Lissencephalies …

Robin Godshalk MS MHA

Developmental Malformations

Updated 12.20.2023
Released 10.31.1994
Expires For CME 12.20.2026

Lissencephalies

Author: Robin Godshalk MS MHA

See Contributor Disclosures

Editor: Ganeshwaran H Mochida MD

Lissencephalies

In This Article

Quick Link

Introduction

Overview

Lissencephaly is a spectrum of congenital disorders of cortical development wherein cerebral convolutions (gyri) are broad or absent. This spectrum encompasses agyria, pachygyria, and subcortical band heterotopia. Patients suffer from intellectual disability, hypotonia, motor delay, and seizures. There are numerous syndromes that include lissencephaly as a feature. Miller-Dieker syndrome is one of the more common of these and is characterized by facial changes, including tall forehead, thickened upper lip with inverted vermillion border, flattened midface, and a variety of extracranial anomalies. Current MRI classification of lissencephaly encompasses 21 patterns. There is some genotype-phenotype correlation.

Key points

	• Lissencephaly is a spectrum congenital disorder of cortical development wherein cerebral convolutions (gyri) are broad or absent.
	• Current MRI classification of lissencephaly encompasses 21 patterns (30). There is some genotype-phenotype correlation.
	• At present, mutations in recognized genes have been identified in over 80% of patients. This implies that additional genes are yet to be found.

Historical note and terminology

Lissencephaly (literally meaning “smooth brain”) is a neuronal migration disorder that includes both agyria and pachygyria but excludes polymicrogyria and other cortical dysplasias. It was first described in 1904 and was considered rare until CT and MRI scans came into widespread use.

A recognizable "lissencephaly syndrome," later renamed Miller-Dieker syndrome, was described in a series of papers between 1962 and 1980 (89; 33; 62). The association between Miller-Dieker syndrome and visible deletions of chromosome band 17p13.3 was first reported in 1983 (39; 121), and submicroscopic deletions of the same region were reported in 1988 (139). Children with classic lissencephaly who lack the facial changes of Miller-Dieker syndrome are classified separately as isolated lissencephaly sequence (38). The association between isolated lissencephaly sequence and smaller submicroscopic deletions in chromosome 17p13.3 was first described in 1992 (78).

Clinical manifestations

Presentation and course

Majority of patients come to medical attention due to hypotonia, feeding difficulties, global developmental delay and seizures. A large majority of patients have no additional major anomalies or facial dysmorphisms.

Historically, children with classic lissencephaly have profound mental retardation, mixed hypotonia (early and persisting), spasticity (later), opisthotonus, poor feeding, poor control of secretions that predisposes them to pneumonia, and seizures that often include infantile spasms. A history of polyhydramnios may be obtained. Many of these children are small for gestational age and experience severe failure-to-thrive. Most children with lissencephaly have recurrent aspiration and many have gastroesophageal reflux. Feeding problems are often noticed during the newborn period, but usually improve within a few weeks or months. The aspiration often worsens later, as spasticity increases. As diagnostic capabilities and experience grow, the spectrum of lissencephaly phenotypes broadens as well, to include patients with milder anatomic changes and neurologic deficits (81).

The infantile spasms usually begin between 3 months and 12 months of age, but earlier and later onsets have been observed. Most children go on to develop multiple seizure types, including atypical absence, myoclonic, tonic, and tonic-clonic seizures, which are often intractable. Surprisingly, a few children never have seizures. Seizures represent a major challenge as up to half do not respond to therapy.

Lissencephaly is always severe in Miller-Dieker syndrome, consisting of complete or widespread agyria with only limited areas of pachygyria (grade 1 and grade 2) (35). Some patients have a punctate midline calcification in the region of the corpus callosum or septum. Mild lissencephaly has been associated with bilateral calcifications of the globus pallidus in one kindred (117). The characteristic facial changes include prominent forehead, bitemporal hollowing, short nose with upturned nares, flat midface, protuberant upper lip, thin vermilion border of the upper lip, and small jaw.

Miller-Dieker syndrome facial features

A child with Miller-Dieker syndrome, including prominent forehead, bitemporal hollowing, flat midface, short nose with upturned nares, thin upper lip, and slightly small jaw. (Contributed by Dr. William Dobyns.)

Lissencephaly spectrum includes agyria, pachygyria, and subcortical band heterotropia. The spectrum of abnormal gyri measurement is what differentiates this MRI based classification. It is further classified based on the positioning of the malformation. MRI is the only postnatal reliable method to diagnose lissencephaly. There are three exceptions to isolated lissencephaly that include Miller-Dieker syndrome (17p13.3 del), patients with Baraitser Winter cerebrofrontofacial syndrome, and X-linked lissencephaly with abnormal genitalia (73). A revised imaging-based classification for lissencephaly and related conditions has been published (30). In all, at least 25 syndromes are associated with lissencephaly or other neuronal migration disorders (14). Classic lissencephaly may occur in other lissencephaly syndromes, especially X-linked lissencephaly in males. It may be confused with other types of neuronal migration disorders such as polymicrogyria, mixed pachygyria-polymicrogyria, variations of lissencephaly associated with agenesis of the corpus callosum, the cobblestone dysplasia form of lissencephaly, microlissencephaly, and other cortical dysplasias. Patients with lissencephaly and some features resembling Miller-Dieker syndrome, but no deletion in 17p13.3, may have Norman-Roberts syndrome (14). In this condition, the forehead is short and sloping, rather than tall, and nasal structures are prominent rather than depressed; micrognathia and clinodactyly are additional findings. X-linked lissencephaly with abnormal genitalia has been termed XLAG and may be complicated by hypothalamic dysfunction, exocrine pancreatic insufficiency, and renal phosphate wasting (51). The cobblestone appearance of frontal lobes in Schinzel-Giedion syndrome is due to widespread meningeal heterotopia, with underlying distortion of neuronal layers and polymicrogyria (76). Lissencephaly has been diagnosed in 1 of 174 autopsy cases of prenatal alcohol exposure/fetal alcohol spectrum disorder (60).

Prognosis and complications

Seizures, feeding problems, and pneumonia are the most common complications. In one follow-up study, 50% of patients were alive at 14 years, and all were severely disabled and needed complete care (29). Research has shown that the extracellular matrix protein reelin, important to cortical layering, also affects neuronal synapses involved in learning and memory and is associated with neuropsychiatric disorders such as depression, schizophrenia, and autism (113). Additional anomalies may be serious in and of themselves, including cleft palate, congenital cardiac defect, omphalocele, duodenal atresia, and cataracts (106; 18; 01; 45). Genitalia may be abnormal, for example, ambiguous, in patients with X-linked lissencephaly (98; 90). The severity of subcortical band heterotopia or pachygyria is associated with increased risk of Lennox-Gastaut syndrome (49). Tight filum terminale, with consequent neurogenic bladder, has been reported in one 8-year-old female with Miller-Dieker syndrome, lissencephaly, and 17p13.3 deletion (20). Because the 17p13.3 region involved in lissencephaly also contains tumor suppressor genes, care givers should remain vigilant to the possibility of cancer in affected patients—1 young male with Miller-Dieker syndrome has been reported with a rare cancer of the gall bladder (136), and an affected 15-month-old girl has been diagnosed with acute lymphoblastic leukemia (23). LIS1 also appears to have a tumor suppressor role in hepatocellular carcinoma (145). Dandy-Walker malformation and additional CNS anomalies have been described in one fetus with type III lissencephaly (24).

