white matter, ACC, and cystic or fragmented basal ganglia (50,69) (Kato et al., submitted). Rare patients with null mutations or missense mutation in the homeobox have a variant with hydranencephaly or isolated ACC, both with abnormal genitalia (Kato et al., submitted). Missense or in frame expansion mutations of ARX cause familial X-linked infantile spasms or West syndrome, sporadic cryptogenic or non-symptomatic West syndrome, X-linked myoclonic epilepsy with spasticity and mental retardation, Partington syndrome (mental retardation and dystonia), non-syndromic X-linked mental retardation, and possibly autism (49,70–74) (Kato et al., submitted). We also found several females with symptomatic or asymptomatic ACC, who were carriers of the same ARX mutations that caused XLAG in males. Thus, mutations of ARX are clearly associated with remarkable pleiotropy that includes seemingly disparate phenotypes both with and without malformations.
LIS AND MECHANISMS OF MIGRATION
For many years, neuronal migration along radial glial fibers has been the most widely accepted mechanism of cortical formation, and disturbance of neuronal migration the cause of LIS (2,75,76). However, recent studies have demonstrated three different modes of migration, including two forms of radial migration (somal translocation and glia-guided locomotion), as well as tangential or non-radial migration (77–79).
Somal translocation consists of movement of the soma and nucleus toward the cortical plate in a long, radially oriented basal process of the cell that terminates at the pial surface (79,80). Glia-guided migration consists of slower movement along the scaffold of radial glial fibers. In general, early-generated cells such as preplate neurons use somal translocation only. Later-migrating pyramidal neurons first use glia-guided locomotion and subsequently somal translocation as they move past earlier-generated neurons to form the ‘inside-out’ pattern of the mammalian neocortex (80,81). Tangential migration is used by GABAergic neurons to migrate from the ventral to the dorsal telencephalon along corticofugal fibers. On reaching the dorsal telencephalon, the cells change direction to migrate into the cortex along either corticofugal projection fibers or radial glial fibers (50,82–84). Some of these cells briefly migrate toward the ventricular zone, before reversing direction to migrate into the neocortex (85).
From the limited data available so far, it appears likely that the three known modes of migration are affected in different ways in the various LIS subtypes. In the cerebral cortex of reeler mice (Reln deficiency), the preplate appears to form normally, but later-migrating neurons fail to split the preplate into marginal zone and subplate. Instead, they form layers below the preplate with a reverse ‘outside-in’ pattern compared with normal cortex (39,86,87). Reln is also required for the formation of the radial glial scaffold in the hippocampus (88). These observations suggest a role for Reln, and presumably human RELN, in glia-guided locomotion.
As mentioned above, LIS1 interacts with tubulin and participates in nucleokinesis and extension of the leading process as well as mitosis (10). In compound heterozygous Lis1 mutant mice, splitting of the preplate is defective, leaving a broad and poorly defined subplate, and cortical lamination is completely disrupted as in humans with LIS (89). In vitro studies of Lis1-deficient cerebellar granule cells demonstrate deficient migration along neurites of other cells in culture (90). While available data is less clear than for Reln, the abnormality of the preplate and the severe, and thus most likely early-onset, cortical disruption seem to implicate a defect of somal translocation. The defective migration along neurites suggests that migration along radial glia may also be deficient. Based on these results, we hypothesize that both somal translocation and glia-guided migration are disrupted by mutations of LIS1. Studies of tangential migration have not yet been reported. The remarkably thick cortex also supports a more severe defect of migration with LIS1 compared to RELN mutations.
DCX is a microtubule-associated protein that may interact with LIS1, and mutations cause severe LIS, similar to that observed with LIS1 mutations (34,35,91). However, its function remains poorly understood. Expression of DCX in both radial columns and tangentially directed neurons of human fetal cortex suggests that it may be involved in both radial and tangential migration (92).
Arx is expressed in the ganglionic eminences and the neocortical ventricular zone, so both radial and tangential migration could be affected. However, the data available to date implicate primarily tangential migration. In Arx mutant mice, mutant GABAergic interneurons originating from the ganglionic eminence remain near the subplate for at least 3 days, and then migrate to the cortex where they are aberrantly scattered throughout the cortical plate (50). In humans with ARX mutations, the cortex contains almost exclusively pyramidal neurons (69), which also implicates tangential migration. The different pathological findings between humans and mice may reflect differences in the origin of GABAergic interneurons (93). We therefore hypothesize that ARX deficiency results in defects primarily of tangential migration.
