Developmental Malformations

Updated 12.20.2023
Released 10.31.1994
Expires For CME 12.20.2026

Lissencephalies

Author: Robin Godshalk MS MHA

Editor: Ganeshwaran H Mochida MD

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).

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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

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Developmental Malformations

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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

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Editor

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ICD & OMIM codes

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Also in This Category

Walker-Warburg syndrome

Porencephaly

Cavum septi pellucidi and cavum Vergae

Aicardi-Goutieres syndrome

22q11.2 deletion syndrome

Oral-facial-digital syndromes

Rett syndrome

Myelomeningocele

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

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Also in This Category

Walker-Warburg syndrome

Porencephaly

Cavum septi pellucidi and cavum Vergae

Aicardi-Goutieres syndrome

22q11.2 deletion syndrome

Oral-facial-digital syndromes

Rett syndrome

Myelomeningocele

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