Biological basis

Etiology and pathogenesis

In 80% of typical cases of lissencephaly or subcortical band heterotopia, the genetic abnormality arises de novo; it is familial in the remaining 20%. At least 20 genes related to lissencephaly have been identified; most are related to microtubule structure proteins (tubulin) or microtubule-associated proteins (MAPs) (125; 134). Genes that either cause or are involved in the pathogenesis of lissencephaly in humans include: LIS1 (PAFAH1B1), DCX (doublecortin), RELN, ARX, TUBA1A, VLDLR, NDE1, and WDR62 (68; 02; 43; 77). Most often, the mutation involves LIS1; however, isolated lissencephaly sequence may also result from mutations of an X-linked lissencephaly gene (09) and probably from other genes involved in neuronal migration (34). The gene for X-linked lissencephaly, XLIS (or DCX), is located at Xq22.3-q23. (X-linked lissencephaly is observed in males, whereas X-linked subcortical band heterotopia occurs mainly in females.) XLIS (DCX) mutations account for some cases of lissencephaly and most cases of subcortical band heterotopia (103; 25). In nearly 20% of all cases of lissencephaly, mutations have not been identified, suggesting that additional genes remain to be discovered (32). In general, environmental factors have not been implicated in cases (52). Sporadic cases tend to be more severe, whereas familial cases are milder; specific DCX mutations are associated with each (07). The gene for bilateral periventricular nodular heterotopia has been mapped to Xq28 (34). This latter condition can also develop in the absence of X chromosomal changes. One patient has been described with periventricular nodular heterotopia, lissencephaly, and an unbalanced translocation involving 17p and 12q (48). In another patient, a balanced parental translocation between 17p and 12qter was identified (71). In some patients, especially those with atypical forms of lissencephaly (eg, lissencephaly with cerebellar hypoplasia), no etiology has been identified positively, although it will likely involve a number of gene mutations (111). A small number of patients with lissencephaly, dysgenesis or agenesis of the corpus callosum, and cerebellar hypoplasia have been identified, with mutations in TUBA1A (120; 99); these findings can also include dysgenesis of the hippocampi and hypoplasia of the brainstem (01). This mutation may also be associated with microphthalmia, congenital cataracts, microcephaly, and other brain malformations (93). Cerebellar dysplasia with subtle cortical irregularities (“dysgyria”) but no lissencephaly is associated with mutations in TUBA1A, TUBB2B, and TUBB3 (96). Other phenotypic changes associated with TUBA1A mutations and lissencephaly include Hirschsprung disease and inappropriate antidiuretic hormone secretion (56). Malformations associated with mutations in TUBA1A, TUBB2B, and other tubulin (microtubule regulating) genes are part of a group of conditions known as “tubulinopathies.” Lissencephaly, pachygyria, polymicrogyria, and polymicrogyria-like cortical dysplasia are included in this group (22; 06). Much remains to be learned about these conditions; to date, tubulin mutations have been identified in only a small subset (1% to 13%) of affected patients (96).

Miller-Dieker syndrome is caused by large deletions (probably involving several genes, especially PAFAH1B1 and YWHAE) on the distal short arm of chromosome 17 (band 17p13.3) in at least 95% of patients (35; 37). The deletions always include the region of the LIS1 gene. Several different cytogenetic mechanisms have been observed, including deletions, rings, inversions, satellite change, reciprocal translocations, and a dicentric translocation. New mutations continue to be identified (91). Patients with unbalanced translocations involving 17p can manifest novel phenotypes, for example partial monosomy 17p and partial trisomy 20p (129; 141). Isolated lissencephaly sequence with classic lissencephaly is caused by smaller deletions involving the LIS1 gene in at least 40% of patients (37). The phenotypic changes of Miller-Dieker syndrome may involve the deletion of additional genes on 17p distal to the LIS1 gene (03). Mutations of ARX are associated with X-linked lissencephaly, asymmetric polymicrogyria, periventricular heterotopia, agenesis of the corpus callosum, and ambiguous genitalia in genotypic males (44; 50; 97).

In these patients, the gyral patterns vary consistently (40). Those with LIS1 (located at 17p13.3) mutations show a posterior-to-anterior gradient of lissencephaly, whereas individuals with XLIS (Xq22.3-q23) mutations have the opposite anterior-to-posterior gradient. These differences may be appreciated through careful imaging. LIS1 missense mutations are associated with milder phenotypes (81; 15). Patients without LIS1 mutations have less severe lissencephaly (grade 4a) and no other brain changes (112). CEP85L is associated with posterior predominant lissencephaly and manifests an autosomal dominant inheritance pattern (134). The gene is part of a complex involving numerous proteins that affect the centrosome, microtubule cytoskeleton, and ultimately, neuronal migration (72).

The cytoarchitecture of the cerebrum shows a severe disorder of neuronal migration, which occurs during the third and fourth gestational months. The thick cortex consists of four primitive layers. The acellular marginal layer appears normal. The superficial cellular layer resembles an immature cortex. There may be some separation into zones similar to layers III, V, and VI of normal cortex, but the cell populations are decreased. The deep cellular layer consists of many heterotopic neurons that failed to reach the true cortex. It is separated from the superficial cellular layer by the cell sparse layer, although the latter varies in thickness and may be absent. In mice with LIS1 mutation, the morphology of cortical neurons and radial glia, cortical plate splitting, and thalamocortical innervation are abnormal, and the rate of migration of neurons is reduced (13). Patients with LIS1 or DCX mutations appear to be different histologically, although few cases have been described (140). The former manifest an inverted, “four layered cortex;” the latter show a “six layered cortex.” LIS1 appears to be necessary for radial neuronal migration (excitatory projection neurons), as well as normal nonradial neural migration; thus, a defect in nonradial cell migration (inhibitory interneurons) may be involved in the phenotypic changes of patients with LIS1 mutations (87; 100). Neuronal migration in patients with defects in LIS1 may also proceed in a complex manner that is partly radial and partly tangential (85). Much remains to be learned about neuronal migration, as evidenced by reports of a new “multipolar” stage of migration. It appears, for example, that transition from this stage of development depends on at least three genes (filamin A, LIS1, and DCX) and that mutations in these genes lead to the defects under discussion (84). Identification of a young girl with lissencephaly, tetralogy of Fallot, and Hirschsprung disease suggests that a global failure may occur in neuronal migration (127). Mutations in ARX result in both structural and functional disorders of the CNS, including lissencephaly. Current experimental evidence suggests that hypothalamic dysfunction in some patients may arise from lost expression of the gene (122).