To whom correspondence should be addressed at: The University of Chicago, Department of Human Genetics, Room 319 CLSC, 920 E. 58th Street, Chicago, IL 60637, USA. Tel: +1 7738343597; Fax: +1 7738348470; Email: wbd@genetics.bsd.uchicago.edu
![Figure 1. Axial T1- (B, C, E, H) and T2- (A, D, F, G) weighted magnetic resonance images at the level of basal ganglia in five types of lissencephaly. In contrast to a normal control (H), all types of LIS have broad or absent gyri and abnormally thick cortex, except for LIS grade 6 or SBH, in which the sulci separating gyri are very shallow. The anterior to posterior or rostro-caudal gradient of LIS is strictly correlated with the causative gene. Specifically, mutations of DCX or RELN result in an anterior more severe than posterior (a>p) gradient (A–D), while mutations of LIS1 with or without 14-3-3ε or ARX lead to a posterior more severe than anterior (p>a) gradient (E–G). The absolute thickness of the cortex and presence of a cell sparse zone also differ based on the causative gene. In patients with mutations of DCX (A, B) or LIS1 (E, F), the cortex is very thick, typically 10–20 mm, and prominent cell sparse zones are seen in areas of agyria (arrowheads in A, E, F). In patients with LIS with cerebellar hypoplasia group b [C, which resembles patients with known RELN mutations (67,94), although a mutation has not been demonstrated in this patient] or ARX (G) mutations, the cortex is only moderately thick, typically 5–10 mm, and cell sparse zones are never seen, even in areas of agyria (G). In LIS with cerebellar hypoplasia group b with or without proven RELN mutations, other images show an abnormal hippocampus and severe cerebellar hypoplasia (not shown). In males with X-linked lissencephaly with abnormal genitalia due to ARX mutations, other images demonstrate poorly demarcated basal ganglia often with small cysts, immature white matter, and agenesis of the corpus callosum (not shown). In heterozygous females, mutations of DCX result in SBH (D), while mutations of ARX often result in agenesis of the corpus callosum (not shown). ILS, isolated lissencephaly; LCHb, lissencephaly with cerebellar hypoplasia group b; MDS, Miller–Dieker syndrome; XLAG, X-linked lissencephaly with abnormal genitalia.](https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/hmg/12/suppl_1/10.1093/hmg/ddg086/2/m_ddg08601.jpeg?Expires=1660138173&Signature=MI7txFKENGys0SZmO9N4X~cFFdgY3N~XSbVOpnQ3Y1zpy3CfVDeR8mFLAnVPI8I6NywvhOBrqxAIm6iQdAMcm6sMngjepcFyblBfoG9pGYNmeG8V6Eiz-VNfdrAcPwHxhpartkO7x6guaH4vmIKWXdF~dPV0TmmvOoQJbhWx3pLMcmSc5UgANQi4v3wjWaDIhSiCxOoMuqk8deSnUBUXY7BuEy86zithnuu8hDm7V61ezPg6NX50dw-doQ8UFTdlDLrUq~IjNJvTH2Q5SP0Fye4LPaovGx6xETlSCqERHyHStSApGMTGBP8OKD~toj9s-71cxmA4yKLhCy8zYdw9VA__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Figure 1. Axial T1- (B, C, E, H) and T2- (A, D, F, G) weighted magnetic resonance images at the level of basal ganglia in five types of lissencephaly. In contrast to a normal control (H), all types of LIS have broad or absent gyri and abnormally thick cortex, except for LIS grade 6 or SBH, in which the sulci separating gyri are very shallow. The anterior to posterior or rostro-caudal gradient of LIS is strictly correlated with the causative gene. Specifically, mutations of DCX or RELN result in an anterior more severe than posterior (a>p) gradient (A–D), while mutations of LIS1 with or without 14-3-3ε or ARX lead to a posterior more severe than anterior (p>a) gradient (E–G). The absolute thickness of the cortex and presence of a cell sparse zone also differ based on the causative gene. In patients with mutations of DCX (A, B) or LIS1 (E, F), the cortex is very thick, typically 10–20 mm, and prominent cell sparse zones are seen in areas of agyria (arrowheads in A, E, F). In patients with LIS with cerebellar hypoplasia group b [C, which resembles patients with known RELN mutations (67,94), although a mutation has not been demonstrated in this patient] or ARX (G) mutations, the cortex is only moderately thick, typically 5–10 mm, and cell sparse zones are never seen, even in areas of agyria (G). In LIS with cerebellar hypoplasia group b with or without proven RELN mutations, other images show an abnormal hippocampus and severe cerebellar hypoplasia (not shown). In males with X-linked lissencephaly with abnormal genitalia due to ARX mutations, other images demonstrate poorly demarcated basal ganglia often with small cysts, immature white matter, and agenesis of the corpus callosum (not shown). In heterozygous females, mutations of DCX result in SBH (D), while mutations of ARX often result in agenesis of the corpus callosum (not shown). ILS, isolated lissencephaly; LCHb, lissencephaly with cerebellar hypoplasia group b; MDS, Miller–Dieker syndrome; XLAG, X-linked lissencephaly with abnormal genitalia.