In all patients with Miller-Dieker syndrome and most with isolated lissencephaly sequence, the gene responsible for classic lissencephaly is LIS1 (108). LIS1 encodes the platelet activating factor acetylhydrolase-1, beta 1 subunit, PAFAH1B1 (108; 16; 15) and is expressed in all tissues examined, although expression is most pronounced in the brain, heart, and skeletal muscle. With regard to this latter observation, it has been shown that Dcx is expressed in the neuromuscular junction of mice, and it may be involved in synaptogenesis. The same may be true in humans because defects in presynaptic and postsynaptic morphology have been identified in the muscle of a patient with subcortical band heterotopia (11). The deduced amino acid sequence shows a series of eight tryptophan sequence repeats of the type found in b-transducin subunits of G proteins. The pathogenesis of the neuronal migration defect in classic lissencephaly is not known, although loss of a critical signal for starting or continuing migration has been proposed based on the structural resemblance to G proteins, which are often involved in signal transduction. Overexpression of LIS1 interferes with cell division and, thus, it is thought that mutations may disrupt the division of neuronal progenitor cells or movement of neuronal nuclei within cell processes (137). This appears to be borne out clinically, in that patients with partial or complete duplication and overexpression of LIS1 display variable structural brain anomalies (microcephaly, ventriculomegaly, dysgenesis of corpus callosum, but not lissencephaly), developmental delay, and failure to thrive (10; 110; 83). The orientation of mitotic spindles and alignment of chromosomes may also be influenced by LIS1, acting with cytoplasmic dynein and dynactin and the nuclear distribution proteins NUDE (ie, Ndel) and NUDEL (ie, Ndell) to affect neuroblast proliferation and nuclear and cellular migration (81; 138; 104; 123). Ndell facilitates the interaction between LIS1 and dynein and, thus, regulates dynein activity; loss of function of Ndell, LIS1, or dynein is associated with defective neuronal positioning or migration (119; 26; 144). This appears to involve a major rearrangement in conformation of the LIS1 molecule (128). LIS1 is an important regulator of the dynein complex and, with the adaptor protein BICD2, affects the initiation of dynein motility (08; 61). This process influences intracellular transport, cell division, and neurodevelopment, but it influences in ways that are complex and not completely understood (28). Experimental inhibition of dynein alters nucleus-centrosome coupling and neuronal migration, the former of which is rescued by Dcx overexpression (126). Dcx furthermore appears to serve as a link between microtubule and cytoskeletal filaments, the cross-linking of which is critical to cell migration (135). This “crosstalk” involves two cytoskeletal systems, involving microtubules (PAFAH1B1 or LIS1, DCX, YWHAE, and tubulin) and actin cytoskeleton (PAFAH1B1 or LIS1, DCX, RELN, and VLDR/LRP8 or APOER2), and is essential to cortical patterning (92). The movement and orientation of radial glial cells (“cytokinesis”) is a necessary component of CNS patterning and is influenced by the microtubule cytoskeleton, which regulates glial and neuronal function, migration, and synaptic connections (95). For these reasons, lissencephaly is considered one of a growing list of “tubulinopathies” (45).

Timing appears to be critical, for early mutations result in more severe phenotypic changes than later ones (16). In fact, aberrations in timing have been postulated for a number of CNS disorders and may influence a wide variety of developmental processes (114). A 400kb critical region has been identified at 17p13.3; the absence of genes in this region appears to contribute to the severe form of lissencephaly encountered in Miller-Dieker syndrome (17). In addition, the gene that encodes 14-3-3epsilon (YWHAE) is deleted in all patients with Miller-Dieker syndrome; the deficiency of 14-3-3epsilon associated with 17p13.3 deletions causes mislocalization of NUDEL and LIS1 and reduced function of cytoplasmic dynein (133). Patients with microdeletions that include YWHAE have facial anomalies, growth restriction, structural brain changes, and cognitive impairment (94).

In addition to altered cell migration, cell proliferation may be affected and is receiving increased attention as well (47). In addition to LIS1, another gene located on 17p13.3, Mnt, appears to be important to cellular proliferation and may be involved in the pathogenesis of some craniofacial defects in Miller-Dieker syndrome (132). Study of a 33-week fetus with Miller-Dieker syndrome and haploinsufficiency of LIS1 showed neuropathologic findings consistent with both migratory and proliferative abnormalities (115; 116). Microdeletions and microduplications in the Miller-Dieker critical region result in specific and different phenotypes (12; 57; 21). Copy number variation in this region may also be associated with epileptogenesis (118).

There are numerous recent updates on molecular findings regarding patients with lissencephaly. A study of bi-allelic CAMSAP1 variants identified a distinct clinical, neuroradiological, and pathophysiological neuronal migration disorder. These patients were found to have radiological findings that were more severe posterior to anterior finding that is similar to patients with LIS1 changes (70). Additional studies of patients with both biallelic mutations, as well as monoallelic mutations have been found to have a frontotemporal lissencephaly with normal cerebellar structure, which is found in patients with a spectrum of neurodevelopmental disorders (31). In the case of a small number of patients with both a chronic airway disease as well as a brain malformation consistent with lissencephaly, patients have a biallelic loss of function of TP73; however, this has not been seen in isolated lissencephaly (142).

Diagnostic workup

The clinical diagnosis of lissencephaly is most often made by MRI, and imaging patterns can be helpful in predicting causative genes (30). If MRI images are suboptimal, as may be the case during the first months of life, then an MRI should be repeated several months later to look for variant types of neuronal migration disorders such as partial lissencephaly (partial agyria-pachygyria), polymicrogyria, or lissencephaly with cerebellar hypoplasia. MRI appearances vary with the precise form of lissencephaly. In the classic form, cerebral gyri are absent or broad, the cortex is thickened, white matter reduced, and border smoothed between gray and white matter. In cobblestone lissencephaly, the cortex is thick and gyri deficient, with a cobblestone-like appearance. When associated with cerebellar hypoplasia, the brain shows pachygyria and hippocampal dysplasia (82). Additional imaging features include microphthalmia, arachnoid cyst, and thalamostriate vasculopathy (55). It appears that the MR appearance of the cerebral cortex can evolve over time as well, as brain development proceeds, yielding a more diagnostic appearance (124). The prenatal diagnosis of lissencephaly/agyria has been suggested by ultrasound in mid-gestational fetuses, ie, prior to 24 weeks (and as early as 17 weeks), and subsequently confirmed by MRI (42; 130; 46; 107; 109). Three-dimensional ultrasonography and multiplanar neurosonography may be helpful in confirming suspicions made by standard ultrasound examination (80; 131). Such diagnostic success is not guaranteed, though, for the brain continues to develop throughout gestation. On occasion, CNS anomalies may not become visible until the third trimester (146), and thus, serial imaging in the third trimester is recommended (143). In one large European series, MRI of fetuses with isolated ventriculomegaly identified by ultrasound revealed lissencephaly in 13% of cases (41). Some work suggests that the pattern of forebrain commissures and configuration of corpus callosum may be useful in differentiating types of lissencephaly (67).

Other diagnostic modalities continue to be developed. Diffusion tensor MRI (DTI) has proven successful in identifying the layers of the cortex as well as different cortical tracts (05; 66). EEG may show specific patterns that correlate with imaging (88).

Regarding genetic workups, testing can begin with a microarray to identify chromosome deletions connected to Miller-Dieker syndrome. Panel testing can look at the 18 genes that have been identified as of now for genetic causes of isolated lissencephaly (73). Whole exome sequencing has proven successful in identifying mutations in patients with lissencephaly, subcortical band heterotopia, and other cortical malformations (59).

Proton magnetic resonance spectroscopy has been used to measure concentrations of cerebral metabolites. Findings in patients with lissencephaly have shown two changes: (1) significantly decreased amounts of N-acetylaspartate reflects abnormalities in neuronal number, maturity, or function; and (2) decreased choline supports the notion of abnormal glial proliferation and membrane function (65).

If Walker-Warburg syndrome (muscle-eye-brain disease) with cobblestone (type II) lissencephaly is suspected, serum creatine kinase, eye examination, and sometimes electromyography, muscle biopsy, or electroretinograms should be performed. In one 6-year-old boy, lissencephaly was discovered by imaging after abnormal eye examination and otherwise normal neurologic examination (86).

References

01: Abumansour IS, Wrogemann J, Chudley AE, Chodirker BN, Salman MS. Lissencephaly with brainstem and cerebellar hypoplasia and congenital cataracts. J Child Neurol 2013;29(6):860-4. PMID 23625088
02: Alkuraya FS, Cai X, Emery C, et al. Human mutations in NDE1 cause extreme microcephaly with lissencephaly. Am J Hum Genet 2011;88(5):536-47. PMID 21529751
03: Allanson JE, Ledbetter DH, Dobyns WB. Classical lissencephaly syndromes: does the face reflect the brain. J Med Genet 1998;35:920-3. PMID 9832039
04: Aslan H, Gungorduk K, Yildirim D, Aslan O, Yildrim G, Ceylan Y. Prenatal diagnosis of lissencephaly: a case report. J Clin Ultrasound 2009;37:245-8. PMID 19260111
05: Aziz ZA, Saini J, Bindu PS, Sharath Kumar GG. Demonstration of different histological layers of the pachygyria/agyria cortex using diffusion tensor MR imaging. Surg Radiol Anat 2013;35(5):427-33. PMID 23262553
06: Bahi-Buisson N, Poirier K, Fourniol F, et al. The wide spectrum of tubulinopathies: what are the key features for the diagnosis. Brain 2014;137(Pt 6):1676-700. PMID 24860126
07: Bahi-Buisson N, Souville I, Fourniol FJ, et al. New insights into genotype-phenotype correlations for the doublecortin-related lissencephaly spectrum. Brain 2013;136(Pt 1):223-44. PMID 23365099
08: Baumbach J, Murthy A, McClintock MA, et al. Lissencephaly-1 is a context-dependent regulator of the human dynein complex. Elife 2017;6. PMID 28406398
09: Berry-Kravis E, Israel J. X-linked pachygyria and agenesis of the corpus callosum in 2 generations: a new CNS migration disorder. Ann Neurol 1992;32:482-3. PMID 8053659
10: Bi W, Sapir T, Shchelochkov OA, et al. Increased LIS1 expression affects human and mouse brain development. Nat Genet 2009;41:168-77. PMID 19136950
11: Bourgeois F, Messeant J, Kirdeli E, et al. A critical and previously unsuspected role for doublecortin at the neuromuscular junction in mouse and human. Neuromuscul Disord 2015;25(6):461-73. PMID 25817838
12: Bruno DL, Anderlid BM, Lindstrand A, et al. Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes. J Med Genet 2010;47(5):299-311. PMID 20452996
13: Cahana A, Escamez T, Nowakowski RS, et al. Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization. Proc Natl Acad Sci USA 2001;98;6429-34. PMID 11344260
14: Caksen H, Tuncer O, Kirimi E, et al. Report of two Turkish infants with Norman-Roberts syndrome. Genet Couns 2004;15(1):9-17. PMID 15083694
15: Cardoso C, Leventer RJ, Dowling JJ, et al. Clinical and molecular basis of classical lissencephaly: mutations in the LIS1 gene (PAFAH1B1). Hum Mutat 2002;19:4-15. PMID 11754098
16: Cardoso C, Leventer RJ, Matsumoto N, et al. The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene. Hum Mol Genet 2000;12:3019-28. PMID 11115846
17: Cardoso C, Leventer RJ, Ward HL, et al. Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet 2003;72:918-30. PMID 12621583
18: Chen CP. Chromosomal abnormalities associated with omphalocele. Taiwan J Obstet Gynecol 2007;46(1):1-8. PMID 17389182
19: Chen CP, Liu YP, Lin SP, et al. Ventriculomegaly, intrauterine growth restriction, and congenital heart defects as salient prenatal sonographic findings of Miller-Dieker lissencephaly syndrome associated with monosomy 17p (17p13.2àpter) in a fetus. Taiwan J Obstet Gynecol 2010;49(1):81-6. PMID 20466299
20: Chen SJ, Peng SS, Kuo MF, et al. Miller-Dieker syndrome associated with tight filum terminale. Pediatr Neurol 2006;34:228-30. PMID 16504794
21: Classen S, Goecke T, Drechsler M, et al. A novel inverted 17p13.3 microduplication disrupting PAFAH1B1 (LIS1) in a girl with syndromic lissencephaly. Am J Med Genet A 2013;161(6):1453-8. PMID 23633430
22: Cushion TD, Dobyns WB, Mullins JG, et al. Overlapping cortical malformations and mutations in TUBB2B and TUBA1A. Brain 2013;136(Pt 2):536-48. PMID 23361065
23: Czuchlewski DR, Andrews J, Madden R, Clericuzio CL, Zhang QY. Acute lymphoblastic leukemia in a patient with Miller-Dieker syndrome. J Pediatr Hematol Oncol 2008;30:865-8. PMID 18989166
24: Darouich S, Amraoui J, Amraoui N. Prenatal sonographic diagnosis of Dandy-Walker malformation and type III lissencephaly: a novel association. J Clin Ultrasound 2020;48(4):235-9. PMID 31859376
25: Demelas L, Serra G, Conti M, et al. Incomplete penetrance with normal MRI in a woman with germline mutation of the DCX gene. Neurology 2001;57:327-30. PMID 11468322
26: Derewenda U, Tarricone C, Choi WC, et al. The structure of the coiled-coil domain of Ndel1 and the basis of its interaction with Lis1, the causal protein of Miller-Dieker lissencephaly. Structure 2007;15(11):1467-81. PMID 17997972
27: de Rijk-van Andel JF, Arts WF, Hofman A, Staal A, Niermeijer MF. Epidemiology of lissencephaly type I. Neuroepidemiology 1991;10:200-4. PMID 1745330
28: DeSantis ME, Cianfrocco MA, Htet ZM, Tran PT, Reck-Peterson SL, Leschziner AE. Lis1 has two opposing modes of regulating cytoplasmic dynein. Cell 2017;170(6):1197-1208. PMID 28886386
29: de Wit MC, de Rijk-van Andel J, Halley DJ, et al. Long-term follow-up of type 1 lissencephaly: survival is related to neuroimaging abnormalities. Dev Med Child Neurol 2011;53(5):417-21. PMID 21410694
30: Di Donato N, Chiari S, Mirzaa GM, et al. Lissencephaly: expanded imaging and clinical classification. Am J Med Genet A 2017;173(6):1473-88. PMID 28440899