Figure 1. Axial T1- (B, C, E, H) and T2- (A, D, F, G) weighted magnetic resonance images at the level of basal ganglia in five types of lissencephaly. In contrast to a normal control (H), all types of LIS have broad or absent gyri and abnormally thick cortex, except for LIS grade 6 or SBH, in which the sulci separating gyri are very shallow. The anterior to posterior or rostro-caudal gradient of LIS is strictly correlated with the causative gene. Specifically, mutations of DCX or RELN result in an anterior more severe than posterior (a>p) gradient (A–D), while mutations of LIS1 with or without 14-3-3ε or ARX lead to a posterior more severe than anterior (p>a) gradient (E–G). The absolute thickness of the cortex and presence of a cell sparse zone also differ based on the causative gene. In patients with mutations of DCX (A, B) or LIS1 (E, F), the cortex is very thick, typically 10–20 mm, and prominent cell sparse zones are seen in areas of agyria (arrowheads in A, E, F). In patients with LIS with cerebellar hypoplasia group b [C, which resembles patients with known RELN mutations (67,94), although a mutation has not been demonstrated in this patient] or ARX (G) mutations, the cortex is only moderately thick, typically 5–10 mm, and cell sparse zones are never seen, even in areas of agyria (G). In LIS with cerebellar hypoplasia group b with or without proven RELN mutations, other images show an abnormal hippocampus and severe cerebellar hypoplasia (not shown). In males with X-linked lissencephaly with abnormal genitalia due to ARX mutations, other images demonstrate poorly demarcated basal ganglia often with small cysts, immature white matter, and agenesis of the corpus callosum (not shown). In heterozygous females, mutations of DCX result in SBH (D), while mutations of ARX often result in agenesis of the corpus callosum (not shown). ILS, isolated lissencephaly; LCHb, lissencephaly with cerebellar hypoplasia group b; MDS, Miller–Dieker syndrome; XLAG, X-linked lissencephaly with abnormal genitalia.
Figure 2. Correlation of LIS grade and gradient and associated brain malformations with causative genes. LIS grades 1 and 2 consist of diffuse agyria, although patients with LIS grade 2 have a few shallow sulci over the frontal or occipital pole. LIS grade 3 comprises mixed agyria and pachygyria, grade 4 pachygyria only, grade 5 mixed pachygyria and SBH, and grade 6 SBH only. The most severe form of LIS (grade 1) is typically caused by either combined LIS1 and 14-3-3ε deletion or a severe mutation of DCX. Mutations of LIS1 alone typically cause LIS grades 2–4, most often grade 3, with very rare patients having posterior SBH. Mutations of DCX cause a wide range of LIS, although grade 3 has proven to be rare. Mutations of RELN cause both cerebral (LIS) and cerebellar malformations, which resembles the defects found in the reeler mouse. Mutations of ARX most often result in LIS grade 3, in addition to the basal ganglia, white matter and callosal abnormalities. At least half of all female carriers of ARX mutations that cause XLAG in males have ACC. Black box, most frequently observed; dark grey box, sometimes observed; light grey box, rarely observed. CBLH, cerebellar hypoplasia. The asterisk indicates it may result from somatic mosaicism.
Figure 2. Correlation of LIS grade and gradient and associated brain malformations with causative genes. LIS grades 1 and 2 consist of diffuse agyria, although patients with LIS grade 2 have a few shallow sulci over the frontal or occipital pole. LIS grade 3 comprises mixed agyria and pachygyria, grade 4 pachygyria only, grade 5 mixed pachygyria and SBH, and grade 6 SBH only. The most severe form of LIS (grade 1) is typically caused by either combined LIS1 and 14-3-3ε deletion or a severe mutation of DCX. Mutations of LIS1 alone typically cause LIS grades 2–4, most often grade 3, with very rare patients having posterior SBH. Mutations of DCX cause a wide range of LIS, although grade 3 has proven to be rare. Mutations of RELN cause both cerebral (LIS) and cerebellar malformations, which resembles the defects found in the reeler mouse. Mutations of ARX most often result in LIS grade 3, in addition to the basal ganglia, white matter and callosal abnormalities. At least half of all female carriers of ARX mutations that cause XLAG in males have ACC. Black box, most frequently observed; dark grey box, sometimes observed; light grey box, rarely observed. CBLH, cerebellar hypoplasia. The asterisk indicates it may result from somatic mosaicism.
Figure 3. Flow chart to predict the most likely causative gene in patients with LIS by analysis of brain MRI.
Figure 3. Flow chart to predict the most likely causative gene in patients with LIS by analysis of brain MRI.
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