31: Di Donato N, Guerrini R, Billington CJ, et al. Monoallelic and biallelic mutations in RELN underlie a graded series of neurodevelopmental disorders. Brain 2022;145(9):3274-87. PMID 35769015
32: Di Donato N, Timms AE, Aldinger KA, et al. Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly. Genet Med 2018;20(11):1354-64. PMID 29671837
33: Dieker H, Edwards RH, ZuRhein G, et al. The lissencephaly syndrome. Birth Defects 1969;5:53-64.
34: Dobyns WB, Andermann E, Andermann F, et al. X-linked malformations of neuronal migration. Neurology 1996;47:331-9. PMID 8757001
35: Dobyns WB, Curry CJ, Hoyme HE, Turlington L, Ledbetter DH. Clinical and molecular diagnosis of Miller-Dieker syndrome. Am J Hum Genet 1991;48:584-94. PMID 1671808
36: Dobyns WB, Elias ER, Newlin AC, Pagon RA, Ledbetter DH. Causal heterogeneity in isolated lissencephaly. Neurology 1992;42:1375-88. PMID 1620349
37: Dobyns WB, Reiner O, Carrozzo R, Ledbetter DH. Lissencephaly: a human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13. JAMA 1993; 270:2838-42. PMID 7907669
38: Dobyns WB, Stratton RF, Greenberg F. Syndromes with lissencephaly. I: Miller-Dieker and Norman-Roberts syndromes and isolated lissencephaly. Am J Med Genet 1984;18:509-26. PMID 6476009
39: Dobyns WB, Stratton RF, Parke JT, et al. Miller-Dieker syndrome and monosomy 17p. J Pediatr 1983;102:552-8. PMID 6834189
40: Dobyns WB, Truwit CL, Ross ME, et al. Differences in the gyral pattern distinguish chromosome 17-linked and X-linked lissencephaly. Neurology 1999;53:270-7. PMID 10430413
41: ENSO Working Group. Role of prenatal magnetic resonance imaging in fetuses with isolated mild or moderate ventriculomegaly in the era of neurosonography: a multicenter study. Ultrasound Obstet Gynecol 2020;56(3):340-7. PMID 31917496
42: Fong KW, Ghai S, Toi A, Blaser S, Winsor EJ, Chitayat D. Prenatal ultrasound findings of lissencephaly associated with Miller-Dieker syndrome and comparison with pre- and postnatal magnetic resonance imaging. Ultrasound Obstet Gynecol 2004;24(7):716-723. PMID 15586369
43: Friocourt G, Marcorelles P, Saugier-Veber P, Quille ML, Marret S, Laguerriere A. Role of cytoskeletal abnormalities in the neuropathology and pathophysiology of type I lissencephaly. Acta Neuropathol 2011;121(2):149-70. PMID 21046408
44: Friocourt G, Poirier K, Rakic S, et al. The role of ARX in cortical development. Eur J Neurosci 2006;23:869-76. PMID 16519652
45: Fry AE, Cushion TD, Pilz DT. The genetics of lissencephaly. Am J Med Genet C Semin Med Genet 2014;166C(2):198-210. PMID 24862549
46: Ghai S, Fong KW, Toi A, Chitayat D, Pantazi S, Blaser S. Prenatal US and MR imaging findings of lissencephaly: review of fetal cerebral sulcal development. Radiographics 2006;26:389-405. PMID 16549605
47: Gressens P. Pathogenesis of migration disorders. Curr Opin Neurol 2006;19:135-40. PMID 16538086
48: Grosso S, Fichera M, Galesi O, et al. Bilateral periventricular nodular heterotopia and lissencephaly in an infant with unbalanced t(12;17)(q24.31; p13.3) translocation. Dev Med Child Neurol 2008;50(6):473-6. PMID 18384621
49: Guerrini R. Genetic malformations of the cerebral cortex and epilepsy. Epilepsia 2005;46 Suppl 1:32-7. PMID 15816977
50: Guerrini R, Marini C. Genetic malformations of cortical development. Exp Brain Res 2006;173(2):322-33. PMID 16724181
51: Hahn A, Gross C, Uyanik G, et al. X-linked lissencephaly with abnormal genitalia associated with renal phosphate wasting. Neuropediatrics 2004;35(3):202-5. PMID 15248105
52: Hayashi MA, Felicori LF, Fresqui MA, Yonamine CM. Protein-protein and peptide-protein interactions of NudE-like 1 (Ndel1): a protein involved in schizophrenia. Curr Protein Pept Sci 2015;16(8):754-67. PMID 25961396
53: Hehr U, Uyanik G, Aigner L, et al. DCX-related disorders. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews® [Internet]. Seattle: University of Washington, 2019. PMID 20301364
54: Herbst SM, Proepper CR, Geis T, et al. LIS1-associated classic lissencephaly: A retrospective, multicenter survey of the epileptogenic phenotype and response to antiepileptic drugs. Brain Dev 2016;38(4):399-406. PMID 26494205
55: Herman TE, Siegel MJ. Miller--Dieker syndrome, type 1 lissencephaly. J Perinatol 2008;28(4):313-5. PMID 18379572
56: Hikita N, Hattori H, Kato M, et al. A case of TUBA1A mutation presenting with lissencephaly and Hirschsprung disease. Brain Dev 2014;36(2):159-62. PMID 23528852
57: Hyon C, Marlin S, Chantot-Bastaraud S, et al. A new 17p13.3 microduplication including the PAFAH1B1 and YWHAE genes resulting from an unbalanced X;17 translocation. Eur J Med Genet 2011;54(3):287-91. PMID 21195811
58: Ikemoto S, Hamano SI, Hirata Y, Matsuura R, Koichihara R. Perampanel in lissencephaly-associated epilepsy. Epilepsy Behav Case Rep 2019;11:67-9. PMID 30723672
59: Jang MA, Woo HI, Kim JW, Lee J, Ki CS. Identification of DCX gene mutation in lissencephaly spectrum with subcortical band heterotopia using whole exome sequencing. Pediatr Neurol 2013;48(5):411-4. PMID 23583063
60: Jarmasz JS, Basalah DA, Chudley AE, Del Bigio MR. Human brain abnormalities associated with prenatal alcohol exposure and fetal alcohol spectrum disorder. J Neuropathol Exp Neurol 2017;76(9):813-33. PMID 28859338
61: Jha R, Roostalu J, Cade NI, Trokter M, Surrey T. Combinatorial regulation of the balance between dynein microtubule end accumulation and initiation of directed motility. EMBO J 2017;36(22):3387-404. PMID 29038173
62: Jones KL, Gilbert EF, Kaveggia EG, Opitz JM. The Miller-Dieker syndrome. Pediatrics 1980;66(2):277-81. PMID 7402813
63: Joyce CA, Dennis NR, Howard F, et al. An 11p;17p telomeric translocation in two families associated with recurrent miscarriages and Miller-Dieker syndrome. Eur J Hum Genet 2002;10:707-14. PMID 12404102
64: Kamida T, Maruyama T, Fujiki M, Kobayashi H, Izumi T, Baba H. Total callosotomy for a case of lissencephaly presenting with West syndrome and generalized seizures. Childs Nerv Syst 2005. PMID 15654631
65: Kaminaga T, Kobayashi M, Abe T. Proton magnetic resonance spectroscopy in disturbances of cortical development. Neuroradiology 2001;43:575-80. PMID 11512591
66: Kamiya K, Tanaka F, Ikeno M, Okumura A, Aoki S. DTI tractography of lissencephaly caused by TUBA1A mutation. Neurol Sci 2014;35(5):801-3. PMID 24510153
67: Kara S, Jissendi-Tchofo P, Barkovich AJ. Developmental differences of the major forebrain commissures in lissencephalies. AJNR Am J Neuroradiol 2010;31(9):1602-7. PMID 20522570
68: Kato M, Dobyns WB. Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet 2003;12(Suppl 1):R89-96. PMID 12668601
69: Kayyali HR, Gustafson M, Myers T, Thompson L, Williams M, Abdelmoity A. Ketogenic diet efficacy in the treatment of intractable epileptic spasms. Pediatr Neurol 2014;50(3):224-7. PMID 24433856
70: Khalaf-Nazzal R, Fasham J, Inskeep KA, et al. Bi-allelic CAMSAP1 variants cause a clinically recognizable neuronal migration disorder. Amer J Hum Genet 2022;109(11):2068-79. PMID 36283405
71: Kim YJ, Byun SY, Jo SA, et al. Miller-Dieker syndrome with der(17)t(12;17)(q24.33;p13.3)pat presenting with a potential risk of mis-identification as a de novo submicroscopic deletion of 17p13.3. Korean J Lab Med 2011;31(1):49-53. PMID 21239872
72: Kodani A, Kenny C, Lai A, et al, Posterior neocortex-specific regulation of neuronal migration by CEP85L identifies maternal centriole-dependent activation of CDK5. Neuron 2020;106(2):246-55. PMID 32097629
73: Koenig M, Dobyns WB, Di Donato ND. Lissencephaly: update on diagnostics and clinical management. Eur J Paediatr Neurol 2021;35:147-52.** PMID 34731701
74: Kojima K, Suzuki Y, Seki K, et al. Prenatal diagnosis of lissencephaly (type II) by ultrasound and fast magnetic resonance imaging. Fetal Diagn Ther 2002;17:34-6. PMID 11803214
75: Kose EA, Bakar B, Ates G, Aliefendioglu D, Apan A. Anesthesia for a child with Walker-Warburg syndrome. Braz J Anesthesiol 2014;64(2):128-30. PMID 24794457
76: Lach B, Arredondo J. Cobblestone lissencephaly in Schinzel-Giedion syndrome. J Child Neurol 2013;28(2):259-63. PMID 22532548
77: Lammert DB, Howell BW. RELN mutations in autism spectrum disorder. Front Cell Neurosci 2016;10:84. PMID 27064498
78: Ledbetter SA, Kuwano A, Dobyns WB, Ledbetter DH. Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly. Am J Hum Genet 1992;50:182-9. PMID 1346078
79: Lenzini E, D’Ottavio, G, Città A, Benussi DG, Petix V, Pecile V. Prenatal diagnosis of Miller-Dieker syndrome by ultrasound and molecular cytogenetic analysis. Clin Genet 2007;72(5):487-9. PMID 17850357
80: Lerman-Sagie T, Leibovitz Z. Malformations of cortical development: from postnatal to fetal imaging. Can J Neurol Sci 2016;43(5):611-8. PMID 27670206
81: Leventer RJ, Cardoso C, Ledbetter DH, et al. LIS missense mutations cause milder lissencephaly phenotypes including a child with normal IQ. Neurology 2001;57:416-22. PMID 11502906
82: Li BX, Guo L, Song YZ. [Analysis of the clinical manifestations and magnetic resonance imaging features of 11 patients with lissencephaly] [Article in Chinese]. Nan Fang Yi Ke Da Xue Xue Bao 2011;31(3):482-6. PMID 21421488
83: Lockrow JP, Holden KR, Dwivedi A, Matheus MG, Lyons MJ. LIS1 duplication: expanding the phenotype. J Child Neurol 2012;27(6):791-5. PMID 22190508
84: Loturco JJ, Bai J. The multipolar stage and disruptions in neuronal migration. Trends Neurosci 2006;29(7):407-13. PMID 16713637
85: Marcorelles P, Laquerriere A, Adde-Michel C, et al. Evidence for tangential migration disturbances in human lissencephaly resulting from a defect in LIS1, DCX and ARX genes. Acta Neuropathol 2010;120(4):503-15. PMID 20461390
86: Marqués-Fernández VE, Sánchez-Tocino H, Escudero-Caro MT, Cancho-Candela R, García-Zamora M. Visual impairment due to lissencephaly. Neuroophthalmology 2016;40(5):229-33. PMID 27928411
87: McManus MF, Nasrallah IM, Pancoast MM, Wynshaw-Boris A, Golden JA. Lis1 is necessary for normal non-radial migration of inhibitory interneurons. Am J Pathol 2004;165(3):775-84. PMID 15331402
88: Menascu S, Weinstock A, Farooq O, Hoffman H, Cortez MA. EEG and neuroimaging correlations in children with lissencephaly. Seizure 2013;22(3):189-93. PMID 23298604
89: Miller JQ. Lissencephaly in two siblings. Neurology 1963;13:841-50. PMID 14066999
90: Minocha P, Choudhary A, Shambhavi, Sitaraman S. A neonate with X-linked lissencephaly with ambiguous genitalia. J Pediatr Neurosci 2017;12(1):80-2. PMID 28553390
91: Mokanszki A, Korhegyi I, Szabo N, et al. Lissencephaly and band heterotopia: LIS1, TUBA1A, and DCX mutations in Hungary. J Child Neurol 2012;27(12):1534-40. PMID 22408144
92: Moon HM, Wynshaw-Boris A. Cytoskeleton in action: Lissencephaly, a neuronal migration disorder. Wiley Interdiscip Rev Dev Biol 2013;2(2):229-45. PMID 23495356
93: Myers KA, Bello-Espinosa LE, Kherani A, Wei XC, Innes AM. TUBA1A mutation associated with eye abnormalities in addition to brain malformation. Pediatr Neurol 2015;53(5):442-4. PMID 26294046
94: Nagamani SC, Zhang F, Shchelochkov OA, et al. Microdeletions including YWHAE in the Miller-Dieker syndrome region on chromosome 17p13.3 result in facial dysmorphisms, growth restriction, and cognitive impairment. J Med Genet 2009;46(12):825-33. PMID 19584063
95: Nulty J, Alsaffar M, Barry D. Radial glial cells organize the central nervous system via microtubule dependant processes. Brain Res 2015;1625:171-9. PMID 26327165
96: Oegema R, Cushion TD, Phelps IG, et al. Recognizable cerebellar dysplasia associated with mutations in multiple tubulin genes. Hum Mol Genet 2015;24(18):5313-25. PMID 26130693
97: Oegema R, Maat-Kievit A, Lequin MH, et al. Asymmetric polymicrogyria and periventricular nodular heterotopia due to mutation in ARX. Am J Med Genet A 2012;158A(6):1472-6. PMID 22585566
98: Okazaki S, Ohsawa M, Kuki I, et al. Aristaless-related homeobox gene disruption leads to abnormal distribution of GABAergic interneurons in human neocortex: evidence based on a case of X-linked lissencephaly with abnormal genitalia (XLAG). Acta Neuropathol 2008;116(4):453-62. PMID 18458920
99: Okumura A, Hayashi M, Tsurui H, et al. Lissencephaly with marked ventricular dilation, agenesis of corpus callosum, and cerebellar hypoplasia caused by TUBA1A mutation. Brain Dev 2013;35(3):274-9. PMID 22633752
100: Pancoast M, Dobyns W, Golden JA. Interneuron deficits in patients with the Miller-Dieker syndrome. Acta Neuropathol (Berl) 2005;109(4):400-404. PMID 15739099
101: Papaioannou G, Garel C. The fetal brain: migration and gyration anomalies – pre and postnatal correlations. Pediatr Radiol 2023;53(4):589-601. PMID 35913508
102: Parrini E, Conti V, Dobyns WB, Guerrini R. Genetic basis of brain malformations. Mol Syndromol 2016;7(4):220-33. PMID 27781032
103: Pilz DT, Matsumoto N, Minnerath SR, et al. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Hum Mol Genet 1998;7:2029-37. PMID 9817918
104: Pilz D, Stoodley N, Golden JA. Neuronal migration, cerebral cortical development, and cerebral cortical anomalies. J Neuropath Exp Neurol 2002;61:1-11. PMID 11829339
105: Pollin TI, Dobyns WB, Crowe CA, et al. Risk of abnormal pregnancy outcome in carriers of balanced reciprocal translocations involving the Miller-Dieker syndrome (MDS) critical region in chromosome 17p13.3. Am J Med Genet 1999;85:369-75. PMID 10398263
106: Porter BE, Brooks-Kayal A, Golden JA. Disorders of cortical development and epilepsy. Arch Neurol 2002;59(3):361-5. PMID 11890838
107: Pugash D, Hendson G, Dunham CP, Dewar K, Money DM, Prayer D. Sonographic assessment of normal and abnormal patterns of fetal cerebral lamination. Ultrasound Obstet Gynecol 2012;40(6):642-51. PMID 22610990
108: Reiner O, Carrozzo R, Shen Y, et al. Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats. Nature 1993;364:717-21. PMID 8355785
109: Righini A, Parazzini C, Doneda C, et al. Early formative stage of human focal cortical gyration anomalies: fetal MRI. AJR Am J Roentgenol 2012;198(2):439-47. PMID 22268191
110: Roos L, Jønch AE, Kjaergaard S, et al. A new microduplication syndrome encompassing the region of the Miller-Dieker (17p13 deletion) syndrome. J Med Genet 2009;46(10):703-10. PMID 19520700
111: Ross ME, Swanson K, Dobyns WB. Lissencephaly with cerebellar hypoplasia (LCH): a heterogeneous group of cortical malformations. Neuropediatrics 2001;32:256-63. PMID 11748497
112: Saillour Y, Carion N, Quelin C, et al. LIS1-related isolated lissencephaly: spectrum of mutations and relationships with malformation severity. Arch Neurol 2009;66(8):1007-15. PMID 19667223
113: Santana J, Marzolo MP. The functions of Reelin in membrane trafficking and cytoskeletal dynamics: implications for neuronal migration, polarization and differentiation. Biochem J 2017;474(18):3137-65. PMID 28887403
114: Sarnat HB, Philippart M, Flores-Sarnat L, Wei XC. Timing in neural maturation: arrest, delay, precociousness, and temporal determination of malformations. Pediatr Neurol 2015;52(5):473-86. PMID 25797487
115: Sheen VL, Ferland RJ, Neal J, et al. Neocortical neuronal arrangement in Miller Dieker syndrome. Acta Neuropathol 2006a;111:489-96. PMID 16456669
116: Sheen VL, Ferland RJ, Harney M, et al. Impaired proliferation and migration in human Miller-Dieker neural precursors. Ann Neurol 2006b;60(1):137-44. PMID 16642511
117: Shi CH, Zhang S, Yang ZH, et al. Identification of a novel PAFAH1B1 missense mutation as a cause of mild lissencephaly with basal ganglia calcification. Brain Dev 2019;41(1):29-35. PMID 30100227
118: Shimojima K, Sugiura C, Takahashi H, et al. Genomic copy number variations at 17p13.3 and epileptogenesis. Epilepsy Res 2010;89(2-3):303-9. PMID 20227246
119: Shu T, Ayala R, Nguyen MD, Xie Z, Gleeson JG, Tsai LH. Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning. Neuron 2004;44(2):263-77. PMID 15473966
120: Sohal AP, Montgomery T, Mitra D, Ramesh V. TUBA1A mutation-associated lissencephaly: case report and review of the literature. Pediatr Neurol 2012;46(2):127-31. PMID 22264709
121: Stratton RF, Dobyns WB, Airhart SD, Ledbetter DH. New chromosomal syndrome. Miller-Dieker syndrome and monosomy 17p13. Hum Genet 1984;67:193-200. PMID 6745939
122: Sunnen CN, Simonet JC, Marsh ED, Golden JA. Arx is required for specification of the zona incerta and reticular nucleus of the thalamus. J Neuropathol Exp Neurol 2014;73(3):253-61. PMID 24487799
123: Tai CY, Dujardin DL, Falkner NE, et al. Role of dynein, dynactin, and CLIP-170 interactions in LIS1 kinetochore function. J Cell Biol 2002;156:959-68. PMID 11889140
124: Takanashi J, Tada H, Fujii K, Barkovich AJ. The evolving MR imaging appearance of lissencephaly: a case report. Brain Dev 2007;29(8):522-4. PMID 17367971
125: Tan AP, Chong WK, Mankad K. Comprehensive genotype-phenotype correlation in lissencephaly. Quant Imaging Med Surg 2018;8(7):673-93. PMID 30211035
126: Tanaka T, Serneo FF, Higgins C, Gambello MJ, Wynshaw-Boris A, Gleeson JG. Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration. J Cell Biol 2004;165(5):709-21. PMID 15173193
127: Tanteles GA, Kurup B, Rauch A, et al. Microcephaly, lissencephaly, Hirschsprung disease and tetralogy of Fallot: a new syndrome. Clin Dysmorphol 2006;15:107-10. PMID 16531738
128: Tarricone C, Perrina F, Monzani S, et al. Coupling PAF signaling to dynein regulation: structure of LIS1 in complex with PAF-acetylhydrolase. Neuron 2004;44(5):809-21. PMID 15572112
129: Thomas MA, Duncan AM, Bardin C, Kaloustian VM. Lissencephaly with der(17)t(17;20)(p13.3;p12.2)mat. Am J Med Genet 2004;124A(3):292-5. PMID 14708103
130: Toi A, Lister WS, Fong KW. How early are fetal cerebral sulci visible at prenatal ultrasound and what is the normal pattern of early fetal sulcal development. Ultrasound Obstet Gynecol 2004;24(7):706-15. PMID 15586358
131: Tonni G, Pattacini P, Bonasoni MP, Araujo Junior E. Prenatal diagnosis of lissencephaly type 2 using three-dimensional ultrasound and fetal MRI: case report and review of the literature. Rev Bras Ginecol Obstet 2016;38(4):201-6. PMID 27088705
132: Toyo-oka K, Hirotsune S, Gambello MJ, et al. Loss of the Max-interacting protein Mnt in mice results in decreased viability, defective embryonic growth and craniofacial defects: relevance to Miller-Dieker syndrome. Hum Mol Genet 2004;13(10):1057-67. PMID 15028671
133: Toyo-Oka K, Shionoya A, Gambello MJ, et al. 14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome. Nat Genet 2003;34(3):274-85. PMID 12796778
134: Tsai MH, Muir AM, Wang WJ, et al, Pathogenic variants in CEP85L cause sporadic and familial posterior predominant lissencephaly. Neuron 2020;106(2):237-45. PMID 32097630
135: Tsukada M, Prokscha A, Ungewickell E, Eichele G. Doublecortin association with actin filaments is regulated by neurabin II. J Biol Chem 2005;280(12):11361-8. PMID 15632197
136: Ueda S, Kubota M, Kuroki S, et al. Gallbladder cancer in a patient with Miller-Dieker syndrome. Acta Paediatr 2006;95:113-4. PMID 16373307
137: Vallee RB, Faulkner NE, Tai CY. The role of cytoplasmic dynein in the human brain developmental disease lissencephaly. Biochim Biophys Acta 2000;1496:89-98. PMID 10722879
138: Vallee RB, Tai C, Faulkner NE. LIS1:cellular function of a disease-causing gene. Trends Cell Biol 2001;11:155-60. PMID 11306294
139: vanTuinen P, Dobyns WB, Rich DC, et al. Molecular detection of microscopic and submicroscopic deletions associated with Miller-Dieker syndrome. Am J Hum Genet 1988;43:587-96. PMID 3189330
140: Viot G, Sonigo P, Simon I, et al. Neocortical neuronal arrangement in LIS1 and DCX lissencephaly may be different. Am J Med Genet A 2004;126(2):123-8. PMID 15057976
141: Vissers LE, Stankiewicz P, Yatsenko SA, et al. Complex chromosome 17p rearrangements associated with low-copy repeats in two patients with congenital anomalies. Hum Genet 2007;121(6):697-709. PMID 17457615
142: Wallmeier J, Bracht D, Alsaif HS. Mutations in TP73 cause impaired mucociliary clearance and lissencephaly. Am Jour of Human Genetics 2021;108(7):1318-29. PMID 34077761
143: Williams F, Griffiths PD. In utero MR imaging in fetuses at high risk of lissencephaly. Br J Radiol 2017;90(1072):20160902. PMID 28134568
144: Wynshaw-Boris A. Lissencephaly and LIS1: insights into the molecular mechanisms of neuronal migration and development. Clin Genet 2007;72(4):296-304. PMID 17850624
145: Xing Z, Tang X, Gao Y, et al. The human LIS1 is downregulated in hepatocellular carcinoma and plays a tumor suppressor function. Biochem Biophys Res Commun 2011;409(2):193-9. PMID 21569763
146: Yinon Y, Katorza E, Nassie DI, et al. Late diagnosis of fetal central nervous system anomalies following a normal second-trimester anatomy scan. Prenat Diagn 2013;33(10):929-34. PMID 23712473

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Robin Godshalk MS MHA

Dr. Godshalk of Fragile X Center at Atlantic Health System in Morristown, New Jersey has no relevant financial relationships to disclose.
See Profile

Editor

Ganeshwaran H Mochida MD

Dr. Mochida of Boston Children's Hospital and Harvard Medical School has no relevant financial relationships to disclose.
See Profile

Former Authors

Joseph R Siebert PhD
William Dobyns MD (original author)

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: heredity may be a factor

heredity typical
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Lissencephaly: 742.2
ICD-10: Lissencephaly: Q04.3
OMIM: Miller-Dieker lissencephaly syndrome: #247200

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Lissencephalies

Associated Disorders

Classic lissencephaly
Cobblestone (type II) lissencephaly
Double cortex syndrome
Fukuyama-type congenital muscular dystrophy
Lennox-Gastaut syndrome
- Lissencephaly with cerebella hypoplasia
- Miller-Dieker syndrome
- Muscle-eye-brain disease
- Norman-Roberts syndrome
- Partial lissencephaly
- Polymicrogyria (pachygyria-polymicrogyria)
- Schinzel-Giedion syndrome
- Schizencephaly
- Subcortical band heterotopias
- Walker-Warburg syndrome
- West syndrome
- Winter-Tsukuhara syndrome
- X-linked lissencephaly
- X-linked lissencephaly with abnormal genitalia (XLAG)

Differential Diagnosis

other types of neuronal migration disorders
polymicrogyria
mixed pachygyria-polymicrogyria
variations of lissencephaly associated with agenesis of the corpus callosum
cobblestone (type II) lissencephaly
- microlissencephaly
- cortical dysplasias
- Norman-Roberts syndrome
- Schinzel-Giedion syndrome

Also Relevant

Cerebellar hypoplasia, dysplasia, and enlargement
Focal cortical dysplasias
Microcephaly
Subcortical laminar heterotopia
Walker-Warburg syndrome

Clinical Categories

Developmental Malformations

Patient Handouts

Web References

Testing

ARX-Related Disorders

Lissencephalies …

Lissencephalies

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

X-linked hydrocephalus (L1 syndrome)

Cerebro-oculo-facio-skeletal syndrome

Schizencephaly

Fetal anticonvulsant syndrome

Rhombencephalosynapsis

Malformations of the brain

Von Hippel-Lindau disease

Vein of Galen malformations

Lissencephalies

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

X-linked hydrocephalus (L1 syndrome)

Cerebro-oculo-facio-skeletal syndrome

Schizencephaly

Fetal anticonvulsant syndrome

Rhombencephalosynapsis

Malformations of the brain

Von Hippel-Lindau disease

Vein of Galen malformations

This is an article preview.
Start a Free Account
to access the full version.